USP28 Serves as a Key Suppressor of Mitochondrial Morphofunctional Defects and Cardiac Dysfunction in the Diabetic Heart.

BACKGROUND: The majority of people with diabetes are susceptible to cardiac dysfunction and heart failure, and conventional drug therapy cannot correct diabetic cardiomyopathy progression. Herein, we assessed the potential role and therapeutic value of USP28 (ubiquitin-specific protease 28) on the metabolic vulnerability of diabetic cardiomyopathy. METHODS: The type 2 diabetes mouse model was established using db/db leptin receptor-deficient mice and high-fat diet/streptozotocin-induced mice. Cardiac-specific knockout of USP28 in the db/db background mice was generated by crossbreeding db/m and Myh6-Cre+/USP28fl/fl mice. Recombinant adeno-associated virus serotype 9 carrying USP28 under cardiac troponin T promoter was injected into db/db mice. High glucose plus palmitic acid-incubated neonatal rat ventricular myocytes and human induced pluripotent stem cell-derived cardiomyocytes were used to imitate diabetic cardiomyopathy in vitro. The molecular mechanism was explored through RNA sequencing, immunoprecipitation and mass spectrometry analysis, protein pull-down, chromatin immunoprecipitation sequencing, and chromatin immunoprecipitation assay. RESULTS: Microarray profiling of the UPS (ubiquitin-proteasome system) on the basis of db/db mouse hearts and diabetic patients' hearts demonstrated that the diabetic ventricle presented a significant reduction in USP28 expression. Diabetic Myh6-Cre+/USP28fl/fl mice exhibited more severe progressive cardiac dysfunction, lipid accumulation, and mitochondrial disarrangement, compared with their controls. On the other hand, USP28 overexpression improved systolic and diastolic dysfunction and ameliorated cardiac hypertrophy and fibrosis in the diabetic heart. Adeno-associated virus serotype 9-USP28 diabetic mice also exhibited less lipid storage, reduced reactive oxygen species formation, and mitochondrial impairment in heart tissues than adeno-associated virus serotype 9-null diabetic mice. As a result, USP28 overexpression attenuated cardiac remodeling and dysfunction, lipid accumulation, and mitochondrial impairment in high-fat diet/streptozotocin-induced type 2 diabetes mice. These results were also confirmed in neonatal rat ventricular myocytes and human induced pluripotent stem cell-derived cardiomyocytes. RNA sequencing, immunoprecipitation and mass spectrometry analysis, chromatin immunoprecipitation assays, chromatin immunoprecipitation sequencing, and protein pull-down assay mechanistically revealed that USP28 directly interacted with PPARα (peroxisome proliferator-activated receptor α), deubiquitinating and stabilizing PPARα (Lys152) to promote Mfn2 (mitofusin 2) transcription, thereby impeding mitochondrial morphofunctional defects. However, such cardioprotective benefits of USP28 were largely abrogated in db/db mice with PPARα deletion and conditional loss-of-function of Mfn2. CONCLUSIONS: Our findings provide a USP28-modulated mitochondria homeostasis mechanism that involves the PPARα-Mfn2 axis in diabetic hearts, suggesting that USP28 activation or adeno-associated virus therapy targeting USP28 represents a potential therapeutic strategy for diabetic cardiomyopathy.

Computational Screening of Promising Deep-Ultraviolet Light Emitters.

Deep-ultraviolet (DUV) light sources are technologically highly important, but DUV light-emitting materials are extremely rare; AlN and its alloys are the only materials known so far, significantly limiting the chemical and structural spaces for materials design. Here, we perform a high-throughput computational search for DUV light emitters based on a set of carefully designed screening criteria relating to the sophisticated electronic structure. In this way, we successfully identify 5 promising material candidates that exhibit comparable or higher radiative recombination coefficients than AlN, including BeGeN2, Mg3NF3, KCaBr3, KHS, and RbHS. Further, we unveil the unique features in the atomic and electronic structures of DUV light emitters and elucidate the fundamental genetic reasons why DUV light emitters are extremely rare. Our study not only guides the design and synthesis of efficient DUV light emitters but also establishes the genetic nature of ultrawide-band-gap semiconductors in general.

Machine learning and related approaches in transcriptomics.

