Dosing Strategies and Quantitative Clinical Pharmacology for Bispecific T-Cell Engagers Development in Oncology.

Bispecific T-cell Engagers (TCEs) are promising anti-cancer treatments that bind to both the CD3 receptors on T cells and an antigen on the surface of tumor cells, creating an immune synapse, leading to killing of malignant tumor cells. These novel therapies have unique development challenges, with specific safety risks of cytokine release syndrome. These on-target adverse events fortunately can be mitigated and deconvoluted from efficacy via innovative dosing strategies, making clinical pharmacology key in the development of these therapies. This review assesses dose selection and the role of quantitative clinical pharmacology in the development of the first eight approved TCEs. Model informed drug development (MIDD) strategies can be used at every stage to guide TCE development. Mechanistic modeling approaches allow for (1) efficacious yet safe first-in-human dose selection as compared with in vitro minimum anticipated biological effect level (MABEL) approach; (2) rapid escalation and reducing number of patients with subtherapeutic doses through model-based adaptive design; (3) virtual testing of different step-up dosing regimens that may not be feasible to be evaluated in the clinic; and (4) selection and justification of the optimal clinical step-up and full treatment doses. As the knowledge base around TCEs continues to grow, the relevance and utilization of MIDD strategies for supporting the development and dose optimization of these molecules are expected to advance, optimizing the benefit-risk profile for cancer patients.

KOH-activated hollow carbon spheres with surface functionalization for high-capacity and long-cycle-life lithium-selenium batteries.

Lithium-selenium (Li-Se) batteries are considered promising alternatives to lithium-ion batteries due to their higher volumetric capacity and energy density. However, they still face limitations in efficiently utilizing the active selenium. Here, we develop surface-functionalized mesoporous hollow carbon nanospheres as the selenium host. By using KOH activation, the surface of the carbon nanospheres is functionalized with hydroxyl groups, which greatly improve the utilization of selenium and facilitate the conversion of lithium selenides, leading to much higher capacities compared to ZnCl2 activation and untreated carbon nanospheres. Theory and experimental evidence suggest that surface hydroxyl groups can enhance the reduction conversion of polyselenides to selenides and facilitate the oxidation reaction of selenides to elemental selenium. In-situ and ex-situ characterization techniques provided additional confirmation of the hydroxyl groups electrochemical durability in catalyzing selenium conversion. The meticulously engineered Se cathode demonstrates a high specific capacity of 594 mA h g-1 at 0.5C, excellent rate capability of 464 mA h g-1 at 2C, and a stable cycling performance of 500 cycles at 2C with a capacity retention of 84.8 %, corresponding to an ultra-low-capacity decay rate of 0.0144 % per cycle, surpassing many reported lithium-selenium battery technologies.

A new subtype of artificial cell-derived vesicles from dental pulp stem cells with the bioequivalence and higher acquisition efficiency compared to extracellular vesicles.

Extracellular vesicles (EVs) derived from dental pulp stem cells (DPSC) have been shown an excellent efficacy in a variety of disease models. However, current production methods fail to meet the needs of clinical treatment. In this study, we present an innovative approach to substantially enhance the production of 'Artificial Cell-Derived Vesicles (ACDVs)' by extracting and purifying the contents released by the DPSC lysate, namely intracellular vesicles. Comparative analysis was performed between ACDVs and those obtained through ultracentrifugation. The ACDVs extracted from the cell lysate meet the general standard of EVs and have similar protein secretion profile. The new ACDVs also significantly promoted wound healing, increased or decreased collagen regeneration, and reduced the production of inflammatory factors as the EVs. More importantly, the extraction efficiency is improved by 16 times compared with the EVs extracted using ultracentrifuge method. With its impressive attributes, this new subtype of ACDVs emerge as a prospective candidate for the future clinical applications in regenerative medicine.

The Effect of Colloids versus Crystalloids for Goal-Directed Fluid Therapy on Prognosis in Patients Undergoing Noncardiac Surgery: A Meta-Analysis of Randomized Controlled Trials.

