The discovery of regional neurotoxicity-associated metabolic alterations induced by carbon quantum dots in brain of mice using a spatial metabolomics analysis.

BACKGROUND: Recently, carbon quantum dots (CQDs) have been widely used in various fields, especially in the diagnosis and therapy of neurological disorders, due to their excellent prospects. However, the associated inevitable exposure of CQDs to the environment and the public could have serious severe consequences limiting their safe application and sustainable development. RESULTS: In this study, we found that intranasal treatment of 5 mg/kg BW (20 µL/nose of 0.5 mg/mL) CQDs affected the distribution of multiple metabolites and associated pathways in the brain of mice through the airflow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) technique, which proved effective in discovery has proven to be significantly alerted and research into tissue-specific toxic biomarkers and molecular toxicity analysis. The neurotoxic biomarkers of CQDs identified by MSI analysis mainly contained aminos, lipids and lipid-like molecules which are involved in arginine and proline metabolism, biosynthesis of unsaturated fatty acids, and glutamine and glutamate metabolism, etc. as well as related metabolic enzymes. The levels or expressions of these metabolites and enzymes changed by CQDs in different brain regions would induce neuroinflammation, organelle damage, oxidative stress and multiple programmed cell deaths (PCDs), leading to neurodegeneration, such as Parkinson's disease-like symptoms. This study enlightened risk assessments and interventions of QD-type or carbon-based nanoparticles on the nervous system based on toxic biomarkers regarding region-specific profiling of altered metabolic signatures. CONCLUSION: These findings provide information to advance knowledge of neurotoxic effects of CQDs and guide their further safety evaluation.

Chitosan modified with PAP as a promising delivery system for melatonin in the treatment of osteoporosis: targeting the divalent metal transporter 1.

The demands for novel and efficient therapies have gradually increased with the rising concerns of osteoporosis (OP). The most popular method in promoting bone regeneration during osteoporotic conditions consists of loading bioactive materials with different drugs to treat osteoporotic bones by either promoting the process of osteogenesis, or by inhibiting the activity of osteoclasts. By analyzing single cell sequencing results, we found that divalent metal transporter 1 (DMT1) played a role in OP. Based on our previous results, we found that melatonin (MT) suppressed expression of DMT1 induced by high glucose during OP, so we determined the efficacy of MT for the treatment of OP. However, the clinical effects of MT on OP were unsatisfactory. To enhance its biological efficacy, we combined MT with porous gelatin chitosan (chitosan) and the conductive material, PLA-b-AP-b-PLA (PAP), then determined how MT incorporation in chitosan@PAP nanoparticles affected the ability to promote MC3T3-E1 osteogenesis and mineralization, both in vitro and in vivo. The results confirmed the effect of MT on DMT1. We then prepared and characterized composites prepared as nanofibers, and determined the efficacy of MT combined with chitosan-PAP modified hydrogels as a slow-release system in a femur model of osteoporosis mice, with associated properties suitable for bone tissue engineering. The results indicated that MT-loaded chitosan@PAP nanospheres showed favorable osteogenic functions, both in vivo and in vitro, providing a practical solution for bone regeneration for OP patients.

Differences in physicochemical properties of pectin extracted from pomelo peel with different extraction techniques.

In order to obtain high yield pomelo peel pectin with better physicochemical properties, four pectin extraction methods, including hot acid extraction (HAE), microwave-assisted extraction (MAE), ultrasound-assisted extraction, and enzymatic assisted extraction (EAE) were compared. MAE led to the highest pectin yield (20.43%), and the lowest pectin recovery was found for EAE (11.94%). The physicochemical properties of pomelo peel pectin obtained by different methods were also significantly different. Pectin samples obtained by MAE had the highest methoxyl content (8.35%), galacturonic acid content (71.36%), and showed a higher apparent viscosity, thermal and emulsion stability. The pectin extracted by EAE showed the highest total phenolic content (12.86%) and lowest particle size (843.69 nm), showing higher DPPH and ABTS scavenging activities than other extract methods. The pectin extracted by HAE had the highest particle size (966.12 nm) and degree of esterification (55.67%). However, Fourier-transform infrared spectroscopy showed that no significant difference occurred among the different methods in the chemical structure of the extracted pectin. This study provides a theoretical basis for the industrial production of pomelo peel pectin.