Data acquisition for transcriptomic studies used to be the bottleneck in the transcriptomic analytical pipeline. However, recent developments in transcriptome profiling technologies have increased researchers' ability to obtain data, resulting in a shift in focus to data analysis. Incorporating machine learning to traditional analytical methods allows the possibility of handling larger volumes of complex data more efficiently. Many bioinformaticians, especially those unfamiliar with ML in the study of human transcriptomics and complex biological systems, face a significant barrier stemming from their limited awareness of the current landscape of ML utilisation in this field. To address this gap, this review endeavours to introduce those individuals to the general types of ML, followed by a comprehensive range of more specific techniques, demonstrated through examples of their incorporation into analytical pipelines for human transcriptome investigations. Important computational aspects such as data pre-processing, task formulation, results (performance of ML models), and validation methods are encompassed. In hope of better practical relevance, there is a strong focus on studies published within the last five years, almost exclusively examining human transcriptomes, with outcomes compared with standard non-ML tools.

Three-dimensional laser micromachining system with integrated sub-100†nm resolution in-situ measurement.

In this study, a three-dimensional (3D) laser micromachining system with an integrated sub-100 nm resolution in-situ measurement system was proposed. The system used the same femtosecond laser source for in-situ measurement and machining, avoiding errors between the measurement and the machining positions. It could measure the profile of surfaces with an inclination angle of less than 10°, and the measurement resolution was greater than 100 nm. Consequently, the precise and stable movement of the laser focus could be controlled, enabling highly stable 3D micromachining. The results showed that needed patterns could be machined on continuous surfaces using the proposed system. The proposed machining system is of great significance for broadening the application scenarios of laser machining.

Sex differences in hemoglobin levels and five-year refracture risk in patients with osteoporotic fractures: a retrospective cohort analysis.

We conducted a retrospective cohort analysis to examine the association between hemoglobin (Hb) levels and refracture risk in elderly patients with osteoporotic fractures (OPFs). Our findings suggest a nonlinear relationship exists in females, and females with Hb levels below 10.7 g/dL may be at a higher risk of refracture. INTRODUCTION: Hematopoiesis and bone health have a reciprocal influence on each other. Nevertheless, there is a scarcity of in-depth research on the association between Hb levels and the occurrence of fractures. The present research aimed to investigate the correlation between Hb levels and the rate of refracture within 5 years among individuals with OPFs. METHODS: A retrospective cohort analysis was undertaken between 2017 and 2022. The study included 1906 individuals who were inhabitants of Kunshan and were over 60 years old. These individuals had experienced an OPF between January 1, 2017, and July 27, 2022, resulting in their hospitalization. Cox proportional hazard regression models were used to evaluate the risk of refracture within 5 years based on the Hb levels acquired during the admission examination, with consideration for sex differences. A nonlinear relationship was identified using smoothed curve fitting and threshold analysis. Kaplan-Meier curves were used to compare refracture rates between patients with low and high Hb levels. RESULTS: Elderly female patients with OPFs and lower Hb levels exhibited a significantly higher risk of a 5-year refracture. Conversely, no significant associations were observed between the two variables in male patients. A nonlinear correlation was found between Hb levels and the probability of refracture in females, with a turning point identified at 10.7 g/dL of Hb levels. A strong negative association was observed with the five-year refracture rate when Hb levels fell below 10.7 g/dL (hazard ratio (HR) = 0.63; 95% confidence interval (CI) 0.48 to 0.83; P-value = 0.0008). This finding suggests that for every 1 g/dL increase in Hb below 10.7 g/dL, the risk of refracture reduced by 37%. However, no statistically significant association was observed when Hb levels were above 10.7 g/dL. CONCLUSIONS: The findings demonstrated a significant negative correlation between Hb levels and the likelihood of refracture in elderly female patients with OPFs and suggested that elderly females with recent OPFs and Hb levels below 10.7 g/dL may be at a higher risk of refracture. Additionally, the Hb levels can serve as an indicator of bone fragility in elderly female patients with OPFs. These findings highlight the importance of monitoring Hb levels as a part of comprehensive management strategies to both assess skeletal health and prevent refractures in this population.

Vonoprazan is Not Inferior to Proton Pump Inhibitors in Bismuth-containing Quadruple Therapy for Helicobacter pylori Eradication: A Meta-analysis of 10 Studies From East Asia.