Background: Goal-directed fluid therapy (GDFT) contributes to improvements in intraoperative fluid infusion based on objective parameters and has been widely recommended in clinical practice. In addition, increasing evidence reveals that GDFT can improve the prognosis of surgical patients. However, considering the individual characteristics of colloids and crystalloids in clinical use, it is uncertain as to which type of fluids administered is associated with better outcomes in the condition of GDFT. Objectives: To evaluate the effect of colloids versus crystalloids under GDFT on prognosis in patients undergoing noncardiac surgery. Data Sources. Randomized controlled trials (RCTs) from PubMed, EMBASE, Ovid MEDLINE, CNKI, Cochrane library, and reference lists of relevant articles. Methods: Two investigators independently screened and reviewed studies for inclusion and performed data extraction. Our primary outcome was a composite of postoperative complications. The secondary outcomes were (1) mortality at the follow-up duration; (2) postoperative complications of several organ systems, including cardiac, pulmonary, digestive, urinary, nervous system, and postoperative infection events; and (3) hospital and ICU length of stay. Heterogeneity was assessed by the I 2 and chi-square tests. The odds ratio (OR) of the dichotomous data, mean difference (MD) of continuous data, and 95% confidence intervals (CI) were calculated to assess the pooled data. Results: Of 332 articles retrieved, 15 RCTs (involving 2,956 patients undergoing noncardiac surgery) were included in the final analysis. When the data were pooled, patients in the colloids and crystalloids group revealed no difference in postoperative composite complications (OR = 0.84, 95% CI = 0.51-1.38, P=0.49) under GDFT. Regarding the secondary outcomes, patients in the colloids group were associated with fewer digestive system complications (OR = 0.64, 95% CI = 0.41-0.98, P=0.04). However, no difference was found in mortality (OR = 1.37, 95% CI = 0.72-2.58, P=0.34), complications of the cardiac system (OR = 1.49, 95% CI = 0.66-3.37, P=0.34), pulmonary system (OR = 0.89, 95% CI = 0.62-1.28, P=0.53), urinary system (OR = 1.05, 95% CI = 0.61-1.80, P=0.87), nervous system (OR = 1.04, 95% CI = 0.55-1.98, P=0.90), postoperative infection events (OR = 0.89, 95% CI = 0.75-1.07, P=0.22), length of hospital stay (difference in mean = -0.71, 95% CI = -1.49-0.07, P=0.07), and ICU stay (difference in mean = -0.01, 95% CI = -0.20-0.18, P=0.95) between patients receiving GDFT with colloids or crystalloids. Conclusion: There is no evidence of a benefit in using colloids over crystalloids under GDFT in patients undergoing noncardiac surgery, despite its use resulting in lower digestive system complications.

State Estimation for Markovian Jump Neural Networks Under Probabilistic Bit Flips: Allocating Constrained Bit Rates.

In this article, the state estimation problem is studied for Markovian jump neural networks (MJNNs) within a digital network framework. The wireless communication channel with limited bandwidth is characterized by a constrained bit rate, and the occurrence of bit flips during wireless transmission is mathematically modeled. A transmission mechanism, which includes coding-decoding under bit-rate constraints and considers probabilistic bit flips, is introduced, providing a thorough characterization of the digital transmission process. A mode-dependent remote estimator is designed, which is capable of effectively capturing the internal state of the neural network. Furthermore, a sufficient condition is proposed to ensure the estimation error to remain bounded under challenging network conditions. Within this theoretical framework, the relationship between the neural network's estimation performance and the bit rate is explored. Finally, a simulation example is provided to validate the theoretical findings.

MCDHGN: heterogeneous network-based cancer driver gene prediction and interpretability analysis.

MOTIVATION: Accurately predicting the driver genes of cancer is of great significance for carcinogenesis progress research and cancer treatment. In recent years, more and more deep-learning-based methods have been used for predicting cancer driver genes. However, deep-learning algorithms often have black box properties and cannot interpret the output results. Here, we propose a novel cancer driver gene mining method based on heterogeneous network meta-paths (MCDHGN), which uses meta-path aggregation to enhance the interpretability of predictions. RESULTS: MCDHGN constructs a heterogeneous network by using several types of multi-omics data that are biologically linked to genes. And the differential probabilities of SNV, DNA methylation, and gene expression data between cancerous tissues and normal tissues are extracted as initial features of genes. Nine meta-paths are manually selected, and the representation vectors obtained by aggregating information within and across meta-path nodes are used as new features for subsequent classification and prediction tasks. By comparing with eight homogeneous and heterogeneous network models on two pan-cancer datasets, MCDHGN has better performance on AUC and AUPR values. Additionally, MCDHGN provides interpretability of predicted cancer driver genes through the varying weights of biologically meaningful meta-paths. AVAILABILITY AND IMPLEMENTATION: https://github.com/1160300611/MCDHGN.

