A hovering bubble with a spontaneous horizontal oscillation.

Active matters, characterized by multi-mode motions, have been emerging for both engineering and biological applications. Generally, active objects rely on the symmetry-broken structures, compositions, or interfacial activities through a physical or chemical approach. Here, we report an active bubble spontaneously hovering with a horizontal oscillation at the solid/liquid interface by impacting a stationary laser beam into a liquid through a transparent solid cover. This spontaneous oscillation mode of the bubble synchronizes with that of the interfacial temperature and hydrodynamical flow. A physical mechanism is proposed, and the scaling analysis of the oscillation frequency agrees well with experiments in various liquids under different laser powers. Additionally, the bubble trajectory rotates azimuthally, arising from the symmetry breaking of the vortex pair accompanying the oscillation. Moreover, the double pendulum of oscillation bubbles has been demonstrated, achieving a preferable oscillation direction in a controllable way. These findings would not only advance our understanding of active matters but also shed light on the bubble-mediated technological applications, such as microrobots and drug deliveries.

Identification of common stria vascularis cellular alteration in sensorineural hearing loss based on ScRNA-seq.

BACKGROUND: The stria vascularis (SV), located in the lateral wall of the cochlea, maintains cochlear fluid homeostasis and mechanoelectrical transduction (MET) activity required for sound wave conduction. The pathogenesis of a number of human inheritable deafness syndromes, age related hearing loss, drug-induced ototoxicity and noise-induced hearing loss results from the morphological changes and functional impairments in the development of the SV. In this study, we investigate the implications of intercellular communication within the SV in the pathogenesis of sensorineural hearing loss (SNHL). We aim to identify commonly regulated signaling pathways using publicly available single-cell transcriptomic sequencing (scRNA-seq) datasets. METHODS: We analyzed scRNA-seq data, which was derived from studying the cochlear SV in mice with SNHL compared to normal adult mice. After quality control and filtering, we obtained the major cellular components of the mouse cochlear SV and integrated the data. Using Seurat's FindAllMarkers and FindMarkers packages, we searched for novel conservative genes and differential genes. We employed KEGG and GSEA to identify molecular pathways that are commonly altered among different types of SNHL. We utilized pySCENIC to discover new specific regulatory factors in SV subpopulation cells. With the help of CellChat, we identified changes in subpopulation cells showing similar trends across different SNHL types and their alterations in intercellular communication pathways. RESULTS: Through the analysis of the integrated data, we discovered new conserved genes to SV specific cells and identified common downregulated pathways in three types of SNHL. The enriched genes for these pathways showing similar trends are primarily associated with the Electron Transport Chain, related to mitochondrial energy metabolism. Using the CellChat package, we further found that there are shared pathways in the incoming signaling of specific intermediate cells in SNHL, and these pathways have common upstream regulatory transcription factor of Nfe2l2. Combining the results from pySCENIC and CellChat, we predicted the transcription factor Nfe2l2 as an upstream regulatory factor for multiple shared cellular pathways in IC. Additionally, it serves as an upstream factor for several genes within the Electron Transport Chain. CONCLUSION: Our bioinformatics analysis has revealed that downregulation of the mitochondrial electron transport chain have been observed in various conditions of SNHL. E2f1, Esrrb, Runx1, Yy1, and Gata2 could serve as novel important common TFs regulating the electron transport chain. Adm has emerged as a potential new marker gene for intermediate cells, while Itgb5 and Tesc show promise as potential new marker genes for marginal cells in the SV. These findings offer a new perspective on SV lesions in SNHL and provide additional theoretical evidence for the same drug treatment and prevention of different pathologies of SNHL.

Self-Lifting Droplet Driven by the Solidification-Induced Solutal Marangoni Flow.

