Characteristics and Prognosis of Type 2 Myocardial Infarction Through Worsening Renal Function and NT-proBNP in Older Adults with Pneumonia.

Background: Type 2 myocardial infarction (MI) is becoming more recognized. This study aimed to assess the factors linked to type 2 MI in older adults with pneumonia and further determine the predictive factors of 90-day adverse events (refractory heart failure, cardiogenic shock, and all-cause mortality). Methods: A single-center retrospective analysis was conducted among older adults with pneumonia. The primary outcome was the prevalence of type 2 MI. The secondary objective was to assess the adverse events in these patients with type 2 MI within 90 days. Results: A total of 2618 patients were included. Of these, 361 patients (13.8%) suffered from type 2 MI. Multivariable predictors of type 2 MI were chronic kidney disease (CKD), age-adjusted Charlson comorbidity index (ACCI) score, and NT-proBNP > 4165pg/mL. Moreover, the independent predictive factors of 90-day adverse events included NT-proBNP > 4165pg/mL, age, ACCI score, and CKD. The Kaplan-Meier adverse events curves revealed that the type 2 MI patients with CKD and NT-proBNP > 4165pg/mL had a higher risk than CKD or NT-proBNP > 4165pg/mL alone. Conclusion: Type 2 MI in older pneumonia hospitalization represents a heterogeneous population. Elevated NT-proBNP level and prevalence of CKD are important predictors of type 2 MI and 90-day adverse events in type 2 MI patients.

Causal relationship between air pollution and chronic obstructive pulmonary disease in European and East Asian populations: a Mendelian randomization study.

Epidemiologic studies have suggested a possible association between air pollution and chronic obstructive pulmonary disease (COPD), but it is controversial and difficult to draw causal inferences. Five methods were adopted to evaluate the causal relationship between air pollution and COPD in European and East Asian populations by using MR Analysis. A statistically significant causal relationship between PM2.5 and COPD was observed in the European population (OR: 2.34; 95% CI: 1.06-5.05; p = 0.033). Statistical significance remained after adjustment for confounding factors (adjusted OR: 2.28; 95% CI: 1.01-5.20; p = 0.048). In East Asian populations, PM2.5 absorbance, a proxy for black carbon, was statistically associated with COPD (OR: 1.41; 95% CI: 1.09-1.81; p = 0.007). We did not adjust for confounders in East Asian populations, as the association was independent of known confounders (e.g. smoking, respiratory tract infections, etc.). In conclusion, increased concentrations of PM2.5 and PM2.5 absorbance were associated with an increased risk of COPD.

Pedigree Analysis of Nonclassical Cholesteryl Ester Storage Disease with Dominant Inheritance in a LIPA I378T Heterozygous Carrier.

BACKGROUND: Cholesterol ester storage disorder (CESD; OMIM: 278,000) was formerly assumed to be an autosomal recessive allelic genetic condition connected to diminished lysosomal acid lipase (LAL) activity due to LIPA gene abnormalities. CESD is characterized by abnormal liver function and lipid metabolism, and in severe cases, liver failure can occur leading to death. In this study, one Chinese nonclassical CESD pedigree with dominant inheritance was phenotyped and analyzed for the corresponding gene alterations. METHODS: Seven males and eight females from nonclassical CESD pedigree were recruited. Clinical features and LAL activities were documented. Whole genome Next-generation sequencing (NGS) was used to screen candidate genes and mutations, Sanger sequencing confirmed predicted mutations, and qPCR detected LIPA mRNA expression. RESULTS: Eight individuals of the pedigree were speculatively thought to have CESD. LAL activity was discovered to be lowered in four living members of the pedigree, but undetectable in the other four deceased members who died of probable hepatic failure. Three of the four living relatives had abnormal lipid metabolism and all four had liver dysfunctions. By liver biopsy, the proband exhibited diffuse vesicular fatty changes in noticeably enlarged hepatocytes and Kupffer cell hyperplasia. Surprisingly, only a newly discovered heterozygous mutation, c.1133T>C (p. Ile378Thr) on LIPA, was found by gene sequencing in the proband. All living family members who carried the p.I378T variant displayed reduced LAL activity. CONCLUSIONS: Phenotypic analyses indicate that this may be an autosomal dominant nonclassical CESD pedigree with a LIPA gene mutation.

The UBE2F-CRL5ASB11-DIRAS2 axis is an oncogene and tumor suppressor cascade in pancreatic cancer cells.

