Identification and Validation of PKR as a Direct Target for the Novel Sulfonamide-Substituted Tetrahydroquinoline Nonselective Inhibitor of the NLRP3 Inflammasome.

The NLRP3 inflammasome is a critical component of the innate immune system. The persistent abnormal activation of the NLRP3 inflammasome is implicated in numerous human diseases. Herein, sulfonamide-substituted tetrahydroquinoline derivative S-9 was identified as the most promising NLRP3 inhibitor, without obvious cytotoxicity. In vitro, S-9 inhibited the priming and activation stages of the NLRP3 inflammasome. Incidentally, we also observed that S-9 had inhibitory effects on the NLRC4 and AIM2 inflammasomes. To elucidate the multiple anti-inflammatory activities of S-9, photoaffinity probe P-2, which contained a photoaffinity label and a functional handle, was developed for target identification by chemical proteomics. We identified PKR as a novel target of S-9 in addition to NLRP3 by target fishing. Furthermore, S-9 exhibited a significant anti-neuroinflammatory effect in vivo. In summary, our findings show that S-9 is a promising lead compound targeting both PKR and NLRP3 that could emerge as a molecular tool for treating inflammasome-related diseases.

Antibiotic-free production of sucrose isomerase in Bacillus subtilis by genome integration.

Sucrose isomerase (SIase) catalyzes the hydrolysis and isomerization of sucrose to form isomaltulose, a valuable functional sugar widely used in the food industry. However, the lack of safe and efficient heterologous expression systems hinders SIase production and application. In this study, we achieved antibiotic-free SIase expression in Bacillus subtilis through genome integration. Using CRISPR/Cas9 system, SIase expression cassettes were integrated into various genomic loci, including amyE and ctc, both individually and in combination, resulting in single-copy and muti-copy integration strains. Engineered strains with a maltose-inducible promoter effectively expressed and secreted SIase. Notably, multi-copy strain exhibited enhanced SIase production, achieving 4.4 U/mL extracellular activity in shake flask cultivations. Furthermore, crude enzyme solution from engineered strain transformed high concentrations sucrose into high yields of isomaltulose, reaching a maximum yield of 94.6%. These findings demonstrate antibiotic-free SIase production in B. subtilis via genome integration, laying the foundation for its industrial production and application.

Right ventricular function indices and platelet parameters for early prediction value of bronchopulmonary dysplasia: a retrospective study.

BACKGROUND: To examine the value of early echocardiographic indices for the right ventricular function combined with platelet(PLT) parameters for predicting bronchopulmonary dysplasia (BPD) in preterm infants. METHODS: This retrospective study included infants with gestational age (GA) below 32 weeks, who were admitted to the neonatal intensive care unit(NICU). The detection rate of tricuspid regurgitation jet velocity (TRVJ), ventricular septal flattening, pulmonary artery widening, right ventricular dilation, and right atrial enlargement on the 7th day of life (DOL 7) were compared between BPD and non-BPD infants. Echocardiographic indices of the right ventricular function including tricuspid annular plane systolic excursion (TAPSE) and right ventricular index of myocardial performance (RIMP) were measured on 1 day of life (DOL 1)、on DOL 7 and on 14 day of life (DOL 14) respectively. The PLT parameters including the PLT count, mean platelet volume (MPV), platelet hematocrit (PCT) level, and platelet distribution width (PDW) were measured on the DOL 1,DOL 7, and DOL 14. Multivariate logistic regression was used to analyze the relationship between these parameters and BPD. Receiver operating characteristic curve analysis was performed to assess the predictive value of the right ventricular function indices and PLT parameters for BPD. RESULTS: A total of 220 preterm infants were included in this study, and of these, 85 infants developed BPD among them. The RIMP of the BPD group on DOL 14 was higher than that of the non-BPD group (P < 0.05). The TAPSE of the BPD group on DOL 14 was lower than that of the non-BPD group (P < 0.05). The PLT count of the BPD group on DOL 1 was lower than that of the non-BPD group (P < 0.05), and the MPV of the BPD group on DOL 1 was higher than that of the non-BPD group (P < 0.05). Using multivariate logistic regression, GA、invasive mechanical ventilation duration ≥ 7 days、 PLT、 MPV、 TAPSE and RIMP were found to be independent risk factors for BPD. The area under the receiver operating characteristic curve was 0.846 (95CI: 0.794∼0.899), which improved when using right ventricular function indices combined with platelet parameters. CONCLUSION: TAPSE and RIMP combined with PLT count and MPV can help identify preterm infants at an increased risk of developing BPD.