Prognosis of immune checkpoint inhibitor-induced myasthenia gravis: a single center experience and systematic review.

Background: Immune checkpoint inhibitors (ICI)-induced myasthenia gravis (MG) is an uncommon but potentially fatal neurotoxicity. We aim to help physicians familiarize themselves with the clinical characteristics of ICI-induced MG, facilitating early diagnosis and prompt intervention. Methods: We searched the Chinese People's Liberation Army General Hospital medical record system from January 2017 to August 2023 for patients diagnosed with ICI-induced MG. We systematically reviewed the literature until August 2023 to identify all similar patients. We collected clinical information on these patients. Results: 110 patients were identified, 9 from our institution and 101 from case reports. In our institution, Median age was 66 years (range: 49-79 years). 6 were males. The most common was lung cancer (n = 4). All patients had no previous history of MG and received PD-1 or PD-L1 inhibitors. The median time from ICI initiation to first MG symptoms was 4 weeks (range: 2-15 weeks). ICIs were discontinued in all patients. Most patients initially received high-dose corticosteroids, and their symptoms improved. Some patients are discharged with corticosteroids maintenance therapy. In addition, 55 patients (50%) with concomitant myositis and/or myocarditis and MG-induced mortality were more common in the myositis and/or myocarditis group (10.9% vs. 34.5%, p = 0.016). Overlap of myositis with MG (OR = 3.148, p = 0.009) and anti-AChR antibody positivity (OR = 3.364, p = 0.005) were both significantly associated with poor outcomes. Conclusion: Our study reveals the prognosis of ICI-induced MG and suggests that myositis and/or myocarditis are severe comorbidities of ICI-induced MG, emphasizing the importance of early diagnosis and clinical intervention.

ProNet DB: a proteome-wise database for protein surface property representations and RNA-binding profiles.

The rapid growth in the number of experimental and predicted protein structures and more complicated protein structures poses a significant challenge for computational biology in leveraging structural information and accurate representation of protein surface properties. Recently, AlphaFold2 released the comprehensive proteomes of various species, and protein surface property representation plays a crucial role in protein-molecule interaction predictions, including those involving proteins, nucleic acids and compounds. Here, we proposed the first extensive database, namely ProNet DB, that integrates multiple protein surface representations and RNA-binding landscape for 326 175 protein structures. This collection encompasses the 16 model organism proteomes from the AlphaFold Protein Structure Database and experimentally validated structures from the Protein Data Bank. For each protein, ProNet DB provides access to the original protein structures along with the detailed surface property representations encompassing hydrophobicity, charge distribution and hydrogen bonding potential as well as interactive features such as the interacting face and RNA-binding sites and preferences. To facilitate an intuitive interpretation of these properties and the RNA-binding landscape, ProNet DB incorporates visualization tools like Mol* and an Online 3D Viewer, allowing for the direct observation and analysis of these representations on protein surfaces. The availability of pre-computed features enables instantaneous access for users, significantly advancing computational biology research in areas such as molecular mechanism elucidation, geometry-based drug discovery and the development of novel therapeutic approaches. Database URL:  https://proj.cse.cuhk.edu.hk/aihlab/pronet/.

DNA methylation remodeling and the functional implication during male gametogenesis in rice.

BACKGROUND: Epigenetic marks are reprogrammed during sexual reproduction. In flowering plants, DNA methylation is only partially remodeled in the gametes and the zygote. However, the timing and functional significance of the remodeling during plant gametogenesis remain obscure. RESULTS: Here we show that DNA methylation remodeling starts after male meiosis in rice, with non-CG methylation, particularly at CHG sites, being first enhanced in the microspore and subsequently decreased in sperm. Functional analysis of rice CHG methyltransferase genes CMT3a and CMT3b indicates that CMT3a functions as the major CHG methyltransferase in rice meiocyte, while CMT3b is responsible for the increase of CHG methylation in microspore. The function of the two histone demethylases JMJ706 and JMJ707 that remove H3K9me2 may contribute to the decreased CHG methylation in sperm. During male gametogenesis CMT3a mainly silences TE and TE-related genes while CMT3b is required for repression of genes encoding factors involved in transcriptional and translational activities. In addition, CMT3b functions to repress zygotic gene expression in egg and participates in establishing the zygotic epigenome upon fertilization. CONCLUSION: Collectively, the results indicate that DNA methylation is dynamically remodeled during male gametogenesis, distinguish the function of CMT3a and CMT3b in sex cells, and underpin the functional significance of DNA methylation remodeling during rice reproduction.

