Albumin-Based Microneedles for Spatiotemporal Delivery of Temozolomide and Niclosamide to Resistant Glioblastoma.

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor. Standard therapy includes maximal surgical resection, radiotherapy, and adjuvant temozolomide (TMZ) administration. However, the rapid development of TMZ resistance and the impermeability of the blood-brain barrier (BBB) significantly hinder the therapeutic efficacy. Herein, we developed spatiotemporally controlled microneedle patches (BMNs) loaded with TMZ and niclosamide (NIC) to overcome GBM resistance. We found that hyaluronic acid (HA) increased the viscosity of bovine serum albumin (BSA) and evidenced that concentrations of BSA/HA exert an impact degradation rates exposure to high-temperature treatment, showing that the higher BSA/HA concentrations result in slower drug release. To optimize drug release rates and ensure synergistic antitumor effects, a 15% BSA/HA solution constituting the bottoms of BMNs was chosen to load TMZ, showing sustained drug release for over 28 days, guaranteeing long-term DNA damage in TMZ-resistant cells (U251-TR). Needle tips made from 10% BSA/HA solution loaded with NIC released the drug within 14 days, enhancing TMZ's efficacy by inhibiting the activity of O6-methylguanine-DNA methyltransferase (MGMT). BMNs exhibit superior mechanical properties, bypass the BBB, and gradually release the drug into the tumor periphery, thus significantly inhibiting tumor proliferation and expanding median survival in mice. The on-demand delivery of BMNs patches shows a strong translational potential for clinical applications, particularly in synergistic GBM treatment.

Rich-club organization of whole-brain spatio-temporal multilayer functional connectivity networks.

Objective: In this work, we propose a novel method for constructing whole-brain spatio-temporal multilayer functional connectivity networks (FCNs) and four innovative rich-club metrics. Methods: Spatio-temporal multilayer FCNs achieve a high-order representation of the spatio-temporal dynamic characteristics of brain networks by combining the sliding time window method with graph theory and hypergraph theory. The four proposed rich-club scales are based on the dynamic changes in rich-club node identity, providing a parameterized description of the topological dynamic characteristics of brain networks from both temporal and spatial perspectives. The proposed method was validated in three independent differential analysis experiments: male-female gender difference analysis, analysis of abnormality in patients with autism spectrum disorders (ASD), and individual difference analysis. Results: The proposed method yielded results consistent with previous relevant studies and revealed some innovative findings. For instance, the dynamic topological characteristics of specific white matter regions effectively reflected individual differences. The increased abnormality in internal functional connectivity within the basal ganglia may be a contributing factor to the occurrence of repetitive or restrictive behaviors in ASD patients. Conclusion: The proposed methodology provides an efficacious approach for constructing whole-brain spatio-temporal multilayer FCNs and conducting analysis of their dynamic topological structures. The dynamic topological characteristics of spatio-temporal multilayer FCNs may offer new insights into physiological variations and pathological abnormalities in neuroscience.

Widespread variation in molecular interactions and regulatory properties among transcription factor isoforms.

Most human Transcription factors (TFs) genes encode multiple protein isoforms differing in DNA binding domains, effector domains, or other protein regions. The global extent to which this results in functional differences between isoforms remains unknown. Here, we systematically compared 693 isoforms of 246 TF genes, assessing DNA binding, protein binding, transcriptional activation, subcellular localization, and condensate formation. Relative to reference isoforms, two-thirds of alternative TF isoforms exhibit differences in one or more molecular activities, which often could not be predicted from sequence. We observed two primary categories of alternative TF isoforms: "rewirers" and "negative regulators", both of which were associated with differentiation and cancer. Our results support a model wherein the relative expression levels of, and interactions involving, TF isoforms add an understudied layer of complexity to gene regulatory networks, demonstrating the importance of isoform-aware characterization of TF functions and providing a rich resource for further studies.

Appropriately Reduced Nitrogen and Increased Phosphorus in Ratooning Rice Increased the Yield and Reduced the Greenhouse Gas Emissions in Southeast China.