UBE2F, a neddylation E2, neddylates CUL5 to activate cullin-RING ligase-5, upon coupling with neddylation E3 RBX2/SAG. Whether and how UBE2F controls pancreatic tumorigenesis is previously unknown. Here, we showed that UBE2F is essential for the growth of human pancreatic cancer cells with KRAS mutation. In the mouse KrasG12D pancreatic ductal adenocarcinoma (PDAC) model, Ube2f deletion suppresses cerulein-induced pancreatitis, and progression of acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia. Mechanistically, Ube2f deletion inactivates the Mapk-c-Myc signals via blocking ubiquitylation of Diras2, a substrate of CRL5Asb11 E3 ligase. Biologically, DIRAS2 suppresses growth and survival of human pancreatic cancer cells harboring mutant KRAS, and Diras2 deletion largely rescues the phenotypes induced by Ube2f deletion. Collectively, Ube2f or Diras2 plays a tumor-promoting or tumor-suppressive role in the mouse KrasG12D PDAC model, respectively. The UBE2F-CRL5ASB11 axis could serve as a valid target for pancreatic cancer, whereas the levels of UBE2F or DIRAS2 may serve as prognostic biomarkers for PDAC patients.

Heterointerface engineering of layered double hydroxide/MAPbBr3 heterostructures enabling tunable synapse behaviors in a two-terminal optoelectronic device.

Solution-processable semiconductor heterostructures enable scalable fabrication of high performance electronic and optoelectronic devices with tunable functions via heterointerface control. In particular, artificial optical synapses require interface manipulation for nonlinear signal processing. However, the limited combinations of materials for heterostructure construction have restricted the tunability of synaptic behaviors with simple device configurations. Herein, MAPbBr3 nanocrystals were hybridized with MgAl layered double hydroxide (LDH) nanoplates through a room temperature self-assembly process. The formation of such heterostructures, which exhibited an epitaxial relationship, enabled effective hole transfer from MAPbBr3 to LDH, and greatly reduced the defect states in MAPbBr3. Importantly, the ion-conductive nature of LDH and its ability to form a charged surface layer even under low humidity conditions allowed it to attract and trap holes from MAPbBr3. This imparted tunable synaptic behaviors and short-term plasticity (STP) to long-term plasticity (LTP) transition to a two-terminal device based on the LDH-MAPbBr3 heterostructures. The further neuromorphic computing simulation under varying humidity conditions showcased their potential in learning and recognition tasks under ambient conditions. Our work presents a new type of epitaxial heterostructure comprising metal halide perovskites and layered ion-conductive materials, and provides a new way of realizing charge-trapping induced synaptic behaviors.

Enhancing Endogenous Hyaluronic Acid in Osteoarthritic Joints with an Anti-Inflammatory Supramolecular Nanofiber Hydrogel Delivering HAS2 Lentivirus.

Osteoarthritis (OA) management remains challenging because of its intricate pathogenesis. Intra-articular injections of drugs, such as glucocorticoids and hyaluronic acid (HA), have certain limitations, including the risk of joint infection, pain, and swelling. Hydrogel-based therapeutic strategies have attracted considerable attention because of their enormous therapeutic potential. Herein, a supramolecular nanofiber hydrogel is developed using dexamethasone sodium phosphate (DexP) as a vector to deliver lentivirus-encoding hyaluronan synthase 2 (HAS2) (HAS2@DexP-Gel). During hydrogel degradation, HAS2 lentivirus and DexP molecules are slowly released. Intra-articular injection of HAS2@DexP-Gel promotes endogenous HA production and suppresses synovial inflammation. Additionally, HAS2@DexP-Gel reduces subchondral bone resorption in the anterior cruciate ligament transection-induced OA mice, attenuates cartilage degeneration, and delays OA progression. HAS2@DexP-Gel exhibited good biocompatibility both in vitro and in vivo. The therapeutic mechanisms of the HAS2@DexP-Gel are investigated using single-cell RNA sequencing. HAS2@DexP-Gel optimizes the microenvironment of the synovial tissue by modulating the proportion of synovial cell subpopulations and regulating the interactions between synovial fibroblasts and macrophages. The innovative nanofiber hydrogel, HAS2@DexP-Gel, effectively enhances endogenous HA production while reducing synovial inflammation. This comprehensive approach holds promise for improving joint function, alleviating pain, and slowing OA progression, thereby providing significant benefits to patients.