Oral vaccination with a recombinant Lactobacillus plantarum expressing the Eimeria tenella rhoptry neck 2 protein elicits protective immunity in broiler chickens infected with Eimeria tenella.

BACKGROUND: Chicken coccidiosis is a protozoan disease that leads to considerable economic losses in the poultry industry. Live oocyst vaccination is currently the most effective measure for the prevention of coccidiosis. However, it provides limited protection with several drawbacks, such as poor immunological protection and potential reversion to virulence. Therefore, the development of effective and safe vaccines against chicken coccidiosis is still urgently needed. METHODS: In this study, a novel oral vaccine against Eimeria tenella was developed by constructing a recombinant Lactobacillus plantarum (NC8) strain expressing the E. tenella RON2 protein. We administered recombinant L. plantarum orally at 3, 4 and 5 days of age and again at 17, 18 and 19 days of age. Meanwhile, each chick in the commercial vaccine group was immunized with 3 × 102 live oocysts of coccidia. A total of 5 × 104 sporulated oocysts of E. tenella were inoculated in each chicken at 30 days. Then, the immunoprotection effect was evaluated after E. tenella infection. RESULTS: The results showed that the proportion of CD4+ and CD8+ T cells, the proliferative ability of spleen lymphocytes, inflammatory cytokine levels and specific antibody titers of chicks immunized with recombinant L. plantarum were significantly increased (P < 0.05). The relative body weight gains were increased and the number of oocysts per gram (OPG) was decreased after E. tenella challenge. Moreover, the lesion scores and histopathological cecum sections showed that recombinant L. plantarum can significantly relieve pathological damage in the cecum. The ACI was 170.89 in the recombinant L. plantarum group, which was higher than the 150.14 in the commercial vaccine group. CONCLUSIONS: These above results indicate that L. plantarum expressing RON2 improved humoral and cellular immunity and enhanced immunoprotection against E. tenella. The protective efficacy was superior to that of vaccination with the commercial live oocyst vaccine. This study suggests that recombinant L. plantarum expressing the RON2 protein provides a promising strategy for vaccine development against coccidiosis.

Bacillus halotolerans attenuates inflammation induced by enterotoxigenic Escherichia coli infection in vivo and in vitro based on its metabolite soyasaponin I regulating the p105-Tpl2-ERK pathway.

Soyasaponins, recognized for their anti-inflammatory and antioxidant effects, have not yet been fully explored for their role in combating enterotoxigenic Escherichia coli (ETEC) infections. Recent findings identified them in small-molecule metabolites of Bacillus, suggesting their broader biological relevance. This research screened 88 strains of B. halotolerans, identifying the strain BH M20221856 as significantly inhibitory against ETEC growth in vitro. It also reduced cellular damage and inflammatory response in IPEC-J2 cells. The antimicrobial activity of BH M20221856 was attributed to its small-molecule metabolites rather than secretory proteins. A total of 69 small molecules were identified from the metabolites of BH M20221856 using liquid chromatography mass spectrometry/mass spectrometry (LC-MS/MS). Among these, soyasaponin I (SoSa I) represented the largest multiple change in the enrichment analysis of differential metabolites and exhibited potent anti-ETEC effects in vivo. It significantly reduced the bacterial load of E. coli in mouse intestines, decreased serum endotoxin, D-lactic acid, and oxidative stress levels and alleviated intestinal pathological damage and inflammation. SoSa I enhanced immune regulation by mediating the p105-Tpl2-ERK signaling pathway. Further evaluations using transepithelial electrical resistance (TEER) and cell permeability assays showed that SoSa I alleviated ETEC-induced damage to epithelial barrier function. These results suggest that BH M20221856 and SoSa I may serve as preventative biologics against ETEC infections, providing new insights for developing strategies to prevent and control this disease.

High-entropy alloy electrocatalysts go to (sub-)nanoscale.