Multicomponent droplets are pertinent to diverse applications ranging from 3D printing to fabrication of electronic devices to medical diagnostics and are typically inherent with the occurrence of the phase transition in the manifestation of evaporation and solidification. Indeed, the versatile transformations and fascinating morphologies of the droplets have been identified, which primarily arise from the evaporation-induced flow. Here, we report the self-lifting behavior of a frozen binary droplet, resulting in a nearly doubling in height, in a fashion that defies against the gravitational effect. This counterintuitive observation is attributed to an internal solutal Marangoni flow up to 1 mm/s, which is driven by the enriched solute concentration locally in the vicinity of the solidification front. Moreover, we perform theoretical analysis by incorporating the propagation of solidification front, and the calculated spatiotemporal evolution of droplet shape agrees with experiments excellently. The effects of several key physical parameters on self-lifting are elucidated quantitatively, providing guidance to control the self-lifting. These results will further advance our understanding of underlying physicochemical hydrodynamics in the multicomponent liquid systems subjected to heat transfer and phase change, consequently shedding light on the relevant technological applications.

Versatile Polymerization-Induced Emission Polymers from Barbier Polymerization of Cinnamic Esters with Tunable Emission.

Cinnamic ester is a common and abundant chemical substance, which can be extracted from natural plants. Compared with traditional esters, cinnamic ester contains α,ß-unsaturated carbonyl structure with multiple reactive sites, resulting in more abundant reactivities and chemical structures. Here, a versatile polymerization-induced emission (PIE) is successfully demonstrated through Barbier polymerization of cinnamic ester. Attributed to its abundant reactivities of α,ß-unsaturated carbonyl structure, Barbier polymerization of cinnamic esters with different organodihalides gives polyalcohol and polyketone via 1,2-addition and 1,4-addition, respectively, which is also confirmed by small molecular model reactions. Meanwhile, these organodihalides dependant polyalcohol and polyketone exhibit different non-traditional intrinsic luminescence (NTIL) from aggregation-induced emission (AIE) type to aggregation-caused quenching (ACQ) type, where novel PIE luminogens (PIEgens) are revealed. Further potential applications in explosive detection are carried out, where it achieves TNT detection sensitivity at ppm level in solution and ng level on the test paper. This work therefore expands the structure and functionality libraries of monomer, polymer and NTIL, which might cause inspirations to different fields including polymer chemistry, NTIL, AIE and PIE.

Clickable Polymerization-Induced Emission Luminogens Toward Color-Tunable Modification of Non-Traditional Intrinsic Luminescent Polymers.

Non-traditional intrinsic luminescent (NTIL) polymer is an emerging field, and its color-tunable modification is highly desirable but still rarely investigated. Here, a click chemistry approach for the color-tunable modifications of NTIL polymers by introducing clickable polymerization-induced emission luminogen (PIEgen), is demonstrated. Through Cu-catalyzed azide-alkyne cycloaddition click chemistry, a series of PIEgens is successful prepared, which is further polymerized via reversible addition-fragmentation chain transfer (RAFT) polymerization. Interestingly, after clickable modification, these monomers are nonemissive in both solution and aggregation states; while, the corresponding polymers exhibit intriguing aggregation-induced emission (AIE) characteristics, confirming their PIEgen characteristics. By varying alkynyl substitutions, color-tunable NTIL polymers are achieved with emission wavelength varying from 448 to 498 nm, revealing a series of PIEgens and verifying the importance of modification of NTIL polymers. Further luminescence energy transfer application is carried out as well. This work therefore designs a series of clickable PIEgens and opens a new avenue for the modification of NTIL polymers via click chemistry, which may cause inspirations to the research fields including luminescent polymer, NTIL, click chemistry, AIE and modification.

Nonlinear association between visceral adipose tissue area and remnant cholesterol in US adults: a cross-sectional study.