Endocrine disrupting chemical Bisphenol A and its association with cancer mortality: a prospective cohort study of NHANES.

Introduction: There is evidence suggesting that Bisphenol A (BPA) is associated with increased all-cause mortality in adults. However, the specific nature of the relationship between BPA exposure and cancer mortality remains relatively unexplored. Methods: The National Health and Nutrition Examination Survey (NHANES) dataset was used to recruit participants. Urinary BPA was assessed using liquid chromatography-mass spectrum (LC-MS). Through the use of multivariable Cox proportional hazard regressions and constrained cubic splines, the relationships between urine BPA and death from all causes and cancer were investigated. Results: This study has a total of 8,035 participants, and 137 died from cancers after a 7.5-year follow-up. The median level of BPA was 2.0 g/mL. Urinary BPA levels were not independently associated with all-cause mortality. For cancer mortality, the second quartile's multivariable-adjusted hazard ratio was 0.51 (95% confidence interval: 0.30 to 0.86; p = 0.011) compared to the lowest quartile. The restricted cubic splines showed that the association was nonlinear (p for nonlinearity = 0.028) and the inflection point was 1.99 ng/mL. Conclusion: Urinary BPA exposure was U-shaped associated with the risk of cancer mortality, and a lower level of BPA less than 1.99 ng/mL was associated with a higher risk of cancer mortality.

A new invertebrate NPY-like polypeptide, ZoaNPY, from the Zoanthus sociatus, as a novel ligand of human NPY Y2 receptor rescues vascular insufficiency via PLC/PKC and Src- FAK-dependent signaling pathways.

Our recent multi-omics studies have revealed rich sources of novel bioactive proteins and polypeptides from marine organisms including cnidarians. In the present study, we initially conducted a transcriptomic analysis to review the composition profile of polypeptides from Zoanthus sociatus. Then, a newly discovered NPY-like polypeptide-ZoaNPY was selected for further in silico structural, binding and virtually pharmacological studies. To evaluate the pro-angiogenic effects of ZoaNPY, we employed an in vitro HUVECs model and an in vivo zebrafish model. Our results indicate that ZoaNPY, at 1-100 pmol, enhances cell survival, migration and tube formation in the endothelial cells. Besides, treatment with ZoaNPY could restore a chemically-induced vascular insufficiency in zebrafish embryos. Western blot results demonstrated the application of ZoaNPY could increase the phosphorylation of proteins related to angiogenesis signaling including PKC, PLC, FAK, Src, Akt, mTOR, MEK, and ERK1/2. Furthermore, through molecular docking and surface plasmon resonance (SPR) verification, ZoaNPY was shown to directly and physically interact with NPY Y2 receptor. In view of this, all evidence showed that the pro-angiogenic effects of ZoaNPY involve the activation of NPY Y2 receptor, thereby activating the Akt/mTOR, PLC/PKC, ERK/MEK and Src- FAK-dependent signaling pathways. Furthermore, in an excision wound model, the treatment with ZoaNPY was shown to accelerate the wound healing process in mice. Our findings provide new insights into the discovery and development of novel pro-angiogenic drugs derived from NPY-like polypeptides in the future.

Oregano essential oil encapsulated in zein-pectin-chitosan nanoparticles to improve the storage quality of Harbin red sausage.

In this study, the effect of oregano essential oil loaded in zein-pectin-chitosan (Zein-PC-CS-OEO) nanoparticles on the quality of Harbin red sausage during storage was examined. Zein-PC-CS-OEO nanoparticles exhibit the better encapsulation efficiency, antioxidant and antibacterial properties than these of other prepared nanoparticles, which were subsequently incorporated into Harbin red sausage with different concentrations. The physicochemical properties, bacterial community structure, and flavor characteristics of the Harbin red sausage were determined. Both thiobarbituric acid values and the growth of dominant spoilage bacteria in Harbin red sausage are inhibited by Zein-PC-CS-OEO nanoparticles, while the total aerobic bacteria count is reduced. These results indicate that the storage quality of Harbin red sausage is improved by Zein-PC-CS-OEO nanoparticles. It is worth noting that the shelf life of Harbin red sausage supplemented with 0.1 % Zein-PC-CS-OEO nanoparticles is extended to 9 d, and the flavor characteristics of which are better maintained. This study provides a new approach to extend the application of essential oil and improve the storage quality of Harbin red sausage.