Coexistence of kaposiform hemangioendothelioma and capillary malformation: More than a coincidence? Two case reports.

The coexistence of kaposiform hemangioendothelioma (KHE) and capillary malformation (CM) is quite rare, and few relevant studies can be found to confirm whether this phenomenon is accidental. We diagnosed and treated two such patients, revealing interesting phenomena associated with the development of vascular diseases. These cases offer the possibility that the coexistence of KHE and CM is not accidental and open up a new field of research related to pediatric vascular tumors and vascular malformations. Personalization and precision are required in the diagnosis and treatment of such patients, and the present findings provide a reliable theoretical and practical basis for further research on the pathogenesis and therapy of patients with multiple vascular diseases.

Spatial spillovers of violent conflict amplify the impacts of climate variability on malaria risk in sub-Saharan Africa.

Africa carries a disproportionately high share of the global malaria burden, accounting for 94% of malaria cases and deaths worldwide in 2019. It is also a politically unstable region and the most vulnerable continent to climate change in recent decades. Knowledge about the modifying impacts of violent conflict on climate-malaria relationships remains limited. Here, we quantify the associations between violent conflict, climate variability, and malaria risk in sub-Saharan Africa using health surveys from 128,326 individuals, historical climate data, and 17,429 recorded violent conflicts from 2006 to 2017. We observe that spatial spillovers of violent conflict (SSVCs) have spatially distant effects on malaria risk. Malaria risk induced by SSVCs within 50 to 100 km from the households gradually increases from 0.1% (not significant, P>0.05) to 6.5% (95% CI: 0 to 13.0%). SSVCs significantly promote malaria risk within the average 20.1 to 26.9 °C range. At the 12-mo mean temperature of 22.5 °C, conflict deaths have the largest impact on malaria risk, with an approximately 5.8% increase (95% CI: 1.0 to 11.0%). Additionally, a pronounced association between SSVCs and malaria risk exists in the regions with 9.2 wet days per month. The results reveal that SSVCs increase population exposure to harsh environments, amplifying the effect of warm temperature and persistent precipitation on malaria transmission. Violent conflict therefore poses a substantial barrier to mosquito control and malaria elimination efforts in sub-Saharan Africa. Our findings support effective targeting of treatment programs and vector control activities in conflict-affected regions with a high malaria risk.

Lymphocyte antigen 96: A new potential biomarker and immune target in Parkinson's disease.

BACKGROUND: Lymphocyte antigen 96 (LY96) plays an important role in innate immunity and has been reported to be associated with various neurological diseases. However, its role in Parkinson's disease (PD) remains unclear. METHODS: Transcriptome data from a total of 49 patients with PD and 34 healthy controls were downloaded from the Gene Expression Omnibus (GEO) database to analyse the expression pattern of LY96 and its relationship with gene function and immune-related markers. In addition, peripheral blood samples were collected from clinical patients to validate LY96 mRNA expression levels. Finally, an in vitro cell model of PD based on highly differentiated SH-SY5Y cells was constructed, with small interfering RNA-silenced LY96 expression, and LY96 mRNA level, cell viability, flow cytometry, and mitochondrial membrane potential assays were performed. RESULTS: The results of the analyses of the GEO database and clinical samples revealed significantly abnormally high LY96 expression in patients with PD compared with healthy controls. The results of cell experiments showed that inhibiting LY96 expression alleviated adverse cellular effects by increasing cell viability, reducing apoptosis, and reducing oxidative stress. Gene set enrichment analysis showed that LY96 was positively correlated with T1 helper cells, T2 helper cells, neutrophils, natural killer T cells, myeloid-derived suppressor cells, macrophages, and activated CD4 cells, and may participate in PD through natural killer cell-mediated cytotoxicity pathways and extracellular matrix receptor interaction pathways. CONCLUSION: These findings suggested that LY96 might be a novel potential biomarker for PD, and offer insights into its immunoregulatory role.