BACKGROUND: Excessive visceral adipose tissue (VAT) is associated with a spectrum of diseases, including diabetes, cancer, and cardiovascular diseases. Remnant cholesterol (RC), denoting cholesterol within triglyceride-rich lipoproteins and their metabolic byproducts, has been identified as a key contributor to cardiovascular diseases and related mortality. However, the association between the VAT and RC remains unclear. In this study, the objective is to provide new evidence regarding the association between VAT and RC concentrations. METHODS: 4727 individuals aged 18-59 were selected from the National Health and Nutrition Examination Survey conducted between 2011 and 2018 as study participants. This study utilized several weighted linear regression models and a restricted cubic spline (RCS) to explore the association and potential nonlinearities between VAT and RC. Subgroup analyses were performed to determine the consistency of findings. RESULTS: The mean VAT value was 103.82 ± 1.42 cm2, and the median RC value was 18 mg/dl. VAT demonstrated a positive association with RC in a fully adjusted model, with a ß and 95% confidence interval (CI) of 0.09 (0.08, 0.11) after adjustment for potential confounders. Analysis using RCS revealed a nonlinear association between the VAT area and RC (P < 0.001 for nonlinearity). Adjusted two-piecewise regression models demonstrated ß coefficients of 0.13 (95%CI: 0.11 ~ 0.16, P < 0.001) for RC in individuals with VAT < 143 cm2, and 0.02 (95%CI: -0.01 ~ 0.06, P = 0.15) for those with VAT ≥ 143 cm2. Interactions were observed among the body mass index (BMI) subgroup; the ß coefficients for RC were 0.14 (95%CI: 0.12 ~ 0.16) in those with BMI < 30 kg/m2 and 0.05 (95%CI:0.04 ~ 0.07) in those with BMI ≥ 30 kg/m2, with a P-value of < 0.001 for interaction. CONCLUSIONS: This study identified a nonlinear association between VAT and RC in American adults. Reducing the VAT area may be beneficial in lowering RC concentration, particularly when VAT is < 143 cm2 and those with a BMI < 30 kg/m2.

LncRNA AC005165.1 Alleviates IL-1ß-Induced Osteoarthritis via miR-199a-3p/TXNIP Axis.

Osteoarthritis (OA) is a chronic musculoskeletal disease and often causes impaired joint mobility and disability. Long noncoding RNAs (lncRNAs) play pivotal roles in OA development. This study was done to explore the role and mechanism of the lncRNA AC005165.1 in the cell model of interleukin-1ß (IL)-1ß-treated chondrocytes. This study recruited 20 surgically treated OA patients and 12 age- and gender-matched controls. Real-time reverse transcription quantitative polymerase chain reaction was used to examine the expression levels of AC005165.1, miR-199a-3p, and thioredoxin-interacting protein (TXNIP) in articular cartilage of patients and IL-1ß-treated human chondrocytes. Cell viability and apoptosis were evaluated by cell counting kit-8 and flow cytometry assays, respectively. The protein levels of inflammatory cytokines were assessed by western blotting. Enzyme-linked immunosorbent assay was conducted to detect the concentrations of the inflammatory cytokines in chondrocytes. Luciferase reporter assay and Pearson's correlation analysis were used for analyzing the interaction and the correlation among AC005165.1, miR-199a-3p, and TXNIP. AC005165.1 expression was downregulated in cartilage of OA patients and chondrocytes treated with IL-1ß, compared to that in the control groups. AC005165.1 knockdown increased apoptosis and aggravated inflammatory response in IL-1ß-treated chondrocytes. AC005165.1 interacted with miR-199a-3p, and TXNIP was targeted by miR-199a-3p. In rescue assay, miR-199a-3p knockdown and TXNIP overexpression significantly reduced apoptosis and mitigated inflammatory response in IL-1ß-treated chondrocytes with AC005165.1 knockdown. AC005165.1 knockdown promoted apoptosis and inflammatory response in IL-1ß-treated chondrocytes via the miR-199a-3p/TXNIP axis.

Identification of serum biomarkers for chronic kidney disease using serum metabolomics.