Choosing the optimal target area for repeated transcranial magnetic stimulation in treating neuropathic pain in spinal cord injury patients: a comparative analysis.

Objective: The specific target area of repeated transcranial magnetic stimulation (rTMS) in treating neuropathic pain resulting from spinal cord injury (SCI-NP) remains uncertain. Methods: Thirty-four participants with SCI-NP were allocated into three groups, namely, the motor cortex (M1, A) group, the left dorsolateral prefrontal cortex (LDLPFC, B) group, and the control (sham stimulation, C) group. The intervention was administered totally 10 times. Outcome measures assessed pre-(T0) and post-(T1)intervention, including Numerical Rating scale (NRS), anxiety (SAS), depression (SDS), sleep quality (PSQI), brief pain inventory (BPI), and impression of change. Results: All outcomes in groups A and B significantly changed after intervention (p < 0.05), and the delta value (T1-T0) also significantly changed than group C (p < 0.05). The delta value of SDS in the group B was better than the group A, and the change of pain degree in the group B was moderately correlated with the change in PSQI (r = 0.575, p < 0.05). Both patients in the groups A and B showed significant impression of change about their received therapy (p < 0.05). Conclusion: Both targets are effective, but LDLPFC is more effective in reducing depression in SCI-NP. Healthcare providers might select the suitable area according to the specific attributes of their patients.

Chronic restraint stress-induced hyperalgesia is modulated by the periaqueductal gray neurons projecting to the rostral ventromedial medulla in mice.

Stress-induced hyperalgesia (SIH) is induced by repeated or chronic exposure to stressful or uncomfortable environments. However, the neural mechanisms involved in the modulatory effects of the periaqueductal gray (PAG) and its associated loops on SIH development hav e not been elucidated. In the present study, we used chronic restraint stress (CRS)-induced hyperalgesia as a SIH model and manipulated neuronal activity via a pharmacogenetic approach to investigate the neural mechanism underlying the effects of descending pain-modulatory pathways on SIH. We found that activation of PAG neurons alleviates CRS-induced hyperalgesia; on the other hand, PAG neurons inhibition facilitates CRS-induced hyperalgesia. Moreover, this modulatory effect is achieved by the neurons which projecting to the rostral ventromedial medulla (RVM). Our data thus reveal the functional role of the PAG-RVM circuit in SIH and provide analgesic targets in the brain for clinical SIH treatment.

Clinical phenotype and genetic function analysis of a family with hypomyelinating leukodystrophy-7 caused by POLR3A mutation.

Hypomyelinating leukodystrophy (HLD) is a rare genetic heterogeneous disease that can affect myelin development in the central nervous system. This study aims to analyze the clinical phenotype and genetic function of a family with HLD-7 caused by POLR3A mutation. The proband (IV6) in this family mainly showed progressive cognitive decline, dentin dysplasia, and hypogonadotropic hypogonadism. Her three old brothers (IV1, IV2, and IV4) also had different degrees of ataxia, dystonia, or dysarthria besides the aforementioned manifestations. Their brain magnetic resonance imaging showed bilateral periventricular white matter atrophy, brain atrophy, and corpus callosum atrophy and thinning. The proband and her two living brothers (IV2 and IV4) were detected to carry a homozygous mutation of the POLR3A (NM_007055.4) gene c. 2300G > T (p.Cys767Phe), and her consanguineous married parents (III1 and III2) were p.Cys767Phe heterozygous carriers. In the constructed POLR3A wild-type and p.Cys767Phe mutant cells, it was seen that overexpression of wild-type POLR3A protein significantly enhanced Pol III transcription of 5S rRNA and tRNA Leu-CAA. However, although the mutant POLR3A protein overexpression was increased compared to the wild-type protein overexpression, it did not show the expected further enhancement of Pol III function. On the contrary, Pol III transcription function was frustrated (POLR3A, BC200, and tRNA Leu-CAA expression decreased), and MBP and 18S rRNA expressions were decreased. This study indicates that the POLR3A p.Cys767Phe variant caused increased expression of mutated POLR3A protein and abnormal expression of Pol III transcripts, and the mutant POLR3A protein function was abnormal.

Extended depth of field for Fresnel zone aperture camera via fast passive depth estimation.