Porous hybrid encapsulation enables high-rate lithium storage for a micron-sized SiO anode.

Establishing a durable interfacial layer between an electrode and electrolyte to enable micron-sized silicon-based lithium-ion battery (LIB) anodes to achieve superior electrochemical performance is highly desired. Recent studies have shown that heterogeneous encapsulation with enhanced ion/electron transport is an effective strategy. However, the structural design of the existing hetero-coated interface lacks a reasonable ion/electron transport channel, resulting in high interfacial impedance. Herein, we designed a heterogenous MXene-mesoporous polypyrrole (mPPy) encapsulation layer onto micron-sized SiO particles. The MXene coating layer functions as a bridging interface that can build a strong chemical link to internal SiO via covalent bonding, thus reinforcing interfacial charge transfer rate. Meanwhile, it forms a dynamic connection with the outer mPPy through hydrogen bonding, which contributes to high interfacial Li+ concentration and ion/electron coupling transport rate. Accordingly, the as-prepared SiO@MXene@mPPy anode delivers a boosted specific capacity of 673.9 mA h g-1 at 2 A g-1 after 1000 cycles and high-rate capability of 777.4 mA h g-1 at 5 A g-1. Further, electrochemical kinetic analysis indicates that the MXene@mPPy coating layer shows a pseudocapacitance controlled Li storage mechanism, thereby displaying improved high-rate capability. This porous hybrid encapsulation strategy offers new possibilities for a micron-sized SiO anode to achieve an excellent performance.

Radiomics based on HRCT can predict RP-ILD and mortality in anti-MDA5 + dermatomyositis patients: a multi-center retrospective study.

OBJECTIVES: To assess the effectiveness of HRCT-based radiomics in predicting rapidly progressive interstitial lung disease (RP-ILD) and mortality in anti-MDA5 positive dermatomyositis-related interstitial lung disease (anti-MDA5 + DM-ILD). METHODS: From August 2014 to March 2022, 160 patients from Institution 1 were retrospectively and consecutively enrolled and were randomly divided into the training dataset (n = 119) and internal validation dataset (n = 41), while 29 patients from Institution 2 were retrospectively and consecutively enrolled as external validation dataset. We generated four Risk-scores based on radiomics features extracted from four areas of HRCT. A nomogram was established by integrating the selected clinico-radiologic variables and the Risk-score of the most discriminative radiomics model. The RP-ILD prediction performance of the models was evaluated by using the area under the receiver operating characteristic curves, calibration curves, and decision curves. Survival analysis was conducted with Kaplan-Meier curves, Mantel-Haenszel test, and Cox regression. RESULTS: Over a median follow-up time of 31.6 months (interquartile range: 12.9-49.1 months), 24 patients lost to follow-up and 46 patients lost their lives (27.9%, 46/165). The Risk-score based on bilateral lungs performed best, attaining AUCs of 0.869 and 0.905 in the internal and external validation datasets. The nomogram outperformed clinico-radiologic model and Risk-score with AUCs of 0.882 and 0.916 in the internal and external validation datasets. Patients were classified into low- and high-risk groups with 50:50 based on nomogram. High-risk group patients demonstrated a significantly higher risk of mortality than low-risk group patients in institution 1 (HR = 4.117) and institution 2 cohorts (HR = 7.515). CONCLUSION: For anti-MDA5 + DM-ILD, the nomogram, mainly based on radiomics, can predict RP-ILD and is an independent predictor of mortality.

Identification of tumor-antigen signatures and immune subtypes for messenger RNA vaccine selection in advanced clear cell renal cell carcinoma.