Synergistic detoxification efficiency and mechanism of triclocarban degradation by a bacterial consortium in the liver-gut-microbiota axis of zebrafish (Danio rerio).

Triclocarban (TCC), an emerging organic contaminant, poses a potential threat to human health with long-term exposure. Here, Rhodococcus rhodochrous BX2 and Pseudomonas sp. LY-1 were utilized to degrade TCC at environmental related concentrations for enhancing TCC biodegradation and investigating whether the toxicity of intermediate metabolites is lower than that of the parent compound. The results demonstrated that the bacterial consortium could degrade TCC by 82.0% within 7 days. The calculated 96 h LC50 for TCC, as well as its main degradation product 3,4-Dichloroaniline (DCA) were 0.134 mg/L and 1.318 mg/L respectively. Biodegradation also alleviated histopathological lesions induced by TCC in zebrafish liver and gut tissues. Liver transcriptome analysis revealed that biodegradation weakened differential expression of genes involved in disrupted immune regulation and lipid metabolism caused by TCC, verified through RT-qPCR analysis and measurement of related enzyme activities and protein contents. 16 S rRNA sequencing indicated that exposure to TCC led to gut microbial dysbiosis, which was efficiently improved through TCC biodegradation, resulting in decreased relative abundances of major pathogens. Overall, this study evaluated potential environmental risks associated with biodegradation of TCC and explored possible biodetoxification mechanisms, providing a theoretical foundation for efficient and harmless bioremediation of environmental pollutants.

A tempo-spatial controllable microfluidic shear-stress generator for in-vitro mimicking of the thrombus.

Pathological conditions linked to shear stress have been identified in hematological diseases, cardiovascular diseases, and cancer. These conditions often exhibit significantly elevated shear stress levels, surpassing 1000 dyn/cm2 in severely stenotic arteries. Heightened shear stress can induce mechanical harm to endothelial cells, potentially leading to bleeding and fatal consequences. However, current technology still grapples with limitations, including inadequate flexibility in simulating bodily shear stress environments, limited range of shear stress generation, and spatial and temporal adaptability. Consequently, a comprehensive understanding of the mechanisms underlying the impact of shear stress on physiological and pathological conditions, like thrombosis, remains inadequate. To address these limitations, this study presents a microfluidic-based shear stress generation chip as a proposed solution. The chip achieves a substantial 929-fold variation in shear stress solely by adjusting the degree of constriction in branch channels after PDMS fabrication. Experiments demonstrated that a rapid increase in shear stress up to 1000 dyn/cm2 significantly detached 88.2% cells from the substrate. Long-term exposure (24 h) to shear stress levels below 8.3 dyn/cm2 did not significantly impact cell growth. Furthermore, cells exposed to shear stress levels equal to or greater than 8.3 dyn/cm2 exhibited significant alterations in aspect ratio and orientation, following a normal distribution. This microfluidic chip provides a reliable tool for investigating cellular responses to the wide-ranging shear stress existing in both physiological and pathological flow conditions.

Mechanical Behaviors of Polymer-Based Composite Reinforcements within High-Field Pulsed Magnets.

The development of pulsed magnets capable of generating magnetic fields exceeding 100 Tesla has been recognized as a crucial pursuit for advancing the scientific research on high magnetic fields. However, the operation of magnets at ultra-high magnetic fields often leads to accidental failures at their ends, necessitating a comprehensive exploration of the underlying mechanisms. To this end, this study investigates, for the first time, the mechanical behaviors of Zylon fiber-reinforced polymers (ZFRPs) within pulsed magnets from a composite perspective. The study begins with mechanical testing of ZFRPs, followed by the development of its constitutive model, which incorporates the plasticity and progressive damage. Subsequently, in-depth analyses are performed on a 95-T double-coil prototype that experienced a failure. The outcomes reveal a notable reduction of approximately 45% in both the radial and axial stiffness of ZFRPs, and the primary reason for the failure is traced to the damage incurred by the end ZFRPs of the inner magnet. The projected failure field closely aligns with the experiment. Additionally, two other magnet systems, achieving 90.6 T and 94.88 T, are analyzed. Finally, the discussion delves into the impact of transverse mechanical strength of the reinforcement and axial Lorentz forces on the structural performance of magnets.