This study aimed to identify biomarkers for chronic kidney disease (CKD) by studying serum metabolomics. Serum samples were collected from 194 non-dialysis CKD patients and 317 healthy controls (HC). Using ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS), untargeted metabolomics analysis was conducted. A random forest model was developed and validated in separate sets of HC and CKD patients. The serum metabolomic profiles of patients with chronic kidney disease (CKD) exhibited significant differences compared to healthy controls (HC). A total of 314 metabolites were identified as significantly different, with 179 being upregulated and 135 being downregulated in CKD patients. KEGG enrichment analysis revealed several key pathways, including arginine biosynthesis, phenylalanine metabolism, linoleic acid metabolism, and purine metabolism. The diagnostic efficacy of the classifier was high, with an area under the curve of 1 in the training and validation sets and 0.9435 in the cross-validation set. This study provides comprehensive insights into serum metabolism in non-dialysis CKD patients, highlighting the potential involvement of abnormal biological metabolism in CKD pathogenesis. Exploring metabolites may offer new possibilities for the management of CKD.

Adherence to dietary approaches to stop hypertension diet and visceral adipose tissue area among U.S. adults, a cross-sectional study.

Excessive visceral adipose tissue (VAT) is a significant risk factor for various diseases. Diet plays a crucial role in controlling obesity. This study examined the association between the Dietary Approaches to Stop Hypertension (DASH) diet and VAT in 9027 adults using data from the National Health and Nutrition Examination Survey. Linear regression models were used to explore this association, with subgroup analyses included. Results showed a significant inverse association between DASH scores and VAT area, even after adjusting for covariates (ß = -2.18, 95% CI: -3.10, -1.27). Participants in the highest DASH score tertile had significantly lower VAT areas compared to those in the lowest tertile (ß = -7.2, 95% CI: -10.40, -4.01). This inverse association was most pronounced in middle-aged participants. Further prospective cohort studies are necessary to confirm these findings.

Advances in immunotherapy for triple-negative breast cancer.

BACKGROUND: Immunotherapy has recently emerged as a treatment strategy which stimulates the human immune system to kill tumor cells. Tumor immunotherapy is based on immune editing, which enhances the antigenicity of tumor cells and increases the tumoricidal effect of immune cells. It also suppresses immunosuppressive molecules, activates or restores immune system function, enhances anti-tumor immune responses, and inhibits the growth f tumor cell. This offers the possibility of reducing mortality in triple-negative breast cancer (TNBC). MAIN BODY: Immunotherapy approaches for TNBC have been diversified in recent years, with breakthroughs in the treatment of this entity. Research on immune checkpoint inhibitors (ICIs) has made it possible to identify different molecular subtypes and formulate individualized immunotherapy schedules. This review highlights the unique tumor microenvironment of TNBC and integrates and analyzes the advances in ICI therapy. It also discusses strategies for the combination of ICIs with chemotherapy, radiation therapy, targeted therapy, and emerging treatment methods such as nanotechnology, ribonucleic acid vaccines, and gene therapy. Currently, numerous ongoing or completed clinical trials are exploring the utilization of immunotherapy in conjunction with existing treatment modalities for TNBC. The objective of these investigations is to assess the effectiveness of various combined immunotherapy approaches and determine the most effective treatment regimens for patients with TNBC. CONCLUSION: This review provides insights into the approaches used to overcome drug resistance in immunotherapy, and explores the directions of immunotherapy development in the treatment of TNBC.

Discovery of potential novel TRPC5 inhibitors by virtual screening and bioassay.