BACKGROUND: Advanced clear cell renal cell carcinoma still lacks reliable diagnostic and prognostic biomarkers. Recently, tumor vaccines targeting specific molecules have been proposed as a promising treatment in mitigating tumor progression, which was rekindled under the background of the COVID-19 pandemic. However, the application of messenger RNA vaccine against advanced clear cell renal cell carcinoma antigens remains stagnant, and no subgroup of patients deemed suitable for vaccination has been extensively studied or validated. Our study aims to explore novel advanced clear cell renal cell carcinoma antigen signatures to select suitable patients for vaccination. METHODS: Gene expression profiles of advanced clear cell renal cell carcinoma samples and their corresponding clinical data were retrieved from The Cancer Genome Atlas. The least absolute shrinkage and selection operator model was applied to develop signatures to stratify patients with advanced clear cell renal cell carcinoma. Receiver operating characteristic analysis was used to compare the prognostic accuracy of each factor. Tumor Immune Estimation Resource was used to visualize the relationship between the proportion of antigen-presenting cells and the expression of filtered genes. The "CIBERSORT" and "WGCNA" R Packages were employed to ascertain disparities in immune infiltration levels between advanced clear cell renal cell carcinoma subgroups. The Search Tools for the Retrieval of Interacting Genes database and Cytoscape were used to construct the protein-protein interaction network. CCK-8 and colony formation assays were included in the invitro experiment. RESULTS: In total, 244 potential tumor antigens were identified. Using the least absolute shrinkage and selection operator Cox regression, 21 tumor antigens were selected for developing a risk evaluation signature. The risk score signature can be a useful tool to predict the outcome of advanced clear cell renal cell carcinoma patients. According to the differential clinical, molecular, and immune-related genes, we divided advanced clear cell renal cell carcinoma patients into the immune "cold" subtype and immune "hot" subtype. By developing a logistic score, the immune subtype signature can better distinguish a patient more likely to be immune "cold" subtype or immune "hot" subtype. Interestingly, patients with high risk scores had a higher proportion of immune "hot" subtype than those with a low risk score. Furthermore, the prognostic value was significantly improved when combining risk score and immune subtype. Distinct immune landscapes and signal pathways were observed between different tumor subtypes. Finally, novel tumor antigens related to oxidative stress were identified. CONCLUSION: The tumor-antigens-based risk score and immune subtype signatures identified potentially effective neo-antigens for advanced clear cell renal cell carcinoma messenger RNA vaccine development, and patients with low risk scores and immune "cold" subtype tumors are more prone to benefit from messenger RNA vaccination. Furthermore, our study highlights the significant role of oxidative stress in determining the efficacy of the messenger RNA vaccine.

Investigation of the impact of planar microelectrodes on macrophage-mediated mesenchymal stem cell osteogenesis.

Osseointegration commences with foreign body inflammation upon implant placement, where macrophages play a crucial role in the immune response. Subsequently, during the intermediate and late stages of osseointegration, mesenchymal stem cells (MSCs) migrate and initiate their osteogenic functions, while macrophages support MSCs in osteogenesis. The utilization of ferroelectric P(VDF-TrFE) covered ITO planar microelectrodes facilitated the simulation of various surface charge to investigate their effects on MSCs' osteogenic differentiation and macrophage polarization and the results indicated a parabolic increase in the promotional effect of both with the rise in piezoelectric coefficient. Furthermore, the surface charge with a piezoelectric coefficient of -18 exhibited the strongest influence on the promotion of M1 polarization of macrophages and the promotion of MSCs' osteogenic differentiation. The impact of macrophage polarization and MSC osteogenesis following the interaction of macrophages affected by surface charge and MSC was ultimately investigated. It was observed that macrophages affected by the surface charge of -18 piezoelectric coefficient still exerted the most profound induced osteogenic effect, validating the essential role of M1-type macrophages in the osteogenic differentiation of MSCs.

Regional brain structure mediates the association between sleep quality and intellectual abilities: the moderating role of socioeconomic status.