OBJECTIVE: To investigate the efficacy and safety of vonoprazan based bismuth-containing quadruple therapy (VBCQ) in eradicating Helicobacter pylori (Hp). MATERIALS AND METHODS: The VBCQ and the proton pump inhibitor-based bismuth-containing quadruple regimen (PBCQ) were compared by retrieving relevant studies in Pubmed, Embase, Cochrane Library, CNKI, and Wanfang data. Combined analysis was performed with risk ratio (RR) and 95% CI as effect values. RESULTS: A total of 10 studies were enrolled, including 7 randomized controlled trials and 3 cohort studies. In intention-to-treat analysis, the eradication rate of VBCQ (89.24%, 1103/1236) was significantly higher than that of PBCQ (84.03%, 1021/1215), with RR = 1.06 (95% CI: 1.03~1.10). In per-protocol analysis, the eradication rates of VBCQ and PBCQ were 92.94% (895/963) and 87.82% (829/944), respectively, with a significant difference (RR = 1.06, 95% CI: 1.03~1.09). Subgroup analysis of study design types shared similar results. VBCQ and PBCQ showed an incidence of adverse reactions of 37.30% (304/815) and 34.94% (282/807), respectively. Significant differences were not found between the two groups (RR = 1.07, 95% CI: 0.96-1.19), nor in subgroup analysis. The good compliance rates in VBCQ and PBCQ groups were 94.32% (216/229) and 95.13% (215/226), respectively, with no significant difference (RR = 0.99, 95% CI: 0.95~1.04). CONCLUSION: VBCQ has a higher eradication rate on Hp than PBCQ, while its adverse reactions and compliance are similar to PBCQ. However, we conservatively believe that in Hp eradication, the VBCQ is not inferior to PBCQ because of the small absolute difference.

Quercetin prevents methylmercury-induced mitochondrial dysfunction in the cerebral cortex of mice.

Methylmercury (MeHg) exposure can cause nerve damage and mitochondrial dysfunction. Mitochondrial dysfunction is mainly mediated by mitochondrial biogenesis and mitochondrial dynamics disorders. Quercetin (QE) plays an important role in activating silencing information regulator 2 related enzyme 1 (SIRT1), and SIRT1 activates peroxisome-proliferator-activated receptor-γ co-activator 1α (PGC-1α), which can regulate mitochondrial biogenesis and mitochondrial dynamics. The main purpose of this study was to explore the alleviating effects of QE on MeHg-induced nerve damage and mitochondrial dysfunction. The results showed that QE could reduce the excessive production of reactive oxygen species (ROS) and the loss of membrane potential induced by MeHg. Meanwhile, QE activated SIRT1 activity and SIRT1/PGC-1α signaling pathway, improved mitochondrial biogenesis and fusion and reduced mitochondrial fission. In summary, we hypothesized that QE prevents MeHg-induced mitochondrial dysfunction by activating SIRT1/PGC-1α signaling pathway.

Cla4A, a Novel Regulator of Gene Expression Networks Required for Asexual and Insect-Pathogenic Lifecycles of Beauveria bassiana.

Cla4, an orthologous p21-activated kinase crucial for non-entomopathogenic fungal lifestyles, has two paralogs (Cla4A/B) functionally unknown in hypocrealean entomopathogens. Here, we report a regulatory role of Cla4A in gene expression networks of Beauveria bassiana required for asexual and entomopathogenic lifecycles while Cla4B is functionally redundant. The deletion of cla4A resulted in severe growth defects, reduced stress tolerance, delayed conidiation, altered conidiation mode, impaired conidial quality, and abolished pathogenicity through cuticular penetration, contrasting with no phenotype affected by cla4B deletion. In ∆cla4A, 5288 dysregulated genes were associated with phenotypic defects, which were restored by targeted gene complementation. Among those, 3699 genes were downregulated, including more than 1300 abolished at the transcriptomic level. Hundreds of those downregulated genes were involved in the regulation of transcription, translation, and post-translational modifications and the organization and function of the nuclear chromosome, chromatin, and protein-DNA complex. DNA-binding elements in promoter regions of 130 dysregulated genes were predicted to be targeted by Cla4A domains. Samples of purified Cla4A extract were proven to bind promoter DNAs of 12 predicted genes involved in multiple stress-responsive pathways. Therefore, Cla4A acts as a novel regulator of genomic expression and stability and mediates gene expression networks required for insect-pathogenic fungal adaptations to the host and environment.