The transient receptor potential canonical channel 5 (TRPC5), a member of the TRPC family, plays a crucial role in the regulation of various physiological activities and diseases, including those related to the central nervous system, cardiovascular system, kidney, and cancer. As a nonselective cation channel, TRPC5 mainly controls the influx of extracellular Ca2+ into cells, thereby modulating cellular depolarization and intracellular ion concentration. Inhibition of TRPC5 by small molecules presents a promising approach for the treatment of TRPC5-associated diseases. In this study, we conducted a comprehensive virtual screening of more than 1.5 million molecules from the Chemdiv database (https://www.chemdiv.com) to identify potential inhibitors of hTRPC5, utilizing the published structures and binding sites of hTRPC5 as a basis. Lipinski's rule, Veber's rule, PAINS filters, pharmacophore analysis, molecular docking, ADMET evaluation and cluster analysis methods were applied for the screening. From this rigorous screening process, 18 candidates exhibiting higher affinities to hTRPC5 were subsequently evaluated for their inhibitory effects on Ca2+ influx using a fluorescence-based assay. Notably, two molecules, namely SML-1 and SML-13, demonstrated significant inhibition of intracellular Ca2+ levels in hTRPC5-overexpressing HEK 293T cells, with IC50 values of 10.2 µM and 10.3 µM, respectively. These findings highlight SML-1 and SML-13 as potential lead molecules for the development of therapeutics targeting hTRPC5 and its associated physiological activities and diseases.

Gene editing in a Myo6 semi-dominant mouse model rescues auditory function.

Myosin VI（MYO6） is an unconventional myosin that is vital for auditory and vestibular function. Pathogenic variants in the human MYO6 gene cause autosomal-dominant or -recessive forms of hearing loss. Effective treatments for Myo6 mutation causing hearing loss are limited. We studied whether adeno-associated virus (AAV)-PHP.eB vector-mediated in vivo delivery of Staphylococcus aureus Cas9 (SaCas9-KKH)-single-guide RNA (sgRNA) complexes could ameliorate hearing loss in a Myo6WT/C442Y mouse model that recapitulated the phenotypes of human patients. The in vivo editing efficiency of the AAV-SaCas9-KKH-Myo6-g2 system on Myo6C442Y is 4.05% on average in Myo6WT/C442Y mice, which was ∼17-fold greater than editing efficiency of Myo6WT alleles. Rescue of auditory function was observed up to 5 months post AAV-SaCas9-KKH-Myo6-g2 injection in Myo6WT/C442Y mice. Meanwhile, shorter latencies of auditory brainstem response (ABR) wave I, lower distortion product otoacoustic emission (DPOAE) thresholds, increased cell survival rates, more regular hair bundle morphology, and recovery of inward calcium levels were also observed in the AAV-SaCas9-KKH-Myo6-g2-treated ears compared to untreated ears. These findings provide further reference for in vivo genome editing as a therapeutic treatment for various semi-dominant forms of hearing loss and other semi-dominant diseases.

The Influence of Informal Caregivers' Preparedness on Psychological Symptoms and Quality of Life Among Patients With Heart Failure And Insufficient Self-care.

BACKGROUND: Most patients with heart failure find self-care difficult to perform and rely on family caregivers for support. Informal caregivers, however, often face insufficient psychological preparation and challenges in providing long-term care. Insufficient caregiver preparedness not only results in psychological burden for the informal caregivers but may also lead to a decline in caregiver contributions to patient self-care that affects patient outcomes. OBJECTIVE: Our objective was to test (1) the association of baseline informal caregivers' preparedness with psychological symptoms (anxiety and depression) and quality of life 3 months after baseline among patients with insufficient self-care and (2) the mediating effects of caregivers' contributions to self-care of heart failure (CC-SCHF) on the relationship of caregivers' preparedness with patients' outcomes at 3 months. METHODS: A longitudinal design was used to collect data between September 2020 and January 2022 in China. Data analyses were conducted using descriptive statistics, correlations, and linear mixed models. We used model 4 of the PROCESS program in SPSS with bootstrap testing to evaluate the mediating effect of CC-SCHF of informal caregivers' preparedness at baseline with psychological symptoms or quality of life among patients with HF 3 months later. RESULTS: Caregiver preparedness was positively associated with CC-SCHF maintenance ( r = 0.685, P < .01), CC-SCHF management ( r = 0.403, P < .01), and CC-SCHF confidence ( r = 0.600, P < .01). Good caregiver preparedness directly predicted lower psychological symptoms (anxiety and depression) and higher quality of life for patients with insufficient self-care. The associations of caregiver preparedness with short-term quality of life and depression of patients with HF with insufficient self-care were mediated by CC-SCHF management. CONCLUSIONS: Enhancing the preparedness of informal caregivers may improve psychological symptoms and quality of life of heart failure patients with insufficient self-care.