This study aims to reveal the association between sleep quality and crystallized intelligence (Gc), fluid intelligence (Gf), and the underlying brain structural basis. Using the data from the Human Connectome Project (N = 1087), we performed mediation analysis to explore whether regional brain structure related to sleep quality mediate the association between sleep quality and intellectual abilities, and further examined whether socioeconomic status (i.e., income and education level) moderate the mediation effect. Results showed that poorer sleep quality was associated with lower Gc rather than Gf, and worse sleep quality was associated with smaller volume and surface area in temporal lobe, including inferior temporal gyrus and middle temporal gyrus. Notably, temporal lobe structures mediated the association between sleep quality and Gc rather than Gf. Furthermore, socioeconomic status (i.e., income and education level) moderated the mediating effect, showing low socioeconomic status has a more significant mediating effect with stronger association between sleep quality and Gc as well as stronger association between temporal lobe structure and Gc in low socioeconomic status group. These findings suggest that individuals with higher socioeconomic status are less susceptible to the effect of sleep quality on Gc.

Advancing perspectives on the off-label use of anticancer drugs: an updated classification and exploration of categories.

To date, the definition that the off-label usage of drugs refers to the unapproved use of approved drugs, which covers unapproved indications, patient populations, doses, and/or routes of administration, has been in existence for many years. Currently, there is a limited frequency and prevalence of research on the off-label use of antineoplastic drugs, mainly due to incomplete definition and classification issues. It is time to embrace new categories for the off-label usage of anticancer drugs. This review provided an insight into an updated overview of the concept and categories of the off-label use of anticancer drugs, along with illustrating specific examples to establish the next studies about the extent of the off-label usage of anticancer drugs in the oncology setting. The scope of the off-label use of current anticancer drugs beyond the previous definitions not only includes off-label uses in terms of indications, patient populations, doses, and/or routes of administration but also off-label use in terms of medication course, combination, sequence of medication, clinical purpose, contraindications scenarios, etc. In addition, the definition of the off-label usage of anticancer drugs should be added to the condition at a given time, and it varies from approval authorities. We presented a new and relatively comprehensive classification, providing extensive analysis and illustrative examples of the off-label usage of antineoplastic drugs for the first time. Such a classification has the potential to promote practical adoption and enhance management strategies for the off-label use of antitumor drugs.

Development of an engineered Bacillus subtilis strain for antibiotic-free sucrose isomerase production.

Sucrose isomerase (SIase) catalyzes the hydrolysis and isomerization of sucrose into isomaltulose, a functional sugar extensively used in the food industry. However, the lack of safe and efficient heterologous expression systems for SIase has constrained its production and application. In this study, an engineered Bacillus subtilis strain for antibiotic-free SIase production was developed via a food-grade expression system. First, the B. subtilis strain TEA was modified through the CRISPR/Cas9 system, resulting in a mutant strain TEA4, which exhibited enhanced capabilities for recombinant protein expression. For efficient and safe production of SIase, different constitutive and inducible promoters were evaluated. The maltose-inducible promoter Poglv was found to have an extracellular SIase activity of 21.7 U mL-1 in engineered strain TEA4. Subsequent optimization of the culture medium further increased SIase activity to 26.4 U mL-1 during shake flask cultivation. Eventually, using the crude enzyme solution of the engineered strain in biotransformation reactions resulted in a high yield of isomaltulose under high concentrations sucrose, achieving a maximum yield of 83.1%. These findings demonstrated an engineered B. subtilis strain for antibiotic-free SIase production, paving the way for its scale-up industrial production and application.

Objectivizing issues in the diagnosis of complex rare diseases: lessons learned from testing existing diagnosis support systems on ciliopathies.

BACKGROUND: There are approximately 8,000 different rare diseases that affect roughly 400 million people worldwide. Many of them suffer from delayed diagnosis. Ciliopathies are rare monogenic disorders characterized by a significant phenotypic and genetic heterogeneity that raises an important challenge for clinical diagnosis. Diagnosis support systems (DSS) applied to electronic health record (EHR) data may help identify undiagnosed patients, which is of paramount importance to improve patients' care. Our objective was to evaluate three online-accessible rare disease DSSs using phenotypes derived from EHRs for the diagnosis of ciliopathies. METHODS: Two datasets of ciliopathy cases, either proven or suspected, and two datasets of controls were used to evaluate the DSSs. Patient phenotypes were automatically extracted from their EHRs and converted to Human Phenotype Ontology terms. We tested the ability of the DSSs to diagnose cases in contrast to controls based on Orphanet ontology. RESULTS: A total of 79 cases and 38 controls were selected. Performances of the DSSs on ciliopathy real world data (best DSS with area under the ROC curve = 0.72) were not as good as published performances on the test set used in the DSS development phase. None of these systems obtained results which could be described as "expert-level". Patients with multisystemic symptoms were generally easier to diagnose than patients with isolated symptoms. Diseases easily confused with ciliopathy generally affected multiple organs and had overlapping phenotypes. Four challenges need to be considered to improve the performances: to make the DSSs interoperable with EHR systems, to validate the performances in real-life settings, to deal with data quality, and to leverage methods and resources for rare and complex diseases. CONCLUSION: Our study provides insights into the complexities of diagnosing highly heterogenous rare diseases and offers lessons derived from evaluation existing DSSs in real-world settings. These insights are not only beneficial for ciliopathy diagnosis but also hold relevance for the enhancement of DSS for various complex rare disorders, by guiding the development of more clinically relevant rare disease DSSs, that could support early diagnosis and finally make more patients eligible for treatment.