The lensless camera with incoherent illumination has gained significant research interest for its thin and flexible structure. However, it faces challenges in resolving scenes with a wide depth of field (DoF) due to its depth-dependent point spread function (PSF). In this paper, we present a single-shot method for extending the DoF in Fresnel zone aperture (FZA) cameras at visible wavelengths through passive depth estimation. The improved ternary search method is utilized to determine the depth of targets rapidly by evaluating the sharpness of the back propagation reconstruction. Based on the depth estimation results, a set of reconstructed images focused on targets at varying depths are derived from the encoded image. After that, the DoF is extended through focus stacking. The experimental results demonstrate an 8-fold increase compared with the calibrated DoF at 130 mm depth. Moreover, our depth estimation method is five times faster than the traversal method, while maintaining the same level of accuracy. The proposed method facilitates the development of lensless imaging in practical applications such as photography, microscopy, and surveillance.

DGS1 improves rice disease resistance by elevating pathogen-associated molecular pattern-triggered immunity.

Rice yield and disease resistance are two crucial factors in determining the suitability of a gene for agricultural breeding. Decreased grain size1 (DGS1), encoding an RING-type E3 ligase, has been found to have a positive effect on rice yield by regulating rice grain number and 1000-grain weight. However, the role of DGS1 in rice blast resistance is still unknown. In this study, we report that DGS1 enhances disease resistance by improving PTI responses, including stronger ROS burst and MAPK activation, and also increased expression of defense-related genes. Furthermore, DGS1 works in conjunction with ubiquitin conjugating enzyme OsUBC45 as an E2-E3 pair to facilitate the ubiquitin-dependent degradation of OsGSK3 and OsPIP2;1, thereby influencing rice yield and immunity, respectively. Therefore, the DGS1-OsUBC45 module has the potential in facilitating rice agricultural breeding. Supplementary Information: The online version contains supplementary material available at 10.1007/s42994-024-00137-9.

Construction of the underlying circRNA-miRNA-mRNA regulatory network and a new diagnostic model in ulcerative colitis by bioinformatics analysis.

BACKGROUND: Circular RNAs (circRNAs) are involved in the pathogenesis of many diseases through competing endogenous RNA (ceRNA) regulatory mechanisms. AIM: To investigate a circRNA-related ceRNA regulatory network and a new predictive model by circRNA to understand the diagnostic mechanism of circRNAs in ulcerative colitis (UC). METHODS: We obtained gene expression profiles of circRNAs, miRNAs, and mRNAs in UC from the Gene Expression Omnibus dataset. The circRNA-miRNA-mRNA network was constructed based on circRNA-miRNA and miRNA-mRNA interactions. Functional enrichment analysis was performed to identify the biological mechanisms involved in circRNAs. We identified the most relevant differential circRNAs for diagnosing UC and constructed a new predictive nomogram, whose efficacy was tested with the C-index, receiver operating characteristic curve (ROC), and decision curve analysis (DCA). RESULTS: A circRNA-miRNA-mRNA regulatory network was obtained, containing 12 circRNAs, three miRNAs, and 38 mRNAs. Two optimal prognostic-related differentially expressed circRNAs, hsa_circ_0085323 and hsa_circ_0036906, were included to construct a predictive nomogram. The model showed good discrimination, with a C-index of 1(> 0.9, high accuracy). ROC and DCA suggested that the nomogram had a beneficial diagnostic ability. CONCLUSION: This novel predictive nomogram incorporating hsa_circ_0085323 and hsa_circ_0036906 can be conveniently used to predict the risk of UC. The circRNa-miRNA-mRNA network in UC could be more clinically significant.

circular RNA circ-231 promotes protein biogenesis of TPI1 and PRDX6 through mediating the interaction of eIF4A3 with STAU1 to facilitate unwinding of secondary structure in 5' UTR, enhancing progression of human esophageal squamous cell carcinoma (ESCC).