Pyrrocidine, a molecular off switch for fumonisin biosynthesis.

Sarocladium zeae is a fungal endophyte of maize and can be found co-inhabiting a single seed with Fusarium verticillioides, a major mycotoxigenic food safety threat. S. zeae produces pyrrocidines A and B that inhibit the growth of F. verticillioides and may limit its spread within the seed to locations lacking S. zeae. Although coinhabiting single seeds, the fungi are generally segregated in separate tissues. To understand F. verticillioides' protective physiological response to pyrrocidines we sequenced the F. verticillioides transcriptome upon exposure to purified pyrrocidine A or B at sub-inhibitory concentrations. Through this work we identified a F. verticillioides locus FvABC3 (FVEG_11089) encoding a transporter critical for resistance to pyrrocidine. We also identified FvZBD1 (FVEG_00314), a gene directly adjacent to the fumonisin biosynthetic gene cluster that was induced several thousand-fold in response to pyrrocidines. FvZBD1 is postulated to act as a genetic repressor of fumonisin production since deletion of the gene resulted in orders of magnitude increase in fumonisin. Further, pyrrocidine acts, likely through FvZBD1, to shut off fumonisin biosynthesis. This suggests that S. zeae is able to hack the secondary metabolic program of a competitor fungus, perhaps as preemptive self-protection, in this case impacting a mycotoxin of central concern for food safety.

Plasma membrane phylloquinone biosynthesis in nonphotosynthetic parasitic plants.

Nonphotosynthetic holoparasites exploit flexible targeting of phylloquinone biosynthesis to facilitate plasma membrane redox signaling. Phylloquinone is a lipophilic naphthoquinone found predominantly in chloroplasts and best known for its function in photosystem I electron transport and disulfide bridge formation of photosystem II subunits. Phylloquinone has also been detected in plasma membrane (PM) preparations of heterotrophic tissues with potential transmembrane redox function, but the molecular basis for this noncanonical pathway is unknown. Here, we provide evidence of PM phylloquinone biosynthesis in a nonphotosynthetic holoparasite Phelipanche aegyptiaca. A nonphotosynthetic and nonplastidial role for phylloquinone is supported by transcription of phylloquinone biosynthetic genes during seed germination and haustorium development, by PM-localization of alternative terminal enzymes, and by detection of phylloquinone in germinated seeds. Comparative gene network analysis with photosynthetically competent parasites revealed a bias of P. aegyptiaca phylloquinone genes toward coexpression with oxidoreductases involved in PM electron transport. Genes encoding the PM phylloquinone pathway are also present in several photoautotrophic taxa of Asterids, suggesting an ancient origin of multifunctionality. Our findings suggest that nonphotosynthetic holoparasites exploit alternative targeting of phylloquinone for transmembrane redox signaling associated with parasitism.

The altering in sensory sensitivity: a current issue of female breast surgery.

Breast surgery is an important treatment for women with malignant breast diseases. In addition to breast appearance, the integrity of breast function is increasing in patients with breast diseases. As the basis of breast physiological function, breast skin sensitivity is important to the quality of life of patients after surgery. Breast skin sensitivity gives the patient a "real" breast feeling. The sensory recovery after breast surgery has also become one of the important goals of breast surgery. In this review, we aim to discuss the research progress on recovery of breast skin sensitivity after different treatment modalities for breast disease.

Comprehensive analysis of the expression, prognostic significance, and regulation pathway of G2E3 in breast cancer.