Identification of DNA methylation characteristics associated with metastasis and prognosis in colorectal cancer.

Colorectal cancer (CRC) is prone to metastasis and recurrence after surgery, which is one of the main causes for its poor treatment and prognosis. Therefore, it is essential to identify biomarkers associated with metastasis and recurrence in CRC. DNA methylation has a regulatory role in cancer metastasis, tumor immune microenvironment (TME), and prognosis and may be one of the most valuable biomarkers for predicting CRC metastasis and prognosis. We constructed a diagnostic model and nomogram that can effectively predict CRC metastasis based on the differential methylation CpG sites (DMCs) between metastatic and non-metastatic CRC patients. Then, we identified 17 DMCs associated with progression free survival (PFS) of CRC and constructed a prognostic model. The prognosis model based on 17 DMCs can predict the PFS of CRC with medium to high accuracy. The results of immunohistochemical analysis indicated that the protein expression levels of the genes involved in prognostic DMCs were different between normal and colorectal cancer tissues. According to the results of immune-related analysis, we found that the low-risk patients had better immunotherapy response. In addition, high risk scores were negatively correlated with high tumor mutation burden (TMB) levels, and patients with low TMB levels in the high-risk group had the worst PFS. Our work shows the clinical value of DNA methylation in predicting CRC metastasis and PFS, as well as their correlation with TME, immunotherapy, and TMB, which helps understand the changes of DNA methylation in CRC metastasis and improving the treatment and prognosis of CRC.

Predicting Left Ventricular Adverse Remodeling After Transcatheter Aortic Valve Replacement: A Radiomics Approach.

RATIONALE AND OBJECTIVES: To develop a radiomics model based on cardiac computed tomography (CT) for predicting left ventricular adverse remodeling (LVAR) in patients with severe aortic stenosis (AS) who underwent transcatheter aortic valve replacement (TAVR). MATERIALS AND METHODS: Patients with severe AS who underwent TAVR from January 2019 to December 2022 were recruited. The cohort was divided into adverse remodeling group and non-adverse remodeling group based on LVAR occurrence, and further randomly divided into a training set and a validation set at an 8:2 ratio. Left ventricular radiomics features were extracted from cardiac CT. The least absolute shrinkage and selection operator regression was utilized to select the most relevant radiomics features and clinical features. The radiomics features were used to construct the Radscore, which was then combined with the selected clinical features to build a nomogram. The predictive performance of the models was evaluated using the area under the curve (AUC), while the clinical value of the models was assessed using calibration curves and decision curve analysis. RESULTS: A total of 273 patients were finally enrolled, including 71 with adverse remodeling and 202 with non-adverse remodeling. 12 radiomics features and five clinical features were extracted to construct the radiomics model, clinical model, and nomogram, respectively. The radiomics model outperformed the clinical model (training AUC: 0.799 vs. 0.760; validation AUC: 0.766 vs. 0.755). The nomogram showed highest accuracy (training AUC: 0.859, validation AUC: 0.837) and was deemed most clinically valuable by decision curve analysis. CONCLUSION: The cardiac CT-based radiomics features could predict LVAR after TAVR in patients with severe AS.

[Prediction of quality markers of Angong Niuhuang Pills based on LC-MS and pull-down with SPR chips].