Targeting inflammation as cancer therapy.

Inflammation has accompanied human beings since the emergence of wounds and infections. In the past decades, numerous efforts have been undertaken to explore the potential role of inflammation in cancer, from tumor development, invasion, and metastasis to the resistance of tumors to treatment. Inflammation-targeted agents not only demonstrate the potential to suppress cancer development, but also to improve the efficacy of other therapeutic modalities. In this review, we describe the highly dynamic and complex inflammatory tumor microenvironment, with discussion on key inflammation mediators in cancer including inflammatory cells, inflammatory cytokines, and their downstream intracellular pathways. In addition, we especially address the role of inflammation in cancer development and highlight the action mechanisms of inflammation-targeted therapies in antitumor response. Finally, we summarize the results from both preclinical and clinical studies up to date to illustrate the translation potential of inflammation-targeted therapies.

Soil Cd increased the leaf litter Cd remains of Solanum nigrum and Solanum lycopersicum.

Plant litter decomposition is a natural pathway of heavy metal cycling in soil ecosystems, but the dynamics of heavy metal release during litter decomposition are relatively poorly understood. The purpose of this study was to investigate the effects of species, soil fauna and soil Cd addition on litter decomposition and Cd release dynamics. Therefore, we selected two plants, Solanum nigrum and S. lycopersicum with large differences in Cd accumulation capacity. First, they were enriched with Cd during the growing period and leaf litter was harvested after 6 months of pretreatment. Then, the decomposition of leaf litter was conducted with or without soil Cd and Eisenia fetida through lab pot tests. Our results showed that leaf litter Cd led to a significant decrease in litter decomposition rate (K value), with a maximum decrease of 32.1% in S. nigrum and 30.1% in S. lycopersicum. We observed that the presence of E. fetida significantly increased K value, but the effect was similar in the +leaf Cd treatment and the -leaf Cd treatment, both for S. nigrum and S. lycopersicum. Interestingly, the litter Cd concentration did not decrease during decomposition, but showed an increasing trend, especially for S. nigrum in the +soil Cd treatment. Moreover, the litter Cd remains was higher in the +soil Cd treatment compared to the -soil Cd treatment for both S. nigrum and S. lycopersicum, no matter whether with or without E. fetida. This result suggests that the Cd may be transferred from soil to litter, thus increasing the litter Cd remains. Overall, our study shows that leaf litter Cd slowed down the carbon cycling in ecosystems. In addition, the release of litter Cd has a lag, and the litter has a certain adsorption capacity for soil Cd, which intensifies the harm to the ecology during litter transfer.

Association between body mass index and delirium incidence in critically ill patients: a retrospective cohort study based on the MIMIC-IV Database.

OBJECTIVES: Delirium is a form of brain dysfunction with high incidence and is associated with many negative outcomes in the intensive care unit. However, few studies have been large enough to reliably examine the associations between body mass index (BMI) and delirium, especially in critically ill patients. The objective of this study was to investigate the association between BMI and delirium incidence in critically ill patients. DESIGN: A retrospective cohort study. SETTING: Data were collected from the Medical Information Mart for Intensive Care-IV V2.0 Database consisting of critically ill participants between 2008 and 2019 at the Beth Israel Deaconess Medical Center in Boston. PARTICIPANTS: A total of 20 193 patients with BMI and delirium records were enrolled in this study and were divided into six groups. PRIMARY OUTCOME MEASURE: Delirium incidence. RESULTS: Generalised linear models and restricted cubic spline analysis were used to estimate the associations between BMI and delirium incidence. A total of 30.81% of the patients (6222 of 20 193) developed delirium in the total cohort. Compared with those in the healthy weight group, the patients in the different groups (underweight, overweight, obesity grade 1, obesity grade 2, obesity grade 3) had different relative risks (RRs): RR=1.10, 95% CI=1.02 to 1.19, p=0.011; RR=0.93, 95% CI=0.88 to 0.97, p=0.003; RR=0.88, 95% CI=0.83 to 0.94, p<0.001; RR=0.94, 95% CI=0.86 to 1.03, p=0.193; RR=1.14, 95% CI=1.03 to 1.25, p=0.010, respectively. For patients with or without adjustment variables, there was an obvious U-shaped relationship between BMI as a continuous variable and delirium incidence. CONCLUSION: BMI was associated with the incidence of delirium. Our results suggested that a BMI higher or lower than obesity grade 1 rather than the healthy weight in critically ill patients increases the risk of delirium incidence.