Photoelectrocatalytic Synthesis of Urea from Carbon Dioxide and Nitrate over a Cu2O Photocathode.

Transformation of carbon dioxide and nitrate ions into urea offers an attractive route for both nitrogen fertilizer production and environmental remediation. However, achieving this transformation under mild conditions remains challenging. Herein, we report an efficient photoelectrochemical method for urea synthesis by co-reduction of carbon dioxide and nitrate ion over a Cu2O photocathode, delivering urea formation rate of 29.71±2.20 µmol g-1 h-1 and Faradaic efficiency (FE) of 12.90±1.15 % at low external potential (-0.017 V vs. reversible hydrogen electrode). Experimental data combined with theoretical calculations suggest that the adsorbed CO* and NO2* species are the key intermediates, and associated C-N coupling is the rate-determining step. This work demonstrates that Cu2O is an efficient catalyst to drive co-reduction of CO2 and NO3 - to urea under light irradiation with low external potential, showing great opportunity of photoelectrocatalysis as a sustainable tool for value-added chemical synthesis.

Identification of immune-related lncRNA in sepsis by construction of ceRNA network and integrating bioinformatic analysis.

BACKGROUND: Sepsis is a high mortality disease which seriously threatens human life and health, for which the pathogenetic mechanism still unclear. There is increasing evidence showed that immune and inflammation responses are key players in the development of sepsis pathology. LncRNAs, which act as ceRNAs, have critical roles in various diseases. However, the regulatory roles of ceRNA in the immunopathogenesis of sepsis have not yet been elucidated. RESULTS: In this study, we aimed to identify immune biomarkers associated with sepsis. We first generated a global immune-associated ceRNA (IMCE) network based on data describing interactions pairs of gene-miRNA and miRNA-lncRNA. Afterward, we excavated a dysregulated sepsis immune-associated ceRNA (SPIMC) network from the global IMCE network by means of a multi-step computational approach. Functional enrichment indicated that lncRNAs in SPIMC network have pivotal roles in the immune mechanism underlying sepsis. Subsequently, we identified module and hub genes (CD4 and STAT4) via construction of a sepsis immune-related PPI network. Then, we identified hub genes based on the modular structure of PPI network and generated a ceRNA subnetwork to analyze key lncRNAs associated with sepsis. Finally, 6 lncRNAs (LINC00265, LINC00893, NDUFA6-AS1, NOP14-AS1, PRKCQ-AS1 and ZNF674-AS1) that identified as immune biomarkers of sepsis. Moreover, the CIBERSORT algorithm and the infiltration of circulating immune cells types were performed to identify the inflammatory state of sepsis. Correlation analyses between immune cells and sepsis immune biomarkers showed that the LINC00265 was strongly positive correlated with the macrophages M2 (r = 0.77). CONCLUSION: Collectively, these results may suggest that these lncRNAs (LINC00265, LINC00893, NDUFA6-AS1, NOP14-AS1, PRKCQ-AS1 and ZNF674-AS1) played important roles in the immune pathogenesis of sepsis and provide potential therapeutic targets for further researches on immune therapy treatment in patients with sepsis.

Mucilage secretion by aerial roots in sorghum (Sorghum bicolor): sugar profile, genetic diversity, GWAS and transcriptomic analysis.

Aerial root mucilage can enhance nitrogen fixation by providing sugar and low oxygen environment to the rhizosphere microbiome in Sierra Mixe maize. Aerial root mucilage has long been documented in sorghum (Sorghum bicolor), but little is known about the biological significance, genotypic variation, and genetic regulation of this biological process. In the present study, we found that a large variation of mucilage secretion capacity existed in a sorghum panel consisting of 146 accessions. Mucilage secretion occurred primarily in young aerial roots under adequately humid conditions but decreased or stopped in mature long aerial roots or under dry conditions. The main components of the mucilage-soluble were glucose and fructose, as revealed by sugar profiling of cultivated and wild sorghum. The mucilage secretion capacity of landrace grain sorghum was significantly higher than that of wild sorghum. Transcriptome analysis revealed that 1844 genes were upregulated and 2617 genes were downregulated in mucilage secreting roots. Amongst these 4461 differentially expressed genes, 82 genes belonged to glycosyltransferases and glucuronidation pathways. Sobic.010G120200, encoding a UDP-glycosyltransferase, was identified by both GWAS and transcriptome analysis as a candidate gene, which may be involved in the regulation of mucilage secretion in sorghum through a negative regulatory mechanism.