Elucidating the quality markers(Q-markers) of traditional Chinese medicines is essential for understanding the mechanisms of action and promoting the rational use of traditional Chinese medicines as well as for developing traditional Chinese medicine-derived drugs. Studies have shown that surface plasmon resonance(SPR) is promising in this field. This study proposed a method based on pull-down with SPR chips to predict the Q-markers of Angong Niuhuang pills(AGNHP). Firstly, 71 main chemical components of AGNHP were analyzed by UPLC-Q-TOF-MS, and then network pharmacology was employed to predict the potential targets of AGNHP against stroke. Secondly, the STAT3 protein chip was constructed, and the extract of AGNHP was recovered by pull-down of the SPR system for STAT3 ligand. The potential active ingredients were collected, enriched, and identified as coptisine, palmatine, epiberberine, berberine, worenine, demethyleneberberine, jatrorrhizine, tetrahydrocoptisine, baicalein, and baicalin methyl ester. Next, the affinity constants of the 10 active ingredients were determined as 44.7, 44, 58.1, 51.3, 39.7, 32.1, 49.2, 69.1, 19.7, and 24.9 µmol·L~(-1), respectively. The molecular docking results showed that the 10 compounds could compete for binding with STAT3. This is the first report that SPR combined with UPLC-Q-TOF-MS is reliable and feasible for determining the active ingredients of AGNHP at the molecular level from complex systems. STAT3 could be used as a potential target for the biological quality evaluation of AGNHP.

Mechanisms of Neuronal Reactivation in Memory Consolidation: A Perspective from Pathological Conditions.

Memory consolidation refers to a process by which labile newly formed memory traces are progressively strengthened into long term memories and become more resistant to interference. Recent work has revealed that spontaneous hippocampal activity during rest, commonly referred to as "offline" activity, plays a critical role in the process of memory consolidation. Hippocampal reactivation occurs during sharp-wave ripples (SWRs), which are events associated with highly synchronous neural firing in the hippocampus and modulation of neural activity in distributed brain regions. Memory consolidation occurs primarily through a coordinated communication between hippocampus and neocortex. Cortical slow oscillations drive the repeated reactivation of hippocampal memory representations together with SWRs and thalamo-cortical spindles, inducing long-lasting cellular and network modifications responsible for memory stabilization.In this review, we aim to comprehensively cover the field of "reactivation and memory consolidation" research by detailing the physiological mechanisms of neuronal reactivation and firing patterns during SWRs and providing a discussion of more recent key findings. Several mechanistic explanations of neuropsychiatric diseases propose that impaired neural replay may underlie some of the symptoms of the disorders. Abnormalities in neuronal reactivation are a common phenomenon and cause pathological impairment in several diseases, such as Alzheimer's disease (AD), epilepsy and schizophrenia. However, the specific pathological changes and mechanisms of reactivation in each disease are different. Recent work has also enlightened some of the underlying pathological mechanisms of neuronal reactivation in these diseases. In this review, we further describe how SWRs, ripples and slow oscillations are affected in Alzheimer's disease, epilepsy, and schizophrenia. We then compare the differences of neuronal reactivation and discuss how different reactivation abnormalities cause pathological changes in these diseases. Aberrant neural reactivation provides insights into disease pathogenesis and may even serve as biomarkers for early disease progression and treatment response.

Neural mechanisms of social comparison in subthreshold depression.

Social comparison is a common phenomenon in our daily life, through which people get to know themselves, and plays an important role in depression. In this study, event-related potential (ERP) was used to explore the temporal course of social comparison processing in the subthreshold depression group. Electrophysiological recordings were acquired from 30 subthreshold depressed individuals and 31 healthy individuals while they conducted the adapted dot estimation task. The ERP results revealed that there was a significant difference of feedback-related negativity (FRN) in the process of social comparison. Especially only in the subthreshold depression, the FRN amplitudes of worse off than some, better off than many comparisons were larger than those of upward comparisons and downward comparisons. Our results suggested that the abnormal reward sensitivity for worse off than some, better off than many comparisons might be prodromal symptoms in the subthreshold depression.

Direct synthesis of branched amines enabled by dual-catalyzed allylic C─H amination of alkenes with amines.