Alloying has proven power to upgrade metallic electrocatalysts, while the traditional alloys encounter limitation for optimizing electronic structures of surface metallic sites in a continuous manner. High-entropy alloys (HEAs) overcome this limitation by manageably tuning the adsorption/desorption energies of reaction intermediates. Recently, the marriage of nanotechnology and HEAs has made considerable progresses for renewable energy technologies, showing two important trends of size diminishment and multidimensionality. This review is dedicated to summarizing recent advances of HEAs that are rationally designed for energy electrocatalysis. We first explain the advantages of HEAs as electrocatalysts from three aspects: high entropy, nanometer, and multidimension. Then, several structural regulation methods are proposed to promote the electrocatalysis of HEAs, involving the thermodynamically nonequilibrium synthesis, regulating the (sub-)nanosize and anisotropic morphologies, as well as engineering the atomic ordering. The general relationship between the electronic structures and electrocatalytic properties of HEAs is further discussed. Finally, we outline remaining challenges of this field, aiming to inspire more sophisticated HEA-based nanocatalysts.

Insights into the role of mesenchymal stem cells in cutaneous medical aesthetics: from basics to clinics.

With the development of the economy and the increasing prevalence of skin problems, cutaneous medical aesthetics are gaining more and more attention. Skin disorders like poor wound healing, aging, and pigmentation have an impact not only on appearance but also on patients with physical and psychological issues, and even impose a significant financial burden on families and society. However, due to the complexities of its occurrence, present treatment options cannot produce optimal outcomes, indicating a dire need for new and effective treatments. Mesenchymal stem cells (MSCs) and their secretomics treatment is a new regenerative medicine therapy that promotes and regulates endogenous stem cell populations and/or replenishes cell pools to achieve tissue homeostasis and regeneration. It has demonstrated remarkable advantages in several skin-related in vivo and in vitro investigations, aiding in the improvement of skin conditions and the promotion of skin aesthetics. As a result, this review gives a complete description of recent scientific breakthroughs in MSCs for skin aesthetics and the limitations of their clinical applications, aiming to provide new ideas for future research and clinical transformation.

Response of chlorophyll-a to rainfall event in the basin of the South China sea: Statistical analysis.

Chlorophyll-a (Chl-a) is an essential ecological indicator, and affected by processes such as typhoons, mesoscale eddies, and Rossby waves. However, the impact of more frequent and widespread precipitation events on Chl-a seems to be overlooked. This study utilized remote sensing data and reanalysis data to investigate the response of Chl-a to 240 precipitation events in the central South China Sea from 2005 to 2019. The results indicate that precipitation events have a significant impact on Chl-a concentration. Following a precipitation event in 2019, the Chl-a concentration in the affected area increased by approximately 0.22 mg m-³ from the 3rd to the 7th day. The reasons for the increase in Chl-a concentration were the vertical mixing induced by wind stirring and the upwelling caused by wind stress curl, which transported nutrients to the euphotic zone, lowering the sea surface temperature and triggering a proliferation of phytoplankton. Additionally, dissolved nutrients in precipitation provided a nutrient source for Chl-a growth. The contributions of nutrient supply, wind speed, and wind stress curl to the increase in Chl-a concentration during precipitation events were 18%, 37%, and 45%, respectively. Precipitation events enhanced marine primary productivity, playing a crucial role in deepening our understanding of ocean-atmosphere interactions and their impact on marine ecosystem.

Effects of Intrinsic Defects in Pt-Based Carbon Supports on Alkaline Hydrogen Evolution Reaction.

Carbon material has widely been utilized in the synthesis of efficient carbon-supported Pt (Pt/C) catalysts, in which the structural properties greatly influence the electrocatalytic performances of Pt/C catalysts. However, the effects of intrinsic defects in carbon supports on the performance of the alkaline hydrogen evolution reaction (HER) have not been systematically investigated. Herein, porous carbon supports with different degrees of intrinsic defects were prepared by a simple template-assisted strategy, and the resulting samples were systematically studied by various analytical methods. The results suggested that the presence of abundant intrinsic defects (vacancy and topological defects) in the carbon support was advantageous in terms of favoring the dispersion and anchoring of Pt species, promoting electron transfer between Pt atoms and the carbon support, and tuning the electronic states of Pt species. These features improved the HER performance of Pt/C catalysts. Compared to the nontemplate-assisted carbon-supported Pt catalyst (Pt/NTC) with an overpotential of 178 mV, the optimized template-assisted carbon-supported Pt catalyst (Pt/TC) exhibited a lower overpotential of 58 mV at 10 mA cm-2. Besides, the Pt/TC catalyst displayed better HER durability than the Pt/NTC catalyst owing to its strong metal-support interaction. The DFT calculations confirmed the important role played by intrinsic defects (vacancy and topological defects) in stabilizing Pt atoms, with Pt-C3 coordination identified as the most favorable structure for improving the HER performance of Pt. Overall, novel insights on the significant contribution of intrinsic defects in porous carbon supports on the HER performances of Pt/C catalysts were provided, useful for future design and fabrication of advanced carbon-supported catalysts or other carbon-based electrode materials.