Electrocatalytic Upcycling of Biomass and Plastic Wastes to Biodegradable Polymer Monomers and Hydrogen Fuel at High Current Densities.

Transformation of biomass and plastic wastes to value-added chemicals and fuels is considered an upcycling process that is beneficial to resource utilization. Electrocatalysis offers a sustainable approach; however, it remains a huge challenge to increase the current density and deliver market-demanded chemicals with high selectivity. Herein, we demonstrate an electrocatalytic strategy for upcycling glycerol (from biodiesel byproduct) to lactic acid and ethylene glycol (from polyethylene terephthalate waste) to glycolic acid, with both products being as valuable monomers for biodegradable polymer production. By using a nickel hydroxide-supported gold electrocatalyst (Au/Ni(OH)2), we achieve high selectivities of lactic acid and glycolic acid (77 and 91%, respectively) with high current densities at moderate potentials (317.7 mA/cm2 at 0.95 V vs RHE and 326.2 mA/cm2 at 1.15 V vs RHE, respectively). We reveal that glycerol and ethylene glycol can be enriched at the Au/Ni(OH)2 interface through their adjacent hydroxyl groups, substantially increasing local concentrations and thus high current densities. As a proof of concept, we employed a membrane-free flow electrolyzer for upcycling triglyceride and PET bottles, attaining 11.2 g of lactic acid coupled with 9.3 L of H2 and 13.7 g of glycolic acid coupled with 9.4 L of H2, respectively, revealing the potential of coproduction of valuable chemicals and H2 fuel from wastes in a sustainable fashion.

The MocR family transcriptional regulator DnfR has multiple binding sites and regulates Dirammox gene transcription in Alcaligenes faecalis JQ135.

Microbial ammonia oxidation is vital to the nitrogen cycle. A biological process, called Dirammox (direct ammonia oxidation, NH3 →NH2 OH→N2 ), has been recently identified in Alcaligenes ammonioxydans and Alcaligenes faecalis. However, its transcriptional regulatory mechanism has not yet been fully elucidated. The present study characterized a new MocR-like transcription factor DnfR that is involved in the Dirammox process in A. faecalis strain JQ135. The entire dnf cluster was composed of 10 genes and transcribed as five transcriptional units, that is, dnfIH, dnfR, dnfG, dnfABCDE and dnfF. DnfR activates the transcription of dnfIH, dnfG and dnfABCDE genes, and represses its own transcription. The intact 1506-bp dnfR gene was required for activation of Dirammox. Electrophoretic mobility shift assays and DNase I footprinting analyses showed that DnfR has one binding site in the dnfH-dnfR intergenic region and two binding sites in the dnfG-dnfA intergenic region. Three binding sites of DnfR shared a 6-bp repeated conserved sequence 5'-GGTCTG-N17 -GGTCTG-3' which was essential for the transcription of downstream target genes. Cysteine and glutamate act as possible effectors of DnfR to activate the transcription of transcriptional units of dnfG and dnfABCDE, respectively. This study provided new insights in the transcriptional regulation mechanism of Dirammox by DnfR in A. faecalis JQ135.

Exosomes derived from cardiac fibroblasts with angiotensin II stimulation provoke hypertrophy and autophagy inhibition in cardiomyocytes.

Although accumulating evidence has revealed that autophagy inhibition contributes to the development of pathological cardiac hypertrophy, the mechanisms leading to declined autophagy activity in the hypertrophic heart remain to be elucidated. Exosomes are known to be important mediators of intercellular communication, and the involvement of exosomes in cardiovascular abnormities has attracted increasing attentions. Cardiac fibroblasts (CFs) are the most abundant cell type in the heart. Here, we investigated the potential role of CFs-derived exosomes in regulating cardiomyocyte hypertrophy and autophagy. Exosomes from rat CFs treated with angiotensin II (Ang II-CFs-exosomes) were collected and characterized. Our experiments showed that these exosomes could induce hypertrophic responses and impair autophagy activity in primary neonatal rat cardiomyocytes (NRCMs). Ang II-CFs-exosomes blocked the autophagic flux of NRCMs via inhibiting the formation of autolysosomes. Moreover, the pro-hypertrophic effects and autophagy inhibition induced by Ang II-CFs-exosomes was validated in mice receiving injection of the exosomes. These findings highlight a novel role of Ang II-CFs-exosomes in suppressing cardiomyocyte autophagy, which may help to better understand the pathogenesis of cardiac hypertrophy.