Direct conversion of hydrocarbons into amines represents an important and atom-economic goal in chemistry for decades. However, intermolecular cross-coupling of terminal alkenes with amines to form branched amines remains extremely challenging. Here, a visible-light and Co-dual catalyzed direct allylic C─H amination of alkenes with free amines to afford branched amines has been developed. Notably, challenging aliphatic amines with strong coordinating effect can be directly used as C─N coupling partner to couple with allylic C─H bond to form advanced amines with molecular complexity. Moreover, the reaction proceeds with exclusive regio- and chemoselectivity at more steric hinder position to deliver primary, secondary, and tertiary aliphatic amines with diverse substitution patterns that are difficult to access otherwise.

Targeted drug delivery of engineered mesenchymal stem/stromal-cell-derived exosomes in cardiovascular disease: recent trends and future perspectives.

In recent years, stem cells and their secretomes, notably exosomes, have received considerable attention in biomedical applications. Exosomes are cellular secretomes used for intercellular communication. They perform the function of intercellular messengers by facilitating the transport of proteins, lipids, nucleic acids, and therapeutic substances. Their biocompatibility, minimal immunogenicity, targetability, stability, and engineerable characteristics have additionally led to their application as drug delivery vehicles. The therapeutic efficacy of exosomes can be improved through surface modification employing functional molecules, including aptamers, antibodies, and peptides. Given their potential as targeted delivery vehicles to enhance the efficiency of treatment while minimizing adverse effects, exosomes exhibit considerable promise. Stem cells are considered advantageous sources of exosomes due to their distinctive characteristics, including regenerative and self-renewal capabilities, which make them well-suited for transplantation into injured tissues, hence promoting tissue regeneration. However, there are notable obstacles that need to be addressed, including immune rejection and ethical problems. Exosomes produced from stem cells have been thoroughly studied as a cell-free strategy that avoids many of the difficulties involved with cell-based therapy for tissue regeneration and cancer treatment. This review provides an in-depth summary and analysis of the existing knowledge regarding exosomes, including their engineering and cardiovascular disease (CVD) treatment applications.

New Diterpenes and Diterpene Glycosides with Antibacterial Activity from Soft Coral Lemnalia bournei.

Five new biflorane-type diterpenoids, biofloranates E-I (1-5), and two new bicyclic diterpene glycosides, lemnaboursides H-I (6-7), along with the known lemnabourside, were isolated from the South China Sea soft coral Lemnalia bournei. Their chemical structures and stereochemistry were determined based on extensive spectroscopic methods, including time-dependent density functional theory (TDDFT) ECD calculations, as well as a comparison of them with the reported values. The antibacterial activities of the isolated compounds were evaluated against five pathogenic bacteria, and all of these diterpenes and diterpene glycosides showed antibacterial activities against Staphylococcus aureus and Bacillus subtilis, with MICs ranging from 4 to 64 µg/mL. In addition, these compounds did not exhibit noticeable cytotoxicities on A549, Hela, and HepG2 cancer cell lines, at 20 µM.

The pleiotropic phenotype of FlbA of Aspergillus niger is explained in part by the activity of seven of its downstream-regulated transcription factors.

Inactivation of flbA in Aspergillus niger results in thinner cell walls, increased cell lysis, abolished sporulation, and an increased secretome complexity. A total of 36 transcription factor (TF) genes are differentially expressed in ΔflbA. Here, seven of these genes (abaA, aslA, aslB, azf1, htfA, nosA, and srbA) were inactivated. Inactivation of each of these genes affected sporulation and, with the exception of abaA, cell wall integrity and protein secretion. The impact on secretion was strongest in the case of ΔaslA and ΔaslB that showed increased pepsin, cellulase, and amylase activity. Biomass was reduced of agar cultures of ΔabaA, ΔaslA, ΔnosA, and ΔsrbA, while biomass was higher in liquid shaken cultures of ΔaslA and ΔaslB. The ΔaslA and ΔhtfA strains showed increased resistance to H2O2, while ΔaslB was more sensitive to this reactive oxygen species. Together, inactivation of the seven TF genes impacted biomass formation, sporulation, protein secretion, and stress resistance, and thereby these genes explain at least part of the pleiotropic phenotype of ΔflbA of A. niger.