Deciphering anoikis resistance and identifying prognostic biomarkers in clear cell renal cell carcinoma epithelial cells.

This study tackles the persistent prognostic and management challenges of clear cell renal cell carcinoma (ccRCC), despite advancements in multimodal therapies. Focusing on anoikis, a critical form of programmed cell death in tumor progression and metastasis, we investigated its resistance in cancer evolution. Using single-cell RNA sequencing from seven ccRCC patients, we assessed the impact of anoikis-related genes (ARGs) and identified differentially expressed genes (DEGs) in Anoikis-related epithelial subclusters (ARESs). Additionally, six ccRCC RNA microarray datasets from the GEO database were analyzed for robust DEGs. A novel risk prognostic model was developed through LASSO and multivariate Cox regression, validated using BEST, ULCAN, and RT-PCR. The study included functional enrichment, immune infiltration analysis in the tumor microenvironment (TME), and drug sensitivity assessments, leading to a predictive nomogram integrating clinical parameters. Results highlighted dynamic ARG expression patterns and enhanced intercellular interactions in ARESs, with significant KEGG pathway enrichment in MYC + Epithelial subclusters indicating enhanced anoikis resistance. Additionally, all ARESs were identified in the spatial context, and their locational relationships were explored. Three key prognostic genes-TIMP1, PECAM1, and CDKN1A-were identified, with the high-risk group showing greater immune infiltration and anoikis resistance, linked to poorer prognosis. This study offers a novel ccRCC risk signature, providing innovative approaches for patient management, prognosis, and personalized treatment.

Polyhedral {Ag12} and {Ag16} Clusters: Synthesis, Structural Characterization and Third-Order Nonlinear Optical Properties.

Two polyhedral silver-thiolate clusters, [S@Ag16(Tab)10(MeCN)8](PF6)14 (Ag16) and [Ag12(Tab)6(DMF)12](PF6)12 (Ag12), were synthesized by using electroneutral Tab species as protective ligands (Tab=4-(trimethylammonio)benzenethiolate, DMF=N,N-dimethylformamide, MeCN=acetonitrile). Ag16 has a decahedral shape composed of eight pentagon {Ag5} units and two square {Ag4} units. The structure of Ag12 is a cuboctahedron, a classical Archimedean structure composed of six triangular faces and eight square faces. The former configuration is discovered in silver-thiolate cluster for the first time, possibly benefited from the more flexible coordination between the Tab ligand and Ag+ facilitated by the electropositive -N(CH3)3 + substituent group. Third-order nonlinear optical studies show that both clusters in DMF exhibit reverse saturate absorption response under the irradiation of 532 nm laser.

DIRMC: a database of immunotherapy-related molecular characteristics.

Cancer immunotherapy has brought about a revolutionary breakthrough in the field of cancer treatment. Immunotherapy has changed the treatment landscape for a variety of solid and hematologic malignancies. To assist researchers in efficiently uncovering valuable information related to cancer immunotherapy, we have presented a manually curated comprehensive database called DIRMC, which focuses on molecular features involved in cancer immunotherapy. All the content was collected manually from published literature, authoritative clinical trial data submitted by clinicians, some databases for drug target prediction such as DrugBank, and some experimentally confirmed high-throughput data sets for the characterization of immune-related molecular interactions in cancer, such as a curated database of T-cell receptor sequences with known antigen specificity (VDJdb), a pathology-associated TCR database (McPAS-TCR) et al. By constructing a fully connected functional network, ranging from cancer-related gene mutations to target genes to translated target proteins to protein regions or sites that may specifically affect protein function, we aim to comprehensively characterize molecular features related to cancer immunotherapy. We have developed the scoring criteria to assess the reliability of each MHC-peptide-T-cell receptor (TCR) interaction item to provide a reference for users. The database provides a user-friendly interface to browse and retrieve data by genes, target proteins, diseases and more. DIRMC also provides a download and submission page for researchers to access data of interest for further investigation or submit new interactions related to cancer immunotherapy targets. Furthermore, DIRMC provides a graphical interface to help users predict the binding affinity between their own peptide of interest and MHC or TCR. This database will provide researchers with a one-stop resource to understand cancer immunotherapy-related targets as well as data on MHC-peptide-TCR interactions. It aims to offer reliable molecular characteristics support for both the analysis of the current status of cancer immunotherapy and the development of new immunotherapy. DIRMC is available at http://www.dirmc.tech/. Database URL: http://www.dirmc.tech/.