BACKGROUND: Loss of G2-specific E3-like (G2E3) protein sensitizes tumor cells to chemotherapy. However, the role of G2E3 in breast cancer development and patient's prognosis is unclear. Here, we explored the expression, prognostic significance, and regulatory pathway of G2E3 in breast cancer. METHODS: TCGA and UALCAN database were utilized to explore G2E3 expression in breast cancer and normal tissues and its expression in breast cancer based on clinicopathological characteristics, respectively. The Kaplan-Meier plotter database was utilized to determine the effect of G2E3 on the prognosis of breast cancer patients. RT-PCR was utilized to validate the G2E3 expression in cancerous and normal breast tissues. Immunohistochemistry analysis was utilized to validate the prognostic effect of G2E3 expression in breast cancer patients and the relationship between G2E3 expression and lymphocyte infiltration levels. Receiver operating characteristic (ROC) curves were also generated to validate the diagnostic value of G2E3 expression in recurrence/distant organ metastasis and death. The STRING database, DAVID database, and Sanger-box tools were utilized to perform GO functional, KEGG pathway enrichment, and GSEA analysis. The TISIDB database was utilized to determine the relationship between G2E3 expression and tumor immunity. Finally, CTD database was utilized to screen for potential therapeutic compounds that could reduce the G2E3 mRNA expression. RESULTS: TCGA data presented that G2E3 expression was higher in breast cancer tissues than in normal breast tissues. This result was further validated by RT-PCR (P = 0.003). The Kaplan-Meier plotter database suggested that patients with high G2E3 mRNA expression had significantly shorter RFS and OS than patients with low G2E3 mRNA expression. Immunohistochemistry analysis of 156 breast cancer clinical specimens also validated patients with G2E3-positive expression had a significantly shorter DFS and OS than patients with G2E3-negative expression. Thus, G2E3 expression was an independent prognostic predictor of DFS and OS. The G2E3-positive expression also has a high diagnostic value for recurrence/distant organ metastasis and death. GSEA analysis revealed that G2E3 might be enriched in the E2F, PI3K/AKT/mTOR signaling, DNA repair pathways, and other cancer-related signaling pathways. The TISIDB database showed that G2E3 expression was significantly negatively associated with lymphocyte infiltration. This result was further validated in clinical breast cancer samples (P = 0.048; R = -0.158). Using the CTD database, we found that (+)-JQ1 compound, 1,2-dimethylhydrazine, and other compounds may decrease the G2E3 mRNA expression. These compounds could serve as potential therapeutic compounds for the clinical treatment of breast cancer. CONCLUSIONS: G2E3 expression was higher in breast cancer tissues than in normal tissues. G2E3-positive expression was related to a worse survival outcome in patients with breast cancer. Genes co-expressed with G2E3 may be enriched in the breast cancer-related signaling pathways. The G2E3 expression was significantly negatively associated with lymphocyte infiltration. G2E3 may serve as a novel prognostic biomarker and therapeutic target for breast cancer.

Comprehensive analysis of the expression, prognostic significance, and function of FAM83 family members in breast cancer.