Advanced glycation end products initiate the mutual promoting cycle between centrosome amplification and the release of inflammatory cytokines in human vascular endothelial cells.

Inflammation is implicated in the development of diabetic complications including vascular pathology. Centrosome is known to play a role in cell secretion. We have reported that diabetes can trigger centrosome amplification (CA). Thus, in the present study, we investigated the relationship between CA and the release of proinflammatory cytokines interleukin-1ß, tumor necrosis factor-α and interleukin-6 in hCMEC/D3 human endothelial cells treated with advanced glycation end products (AGEs). We found that AGEs induced CA via PLK4 and increased the biosynthesis of the three cytokines via NF-κB. Importantly, treatment of the cells with AGEs also increased the release of the three cytokines. Inhibiting CA by knockdown of polo like kinase 4 (PLK4) attenuated the cytokine release but not their biosynthesis. Knockdown of the cytokines inhibited the CA, while addition of the cytokines individually to the cell culture increased the protein level of PLK4 and CA to a moderate level. Addition of the three cytokines together into the cell culture markedly enhanced the CA, to a level higher than that in the AGEs-treated group. In conclusion, our results provide the direct evidence that the cytokines can induce CA, and suggest that there is a mutual promoting cycle between CA and cytokine release in the treated samples. It is proposed that the cycle of CA-cytokine release is a candidate biological link between diabetes and its complications such as vascular pathologies.

Inhibition of miR-214-3p attenuates ferroptosis in myocardial infarction via regulating ME2.

Myocardial infarction (MI) contributes to an increased risk of incident heart failure and sudden death, but there is still a lack of effective treatment in clinic. Recently, growing evidence has indicated that abnormal expression of microRNAs (miRNAs) plays a crucial role in cardiovascular diseases. In this research, the involvement of miRNA-214-3p in MI was explored. A mouse model of MI was established by ligation of the left anterior descending coronary artery, and primary cultures of neonatal rat cardiomyocytes (NRCMs) were submitted to hypoxic treatment to stimulate cellular injury in vitro. Our results showed that miR-214-3p level was significantly upregulated in the infarcted region of mouse hearts and in NRCMs exposed to hypoxia, accompanying with an obvious elevation of ferroptosis. Inhibition of miR-214-3p by antagomir injection improved cardiac function, decreased infarct size, and attenuated iron accumulation and oxidant stress in myocardial tissues. MiR-214-3p could also promote ferroptosis and cellular impairments in NRCMs, while miR-214-3p inhibitor effectively protected cells from hypoxia. Furthermore, dual luciferase reporter gene assay revealed that malic enzyme 2 (ME2) is a direct target of miR-214-3p. In cardiomyocytes, overexpression of ME2 ameliorated the detrimental effects and excessive ferroptosis induced by miR-214-3p mimic, whereas ME2 depletion compromised the protective role of miR-214-3p inhibitor against hypoxic injury and ferroptosis. These findings suggest that miR-214-3p contributes to enhanced ferroptosis during MI at least partially via suppressing ME2. Inhibition of miR-214-3p may be a new approach for tackling MI.

Infiltrating myeloid cell-derived properdin markedly promotes microglia-mediated neuroinflammation after ischemic stroke.