Target Cell Extraction and Spectrum-Effect Relationship Coupled with BP Neural Network Classification for Screening Potential Bioactive Components in Ginseng Extract with a Protective Effect against Myocardial Damage.

Cardiovascular disease has become a common ailment that endangers human health, having garnered widespread attention due to its high prevalence, recurrence rate, and sudden death risk. Ginseng possesses functions such as invigorating vital energy, enhancing vein recovery, promoting body fluid and blood nourishment, calming the nerves, and improving cognitive function. It is widely utilized in the treatment of various heart conditions, including palpitations, chest pain, heart failure, and other ailments. Although numerous research reports have investigated the cardiovascular activity of single ginsenoside, there remains a lack of systematic research on the specific components group that predominantly contribute to cardiovascular efficacy in ginseng medicinal materials. In this research, the spectrum-effect relationship, target cell extraction, and BP neural network classification were used to establish a rapid screening system for potential active substances. The results show that red ginseng extract (RGE) can improve the decrease in cell viability and ATP content and inhibit the increase in ROS production and LDH release in OGD-induced H9c2 cells. A total of 70 ginsenosides were identified in RGE using HPLC-Q-TOF-MS/MS analysis. Chromatographic fingerprints were established for 12 batches of RGE by high-performance liquid chromatography (HPLC). A total of 36 common ingredients were found in 12 batches of RGE. The cell viability, ATP, ROS, and LDH of 12 batches RGE were tested to establish gray relationship analysis (GRA) and partial least squares discrimination analysis (PLS-DA). BP neural network classification and target cell extraction were used to narrow down the scope of Spectral efficiency analysis and screen the potential active components. According to the cell experiments, RGE can improve the cell viability and ATP content and reduce the oxidative damage. Then, seven active ingredients, namely, Ginsenoside Rg1, Rg2, Rg3, Rb1, Rd, Re, and Ro, were screened out, and their cardiovascular activity was confirmed in the OGD model. The seven ginsenosides were the main active substances of red ginseng in treating myocardial injury. This study offers a reference for quality control in red ginseng and preparations containing red ginseng for the management of cardiovascular diseases. It also provides ideas for screening active ingredients of the same type of multi-pharmacologically active traditional Chinese medicines.

Neoagarotetraose Alleviates Atherosclerosis via Modulating Cholesterol and Bile Acid Metabolism in ApoE-/- Mice.

Atherosclerosis is closely associated with metabolic disorders such as cholesterol accumulation, bile acid metabolism, and gut dysbiosis. Neoagarotetraose supplementation has been shown to inhibit obesity and alleviate type 2 diabetes, but its effects on modulating the development of atherosclerosis remain unexplored. Therefore, the present study was conducted to investigate the protective effects and potential mechanisms of neoagarotetraose on high-fat, high-cholesterol diet (HFHCD)-induced atherosclerosis in ApoE-/- mice. The results showed that neoagarotetraose supplementation decreased the atherosclerotic lesion area by 50.1% and the aortic arch lesion size by 80.4% compared to the HFHCD group. Furthermore, neoagarotetraose supplementation led to a significant reduction in hepatic lipid content, particularly non-high-density lipoprotein cholesterol. It also resulted in a substantial increase in total bile acid content in both urine and fecal samples by 3.0-fold and 38.7%, respectively. Moreover, neoagarotetraose supplementation effectively downregulated the intestinal farnesoid X receptor by 35.8% and modulated the expressions of its associated genes in both the liver and intestine. In addition, correlation analysis revealed strong associations between gut microbiota composition and fecal bile acid levels. These findings highlight the role of gut microbiota in neoagarotetraose-mitigating atherosclerosis in HFHCD-fed ApoE-/- mice. This study indicates the potential of neoagarotetraose as a functional dietary supplement for the prevention of atherosclerosis.

Genome-wide identification and analysis of the cotton ALDH gene family.