ATR limits Rad18-mediated PCNA monoubiquitination to preserve replication fork and telomerase-independent telomere stability.

Upon replication fork stalling, the RPA-coated single-stranded DNA (ssDNA) formed behind the fork activates the ataxia telangiectasia-mutated and Rad3-related (ATR) kinase, concomitantly initiating Rad18-dependent monoubiquitination of PCNA. However, whether crosstalk exists between these two events and the underlying physiological implications of this interplay remain elusive. In this study, we demonstrate that during replication stress, ATR phosphorylates human Rad18 at Ser403, an adjacent residue to a previously unidentified PIP motif (PCNA-interacting peptide) within Rad18. This phosphorylation event disrupts the interaction between Rad18 and PCNA, thereby restricting the extent of Rad18-mediated PCNA monoubiquitination. Consequently, excessive accumulation of the tumor suppressor protein SLX4, now characterized as a novel reader of ubiquitinated PCNA, at stalled forks is prevented, contributing to the prevention of stalled fork collapse. We further establish that ATR preserves telomere stability in alternative lengthening of telomere (ALT) cells by restricting Rad18-mediated PCNA monoubiquitination and excessive SLX4 accumulation at telomeres. These findings shed light on the complex interplay between ATR activation, Rad18-dependent PCNA monoubiquitination, and SLX4-associated stalled fork processing, emphasizing the critical role of ATR in preserving replication fork stability and facilitating telomerase-independent telomere maintenance.

Research Advances in Neuroblast Migration in Traumatic Brain Injury.

Neuroblasts were first derived from the adult mammalian brains in the 1990s by Reynolds et al. Since then, persistent neurogenesis in the subgranular zone (SGZ) of the hippocampus and subventricular zone (SVZ) has gradually been recognized. To date, reviews on neuroblast migration have largely investigated glial cells and molecular signaling mechanisms, while the relationship between vasculature and cell migration remains a mystery. Thus, this paper underlines the partial biological features of neuroblast migration and unravels the significance and mechanisms of the vasculature in the process to further clarify theoretically the neural repair mechanism after brain injury. Neuroblast migration presents three modes according to the characteristics of cells that act as scaffolds during the migration process: gliophilic migration, neurophilic migration, and vasophilic migration. Many signaling molecules, including brain-derived neurotrophic factor (BDNF), stromal cell-derived factor 1 (SDF-1), vascular endothelial growth factor (VEGF), and angiopoietin-1 (Ang-1), affect vasophilic migration, synergistically regulating the migration of neuroblasts to target areas along blood vessels. However, the precise role of blood vessels in the migration of neuroblasts needs to be further explored. The in-depth study of neuroblast migration will most probably provide theoretical basis and breakthrough for the clinical treatment of brain injury diseases.

Novel aromatic moieties-modified poly(glycidyl amine)s with potent siRNA delivery and cancer treatment effect.

The development of safe and effective delivery systems is critical for the clinical applications of siRNA-based therapeutics. Polymer-based vectors have garnered significant attention owing to their structural flexibility and functional tunability. Polyethyleneimine (PEI) has been extensively studied for nucleic acid delivery; nevertheless, its high cytotoxicity has posed challenges for clinical applications. In this study, we have reported poly(glycidyl amine) (PGAm), a linear PEI analogue, demonstrating remarkable siRNA delivery efficacy and improved biocompatibility. By introducing three aromatic moieties (tyrosine, p-hydroxybenzenepropanoic acid, and phenylalanine) at varying ratios to further modify PGAms, we successfully constructed a library comprising 36 PGAm-based carriers. In vitro evaluations revealed that PGAm-based carriers exhibited significantly enhanced biocompatibility and reduced non-specific protein absorption in comparison to PEI25k. Among them, 10 modified PGAms achieved a knockdown of target gene expressions exceeding 80%, and 26 modified PGAms maintained over 70% cell viability when utilized for the in vitro delivery of siRNA to HeLa cells. Explorations into the structure-activity relationship of PGAm-based polyplex nanoparticles (NPs) indicated that the siRNA delivery efficacy of NPs depended on factors such as the molecular weight of PGAm precursors, the type of modifying moieties, and the modification ratio. Furthermore, it was demonstrated that two top-performing NPs, namely 2T100/siLuc and 2A50/siLuc, exhibited potent silencing of target genes in tumors following i.v. injection into mice bearing HeLa-Luc xenografts. The in vivo efficacy of the selected NPs was further validated by a remarkable anti-cancer effect when employed for the delivery of siRNA targeting polo-like kinase 1 (siPLK1) to mice with PC-3 xenograft tumors. The intravenous administration of NPs resulted in a substantial inhibition of tumor growth without significant toxicity. These findings demonstrate the feasibility of employing PGAm in siRNA delivery and provide valuable insights for the development of efficient siRNA carriers based on PGAm.