Background: The nuclear cap-binding complex (CBC)-dependent translation (CT) is an important initial translation pathway for 5'-cap-dependent translation in normal mammal cells. Eukaryotic translation initiation factor 4A-III (eIF4A3), as an RNA helicase, is recruited to CT complex and enhances CT efficiency through participating in unwinding of secondary structure in the 5' UTR. However, the detailed mechanism for eIF4A3 implicated in unwinding of secondary structure in the 5' UTR in normal mammal cells is still unclear. Specially, we need to investigate whether the kind of mechanism in normal mammal cells extrapolates to cancer cells, e.g. ESCC, and further interrogate whether and how the mechanism triggers malignant phenotype of ESCC, which are important for identifying a potential therapeutic target for patients with ESCC. Methods: Bioinformatics analysis, RNA immunoprecipitation and RNA pulldown assays were performed to detect the interaction of circular RNA circ-231 with eIF4A3. In vitro and in vivo assays were performed to detect biological roles of circ-231 in ESCC. RNA immunoprecipitation, RNA pulldown, mass spectrometry analysis and co-immunoprecipitation assays were used to measure the interaction of circ-231, eIF4A3 and STAU1 in HEK293T and ESCC. In vitro EGFP reporter and 5' UTR of mRNA pulldown assays were performed to probe for the binding of circ-231, eIF4A3 and STAU1 to secondary structure of 5' UTR. Results: RNA immunoprecipitation assays showed that circ-231 interacted with eIF4A3 in HEK293T and ESCC. Further study confirmed that circ-231 orchestrated with eIF4A3 to control protein expression of TPI1 and PRDX6, but not for mRNA transcripts. The in-depth mechanism study uncovered that both circ-231 and eIF4A3 were involved in unwinding of secondary structure in 5' UTR of TPI1 and PRDX6. More importantly, circ-231 promoted the interaction between eIF4A3 and STAU1. Intriguingly, both circ-231 and eIF4A3 were dependent on STAU1 binding to secondary structure in 5' UTR. Biological function assays revealed that circ-231 promoted the migration and proliferation of ESCC via TPI1 and PRDX6. In ESCC, the up-regulated expression of circ-231 was observed and patients with ESCC characterized by higher expression of circ-231 have concurrent lymph node metastasis, compared with control. Conclusions: Our data unravels the detailed mechanism by which STAU1 binds to secondary structure in 5' UTR of mRNAs and recruits eIF4A3 through interacting with circ-231 and thereby eIF4A3 is implicated in unwinding of secondary structure, which is common to HEK293T and ESCC. However, importantly, our data reveals that circ-231 promotes migration and proliferation of ESCC and the up-regulated circ-231 greatly correlates with tumor lymph node metastasis, insinuating that circ-231 could be a therapeutic target and an indicator of risk of lymph node metastasis for patients with ESCC.

Acute exposure to polystyrene nanoparticles promotes liver injury by inducing mitochondrial ROS-dependent necroptosis and augmenting macrophage-hepatocyte crosstalk.

BACKGROUND: The global use of plastic materials has undergone rapid expansion, resulting in the substantial generation of degraded and synthetic microplastics and nanoplastics (MNPs), which have the potential to impose significant environmental burdens and cause harmful effects on living organisms. Despite this, the detrimental impacts of MNPs exposure towards host cells and tissues have not been thoroughly characterized. RESULTS: In the present study, we have elucidated a previously unidentified hepatotoxic effect of 20 nm synthetic polystyrene nanoparticles (PSNPs), rather than larger PS beads, by selectively inducing necroptosis in macrophages. Mechanistically, 20 nm PSNPs were rapidly internalized by macrophages and accumulated in the mitochondria, where they disrupted mitochondrial integrity, leading to heightened production of mitochondrial reactive oxygen species (mtROS). This elevated mtROS generation essentially triggered necroptosis in macrophages, resulting in enhanced crosstalk with hepatocytes, ultimately leading to hepatocyte damage. Additionally, it was demonstrated that PSNPs induced necroptosis and promoted acute liver injury in mice. This harmful effect was significantly mitigated by the administration of a necroptosis inhibitor or systemic depletion of macrophages prior to PSNPs injection. CONCLUSION: Collectively, our study suggests a profound toxicity of environmental PSNP exposure by triggering macrophage necroptosis, which in turn induces hepatotoxicity via intercellular crosstalk between macrophages and hepatocytes in the hepatic microenvironment.

Increased miR-3074-5p expression promotes M1 polarization and pyroptosis of macrophages via ERα/NLRP3 pathway and induces adverse pregnancy outcomes in mice.