BACKGROUND: Aldehyde dehydrogenases (ALDHs) are a family of enzymes that catalyze the oxidation of aldehyde molecules into the corresponding carboxylic acid, regulate the balance of aldehydes and protect plants from the poisoning caused by excessive accumulation of aldehydes; however, this gene family has rarely been studied in cotton. RESULTS: In the present study, genome-wide identification was performed, and a total of 114 ALDH family members were found in three cotton species, Gossypium hirsutum, Gossypium arboreum and Gossypium raimondii. The ALDH genes were divided into six subgroups by evolutionary analysis. ALDH genes in the same subgroup showed similar gene structures and conserved motifs, but some genes showed significant differences, which may result in functional differences. Chromosomal location analysis and selective pressure analysis revealed that the ALDH gene family had experienced many fragment duplication events. Cis-acting element analysis revealed that this gene family may be involved in the response to various biotic and abiotic stresses. The RT‒qPCR results showed that the expression levels of some members of this gene family were significantly increased under salt stress conditions. Gohir.A11G040800 and Gohir.D06G046200 were subjected to virus-induced gene silencing (VIGS) experiments, and the sensitivity of the silenced plants to salt stress was significantly greater than that of the negative control plants, suggesting that Gohir.A11G040800 and Gohir.D06G046200 may be involved in the response of cotton to salt stress. CONCLUSIONS: In total, 114 ALDH genes were identified in three Gossypium species by a series of bioinformatics analysis. Gene silencing of the ALDH genes of G. hirsutum revealed that ALDH plays an important role in the response of cotton to salt stress.

Ent-eudesmane sesquiterpenoids with anti-neuroinflammatory activity from the marine-derived fungus Eutypella sp. F0219.

In this study, twenty-three ent-eudesmane sesquiterpenoids (1-23) including fifteen previously undescribed ones, named eutypelides A-O (1-15) were isolated from the marine-derived fungus Eutypella sp. F0219. Their planar structures and relative configurations were established by HR-ESIMS and extensive 1D and 2D NMR investigations. The absolute configurations of the previously undescribed compounds were determined by single-crystal X-ray diffraction analyses, modified Mosher's method, and ECD calculations. Structurally, eutypelide A (1) is a rare 1,10-seco-ent-eudesmane, whereas 2-15 are typically ent-eudesmanes with 6/6/-fused bicyclic carbon nucleus. The anti-neuroinflammatory activity of all isolated compounds (1-23) was accessed based on their ability to NO production in LPS-stimulated BV2 microglia cells. Compound 16 emerged as the most potent inhibitor. Further mechanistic investigation revealed that compound 16 modulated the inflammatory response by decreasing the protein levels of iNOS and increasing ARG 1 levels, thereby altering the iNOS/ARG 1 ratio and inhibiting macrophage polarization. qRT-PCR analysis showed that compound 16 reversed the LPS-induced upregulation of pro-inflammatory cytokines, including iNOS, TNF-α, IL-6, and IL-1ß, at both the transcriptional and translational levels. These effects were linked to the inhibition of the NF-κB pathway, a key regulator of inflammation. Our findings suggest that compound 16 may be a potential structure basis for developing neuroinflammation-related disease therapeutic agents.

Human dental pulp stem cells mitigate the neuropathology and cognitive decline via AKT-GSK3ß-Nrf2 pathways in Alzheimer's disease.

Oxidative stress is increasingly recognized as a major contributor to the pathophysiology of Alzheimer's disease (AD), particularly in the early stages of the disease. The multiplicity advantages of stem cell transplantation make it fascinating therapeutic strategy for many neurodegenerative diseases. We herein demonstrated that human dental pulp stem cells (hDPSCs) mediated oxidative stress improvement and neuroreparative effects in in vitro AD models, playing critical roles in regulating the polarization of hyperreactive microglia cells and the recovery of damaged neurons. Importantly, these therapeutic effects were reflected in 10-month-old 3xTg-AD mice after a single transplantation of hDPSCs, with the treated mice showing significant improvement in cognitive function and neuropathological features. Mechanistically, antioxidant and neuroprotective effects, as well as cognitive enhancements elicited by hDPSCs, were at least partially mediated by Nrf2 nuclear accumulation and downstream antioxidant enzymes expression through the activation of the AKT-GSK3ß-Nrf2 signaling pathway. In conclusion, our findings corroborated the neuroprotective capacity of hDPSCs to reshape the neuropathological microenvironment in both in vitro and in vivo AD models, which may be a tremendous potential therapeutic candidate for Alzheimer's disease.