BACKGROUND: Emerging evidence has shown that myeloid cells that infiltrate into the peri-infarct region may influence the progression of ischemic stroke by interacting with microglia. Properdin, which is typically secreted by immune cells such as neutrophils, monocytes, and T cells, has been found to possess damage-associated molecular patterns (DAMPs) properties and can perform functions unrelated to the complement pathway. However, the role of properdin in modulating microglia-mediated post-stroke neuroinflammation remains unclear. METHODS: Global and conditional (myeloid-specific) properdin-knockout mice were subjected to transient middle cerebral artery occlusion (tMCAO). Histopathological and behavioral tests were performed to assess ischemic brain injury in mice. Single-cell RNA sequencing and immunofluorescence staining were applied to explore the source and the expression level of properdin. The transcriptomic profile of properdin-activated primary microglia was depicted by transcriptome sequencing. Lentivirus was used for macrophage-inducible C-type lectin (Mincle) silencing in microglia. Conditioned medium from primary microglia was administered to primary cortex neurons to determine the neurotoxicity of microglia. A series of cellular and molecular biological techniques were used to evaluate the proinflammatory response, neuronal death, protein-protein interactions, and related signaling pathways, etc. RESULTS: The level of properdin was significantly increased, and brain-infiltrating neutrophils and macrophages were the main sources of properdin in the ischemic brain. Global and conditional myeloid knockout of properdin attenuated microglial overactivation and inflammatory responses at the acute stage of tMCAO in mice. Accordingly, treatment with recombinant properdin enhanced the production of proinflammatory cytokines and augmented microglia-potentiated neuronal death in primary culture. Mechanistically, recombinant properdin served as a novel ligand that activated Mincle receptors on microglia and downstream pathways to drive primary microglia-induced inflammatory responses. Intriguingly, properdin can directly bind to the microglial Mincle receptor to exert the above effects, while Mincle knockdown limits properdin-mediated microglial inflammation. CONCLUSION: Properdin is a new medium by which infiltrating peripheral myeloid cells communicate with microglia, further activate microglia, and exacerbate brain injury in the ischemic brain, suggesting that targeted disruption of the interaction between properdin and Mincle on microglia or inhibition of their downstream signaling may improve the prognosis of ischemic stroke.

Ferroptosis and Neurodegenerative Diseases: Insights into the Regulatory Roles of SLC7A11.

Programed cell death plays a key role in promoting human development and maintaining homeostasis. Ferroptosis is a recently identified pattern of programmed cell death that is closely associated with the onset and progression of neurodegenerative diseases. Ferroptosis is mainly caused by the intracellular accumulation of iron-dependent lipid peroxides. The cysteine/glutamate antibody Solute carrier family 7 member 11 (SLC7A11, also known as xCT) functions to import cysteine for glutathione biosynthesis and antioxidant defense. SLC7A11 has a significant impact on ferroptosis, and inhibition of SLC7A11 expression promotes ferroptosis. Moreover, SLC7A11 is also closely associated with neurodegenerative diseases. In this paper, we summarize the relationship between ferroptosis and neurodegenerative diseases and the role of SLC7A11 during this process. The various regulatory mechanisms of SLC7A11 are also discussed. In conclusion, we are looking forward to a theoretical basis for further understanding the occurrence and development of ferroptosis in SLC7A11 and neurodegenerative diseases, and to seek new clues for the treatment of neurodegenerative diseases.

Mussel-Inspired Two-Dimensional Halide Perovskite Facilitated Dopamine Polymerization and Self-Adhesive Photoelectric Coating.

Polydopamine (PDA) is a good adhesion agent for lots of gels inspired by the mussel, whereas hybrid organic-inorganic perovskites (HOIPs) usually exhibit extraordinary optoelectronic performance. Herein, mussel-inspired chemistry has been integrated with two-dimensional HOIPs first, leading to the preparation of new crystal (HDA)2PbBr4 (1) (DA = dopamine). The organic cation dopamine can be introduced into PDA resulting in a thin film of (HPDA)2PbBr4 (PDA-1). The dissolved inorganic components of layered perovskite in DMF solution together with H2O2 addition can facilitate DA polymerization greatly. More importantly, PDA-1 can inherit an excellent semiconductor property of HOIPs and robust adhesion of the PDA hydrogel resulting in a self-adhesive photoelectric coating on various interfaces.

Decomposition mechanism of 1,3,5-trinitro-2,4,6-trinitroaminobenzene under thermal and shock stimuli using ReaxFF molecular dynamics simulations.

To obtain atomic-level insights into the decomposition behavior of 1,3,5-trinitro-2,4,6-trinitroaminobenzene (TNTNB) under different stimulations, this study applied reactive molecular dynamics simulations to illustrate the effects of thermal and shock stimuli on the TNTNB crystal. The results show that the initial decomposition of the TNTNB crystal under both thermal and shock stimuli starts with the breakage of the N-NO2 bond. However, the C6 ring in TNTNB undergoes structural rearrangement to form a C3-C5 bicyclic structure at a constant high temperature. Then, the C3 and C5 rings break in turn. The main final products of TNTNB under shock are N2, CO2, and H2O, while NO,  N2, H2O and CO are formed instead at 1 atm under a constant high temperature. Pressure is the main reason for this difference. High pressure promotes the complete oxidation of the reactants.