Decidual macrophages (dMϕs) play critical roles in regulation of immune-microhomeostasis at maternal-fetal interface during pregnancy, but the underlying molecular mechanisms are still unclear. In this study, it was found that litter size and fetal weight were significantly reduced, whereas the rate of embryo resorption was increased in miR-3074-5p knock-in (3074-KI) pregnant mice, compared to that of wild-type (WT) pregnant mice. Plasma levels of pro-inflammatory cytokines in 3074-KI pregnant mice were also significantly elevated compared to WT pregnant mice at GD7.5. The quantity of M1-Mϕs in uterine tissues of 3074-KI pregnant mice was significantly increased compared to WT pregnant mice at GD13.5. Estrogen receptor-α (ERα) was validated to be a target of miR-3074-5p. Either miR-3074-5p overexpression or ERα knockdown promoted transcriptional activity of NF-κB/p65, induced M1-polarization and pyroptosis of THP1-derived Mϕs, accompanied with increased intracellular levels of cleaved Caspase-1, cleaved IL-1ß, NLRP3, cleaved GSDMD and ASC aggregation. Furthermore, ERα could not only bind to NLRP3 or ASC directly, but also inhibit the interaction between NLRP3 and ASC. The endometrial miR-3074-5p expression level at the middle secretory stage of repeated implantation failure (RIF) patients was significantly decreased compared to that of control fertile women. These data indicated that miR-3074-5p could promote M1 polarization and pyroptosis of Mϕs via activation of NLRP3 inflammasome by targeting ERα, and the dysregulation of miR-3074-5p expression in dMϕs might damage the embryo implantation and placentation by interfering with inflammatory microenvironment at the maternal-fetal interface during early pregnancy.

OMA1 competitively binds to HSPA9 to promote mitophagy and activate the cGAS-STING pathway to mediate GBM immune escape.

BACKGROUND: Immunotherapy with checkpoint inhibitors, especially those targeting programmed death receptor 1 (PD-1)/PD-1 ligand (PD-L1), is increasingly recognized as a highly promising therapeutic modality for malignancies. Nevertheless, the efficiency of immune checkpoint blockade therapy in treating glioblastoma (GBM) is constrained. Hence, it is imperative to expand our comprehension of the molecular mechanisms behind GBM immune escape (IE). METHODS: Protein chip analysis was performed to screen aberrantly expressed OMA1 protein in PD-1 inhibitor sensitive or resistant GBM. Herein, public databases and bioinformatics analysis were employed to investigate the OMA1 and PD-L1 relation. Then, this predicted relation was verified in primary GBM cell lines through distinct experimental methods. To investigate the molecular mechanism behind OMA1 in immunosuppression, a series of experimental methods were employed, including Western blotting, co-immunoprecipitation (Co-IP), mass spectrometry (MS), immunofluorescence, immunohistochemistry, and qRT-PCR. RESULTS: Our findings revealed that OMA1 competitively binds to HSPA9 to induce mitophagy and mediates the IE of GBM. Data from TCGA indicated a significant correlation between OMA1 and immunosuppression. OMA1 promoted PD-L1 levels in primary cells from patients with GBM. Next, the results of Co-IP and MS conducted on GBM primary cells revealed that OMA1 interacts with HSPA9 and induces mitophagy. OMA1 promoted not only cGAS-STING activity by increasing mitochondrial DNA release but also PD-L1 transcription by activating cGAS-STING. Eventually, OMA1 has been found to induce immune evasion in GBM through its regulation of PD-1 binding and PD-L1 mediated T cell cytotoxicity. CONCLUSIONS: The OMA1/HSPA9/cGAS/PD-L1 axis is elucidated in our study as a newly identified immune therapeutic target in GBM.

Beyond nothingness in the formation and functional relevance of voids in polymer films.

Voids-the nothingness-broadly exist within nanomaterials and impact properties ranging from catalysis to mechanical response. However, understanding nanovoids is challenging due to lack of imaging methods with the needed penetration depth and spatial resolution. Here, we integrate electron tomography, morphometry, graph theory and coarse-grained molecular dynamics simulation to study the formation of interconnected nanovoids in polymer films and their impacts on permeance and nanomechanical behaviour. Using polyamide membranes for molecular separation as a representative system, three-dimensional electron tomography at nanometre resolution reveals nanovoid formation from coalescence of oligomers, supported by coarse-grained molecular dynamics simulations. Void analysis provides otherwise inaccessible inputs for accurate fittings of methanol permeance for polyamide membranes. Three-dimensional structural graphs accounting for the tortuous nanovoids within, measure higher apparent moduli with polyamide membranes of higher graph rigidity. Our study elucidates the significance of nanovoids beyond the nothingness, impacting the synthesis‒morphology‒function relationships of complex nanomaterials.