BACKGROUND: The FAM83 family plays a key role in tumorigenesis and cancer progression. However, the role of the FAM83 family in the development of breast tumors is unclear to date. This report explores the expression, prognostic significance, and function of the FAM83 family members in breast cancer using public databases. METHODS: UALCAN database was used to explore the expression of FAM83 family members in breast cancer. Furthermore, we validated the expression of FAM83 family members in twenty pairs of breast cancer and normal tissues by RT-PCR. Kaplan-Meier plotter database was used to explore the prognostic significance of FAM83 family members in breast cancer. GeneMANIA and DAVID databases were used for functional and pathway enrichment analysis of genes co-expressed with FAM83A, FAM83D, FAM83F, and FAM83G. MEXPRESS and UALCAN databases were used to analyze the level of DNA promoter methylation of FAM83A, FAM83D, FAM83F, and FAM83G in breast cancer. TIMER database was utilized to explore the relationships between immune cell infiltration and FAM83A, FAM83D, FAM83F, and FAM83G expression. RESULTS: Among FAM83 family members, FAM83A, FAM83D, FAM83F, and FAM83G were higher expressed in breast cancer than in normal tissues. We also validated the significant high expression of FAM83A, FAM83D, FAM83F, and FAM83G mRNA in breast cancer than in normal samples. Their increased expression has an adverse prognostic effect on breast cancer patients. These genes co-expressed with FAM83A, FAM83D, FAM83F, and FAM83G might take part in cell proliferation, G2/M transition of the mitotic cell cycle, regulation of apoptosis process and other cancer-related biological processes. In addition, they were mainly enriched in the Hippo signaling pathway, Hedgehog signaling pathway, PI3K/AKT signaling pathway, and other cancer-related pathways. We also found that promoter DNA methylation might regulate the expression of FAM83A, FAM83D, FAM83F, and FAM83G mRNA in most CpG islands. At last, we found the expression of FAM83A, FAM83D, FAM83F, and FAM83G mRNA was significantly related to immune cell infiltration. CONCLUSIONS: FAM83A, FAM83D, FAM83F, and FAM83G were highly expressed in breast cancer tissues and had an adverse effect on the survival outcomes of breast cancer patients. Also, they were involved in breast cancer-related signal pathways. Therefore, they might serve as potential therapeutic targets for breast cancer clinical treatment.

Blocking ERK-DAPK1 Axis Attenuates Glutamate Excitotoxicity in Epilepsy.

Glutamate excitotoxicity induces neuronal cell death during epileptic seizures. Death-associated protein kinase 1 (DAPK1) expression is highly increased in the brains of epilepsy patients; however, the underlying mechanisms by which DAPK1 influences neuronal injury and its therapeutic effect on glutamate excitotoxicity have not been determined. We assessed multiple electroencephalograms and seizure grades and performed biochemical and cell death analyses with cellular and animal models. We applied small molecules and peptides and knocked out and mutated genes to evaluate the therapeutic efficacy of kainic acid (KA), an analog of glutamate-induced neuronal damage. KA administration increased DAPK1 activity by promoting its phosphorylation by activated extracellular signal-regulated kinase (ERK). DAPK1 activation increased seizure severity and neuronal cell death in mice. Selective ERK antagonist treatment, DAPK1 gene ablation, and uncoupling of DAPK1 and ERK peptides led to potent anti-seizure and anti-apoptotic effects in vitro and in vivo. Moreover, a DAPK1 phosphorylation-deficient mutant alleviated glutamate-induced neuronal apoptosis. These results provide novel insight into the pathogenesis of epilepsy and indicate that targeting DAPK1 may be a potential therapeutic strategy for treating epilepsy.

miR-143-3p Inhibits Aberrant Tau Phosphorylation and Amyloidogenic Processing of APP by Directly Targeting DAPK1 in Alzheimer's Disease.

The neuropathology of Alzheimer's disease (AD) is characterized by intracellular aggregation of hyperphosphorylated tau and extracellular accumulation of beta-amyloid (Aß). Death-associated protein kinase 1 (DAPK1), as a novel therapeutic target, shows promise for the treatment of human AD, but the regulatory mechanisms of DAPK1 expression in AD remain unclear. In this study, we identified miR-143-3p as a promising candidate for targeting DAPK1. miR-143-3p directly bound to the 3' untranslated region of human DAPK1 mRNA and inhibited its translation. miR-143-3p decreased tau phosphorylation and promoted neurite outgrowth and microtubule assembly. Moreover, miR-143-3p attenuated amyloid precursor protein (APP) phosphorylation and reduced the generation of Aß40 and Aß42. Furthermore, restoring DAPK1 expression with miR-143-3p antagonized the effects of miR-143-3p in attenuating tau hyperphosphorylation and Aß production. In addition, the miR-143-3p levels were downregulated and correlated inversely with the expression of DAPK1 in the hippocampus of AD patients. Our results suggest that miR-143-3p might play critical roles in regulating both aberrant tau phosphorylation and amyloidogenic processing of APP by targeting DAPK1 and thus offer a potential novel therapeutic strategy for AD.