Cloning and functional mechanism of the dwarf gene gba affecting stem elongation and cellulose biosynthesis in jute (Corchorus olitorius).

Plant height (PH) is an important factor affecting bast fiber yield in jute. Here, we report the mechanism of dwarfism in the 'Guangbaai' (gba) of jute. The mutant gba had shorter internode length and cell length compared to the standard cultivar 'TaiZi 4' (TZ4). Exogenous GA3 treatment indicated that gba is a GA-insensitive dwarf mutant. Quantitative trait locus (QTL) analysis of three PH-related traits via a high-density genetic linkage map according to re-seq showed that a total of 25 QTLs were identified, including 13 QTLs for PH, with phenotypic variation explained ranging from 2.42 to 74.16%. Notably, the functional mechanism of the candidate gene CoGID1a, the gibberellic acid receptor, of the major locus qPHIL5 was evaluated by transgenic analysis and virus-induced gene silencing. A dwarf phenotype-related single nucleotide mutation in CoGID1a was identified in gba, which was also unique to the dwarf phenotype of gba among 57 cultivars. Cogid1a was unable to interact with the growth-repressor DELLA even in the presence of highly accumulated gibberellins in gba. Differentially expressed genes between transcriptomes of gba and TZ4 after GA3 treatment indicated up-regulation of genes involved in gibberellin and cellulose synthesis in gba. Interestingly, it was found that up-regulation of CoMYB46, a key transcription factor in the secondary cell wall, by the highly accumulated gibberellins in gba promoted the expression of cellulose synthase genes CoCesA4 and CoCesA7. These findings provide valuable insights into fiber development affected by endogenous gibberellin accumulation in plants.

Microneedle Delivery Platform Integrated with Codelivery Nanoliposomes for Effective and Safe Androgenetic Alopecia Treatment.

Although topical application of minoxidil is a widely used, FDA-approved therapy for androgenetic alopecia (AGA) treatment, it suffers from low bioavailability, the requirement for frequent long-term use, and side effects. With a similar structure as minoxidil, kopexil and kopyrrol are less toxic and have been commercialized, but show an inferior hair regeneration effect compared to minoxidil. Herein, we developed a hyaluronic acid (HA)-based dissolvable microneedles (MNs) delivery platform integrated with kopexil and kopyrrol coencapsulated nanoliposomes (KK-NLPs) to effectively and safely treat AGA. Facilitated by nanoliposomes and MNs, the encapsulated KK-NLPs performed efficient skin penetration and enhanced cellular internalization into human dermal papilla cells. Furthermore, within the target cells, the codelivered kopexil and kopyrrol show synergistic effects by orchestrating an upregulation in the expression of Ki67, ß-catenin, vascular endothelial growth factor (VEGF), and CD31. These molecular responses collectively foster cell proliferation, migration, and antioxidative effects, thereby facilitating the expedited progression of hair follicles (HFs) into the anagen phase and promoting peripheral angiogenesis. Notably, the KK-NLPs-integrated MNs treatment group exhibits noteworthy enhanced hair regeneration in vivo, with identical or superior therapeutic effects at a much lower dosage than that of minoxidil. These results suggest the great potential of this kopexil and kopyrrol codelivery nanoliposomes-integrated MNs platform for AGA treatment in a safe and efficient way.