Reducing greenhouse gas emissions while improving productivity is the core of sustainable agriculture development. In recent years, rice ratooning has developed rapidly in China and other Asian countries, becoming an effective measure to increase rice production and reduce greenhouse gas emissions in these regions. However, the lower yield of ratooning rice caused by the application of a single nitrogen fertilizer in the ratooning season has become one of the main reasons limiting the further development of rice ratooning. The combined application of nitrogen and phosphorus plays a crucial role in increasing crop yield and reducing greenhouse gas emissions. The effects of combined nitrogen and phosphorus application on ratooning rice remain unclear. Therefore, this paper aimed to investigate the effect of combined nitrogen and phosphorus application on ratooning rice. Two hybrid rice varieties, 'Luyou 1831' and 'Yongyou 1540', were used as experimental materials. A control treatment of nitrogen-only fertilization (187.50 kg·ha-1 N) was set, and six treatments were established by reducing nitrogen fertilizer by 10% (N1) and 20% (N2), and applying three levels of phosphorus fertilizer: N1P1 (168.75 kg·ha-1 N; 13.50 kg·ha-1 P), N1P2 (168.75 kg·ha-1 N; 27.00 kg·ha-1 P), N1P3 (168.75 kg·ha-1 N; 40.50 kg·ha-1 P), N2P1 (150.00 kg·ha-1 N; 13.50 kg·ha-1 P), N2P2 (150.00 kg·ha-1 N; 27.00 kg·ha-1 P), and N2P3 (150.00 kg·ha-1 N; 40.50 kg·ha-1 P). The effects of reduced nitrogen and increased phosphorus treatments in ratooning rice on the yield, the greenhouse gas emissions, and the community structure of rhizosphere soil microbes were examined. The results showed that the yield of ratooning rice in different treatments followed the sequence N1P2 > N1P1 > N1P3 > N2P3 > N2P2 > N2P1 > N. Specifically, under the N1P2 treatment, the average two-year yields of 'Luyou 1831' and 'Yongyou 1540' reached 8520.55 kg·ha-1 and 9184.90 kg·ha-1, respectively, representing increases of 74.30% and 25.79% compared to the N treatment. Different nitrogen and phosphorus application combinations also reduced methane emissions during the ratooning season. Appropriately combined nitrogen and phosphorus application reduced the relative contribution of stochastic processes in microbial community assembly, broadened the niche breadth of microbial communities, enhanced the abundance of functional genes related to methane-oxidizing bacteria and soil ammonia-oxidizing bacteria in the rhizosphere, and decreased the abundance of functional genes related to methanogenic and denitrifying bacteria, thereby reducing greenhouse gas emissions in the ratooning season. The carbon footprint of ratooning rice for 'Luyou 1831' and 'Yongyou 1540' decreased by 25.82% and 38.99%, respectively, under the N1P2 treatment compared to the N treatment. This study offered a new fertilization pattern for the green sustainable development of rice ratooning.

Microneedle Patch Delivery of PLCG1-siRNA Efficient Enhanced Temozolomide Therapy for Glioblastoma.

The blood-brain barrier (BBB) and drug resistance present challenges for chemotherapy of glioblastoma (GBM). A microneedle (MN) patch with excellent biocompatibility and biodegradability was designed to bypass the BBB and release temozolomide (TMZ) and PLCG1-siRNA directly into the tumor site for synergistic treatment of GBM. The codelivery of TMZ and PLCG1-siRNA enhanced DNA damage and apoptosis. The potential mechanism behind this enhancement is to knockdown of PLCG1 expression, which positively regulates the expression of signal transducer and activator of transcription 3 genes, thereby preventing DNA repair and enhancing the sensitivity of GBM to TMZ. The MN patch enables long-term sustainable drug release through in situ implantation and increases local drug concentrations in diseased areas, significantly extending mouse survival time compared to other drug treatment groups. MN drug delivery provides a platform for the combination treatment of GBM and other central nervous system diseases.

CRISPR-Cas12a based target recognition initiated duplex-specific nuclease enhanced fluorescence and colorimetric analysis of cell-free DNA (cfDNA).

The significant role of cell-free DNA (cfDNA) for disease diagnosis, including cancer, has garnered a lot of attention. The challenges of creating target-specific primers and the possibility of false-positive signals make amplification-based detection methods problematic. Fluorescent biosensors based on CRISPR-Cas have been widely established, however they still require an amplification step before they can be used for detection. To detect cfDNA, researchers have created a CRISPR-Cas12a-based nucleic acid amplification-free fluorescent biosensor that uses a combination of fluorescence and colorimetric signaling improved by duplex-specific nuclease (DSN). DSN-assisted signal recycling is initiated in H1@MBs when the target cfDNA activates the CRISPR-Cas12a complex, leading to the degradation of single-strand DNA (ssDNA) sequences. This method has an extremely high detection limit for the BRCA-1 breast cancer gene. In addition to measuring viral DNA in a field-deployable and point-of-care testing (POCT) platform, this fast and highly selective sensor can be used to evaluate additional nucleic acid biomarkers.

Integrating transcriptomics and network pharmacology to reveal the mechanisms of total Rhizoma Coptidis alkaloids against nonalcoholic steatohepatitis.

ETHNOPHARMACOLOGICAL RELEVANCE: Non-alcoholic steatohepatitis (NASH) has emerged as a major cause of cirrhosis and hepatocellular carcinoma, posing a significant threat to public health. Rhizoma Coptidis, a traditional Chinese medicinal herb has been shown to have significant curative effects on liver diseases. Total Rhizoma Coptidis Alkaloids (TRCA) is a primarily alkaloid mixture extracted from Rhizoma Coptidis, and its constituents are widely accepted to have hepatoprotective effects. AIM OF THE STUDY: This work aimed to investigate the efficacy and potential mechanisms of TRCA in ameliorating NASH through both in vitro experiments and in vivo mouse models. MATERIALS AND METHODS: The study employed a mice model induced by a high-fat diet (HFD) to evaluate the effectiveness and pharmacological mechanisms of TRCA in alleviating NASH. Transcriptomic sequencing and network pharmacology were used to explore the possible targets and mechanisms of TRCA to ameliorate NASH. Further validation was performed in free fatty acid (FFA)-induced human hepatocytes (LO2) and human hepatocellular carcinoma cells (HepG2). RESULTS: TRCA effectively ameliorated the main features of NASH such as lipid accumulation, hepatitis and hepatic fibrosis in the liver tissue of mice induced by HFD, as well as improved glucose tolerance and insulin resistance in mice. Combined with transcriptomic and network pharmacological analyses, 68 core targets associated with the improvement of NASH by TRCA were obtained. According to the KEGG results, the core targets were significantly enriched in the PI3K-AKT signaling pathway whereas TRCA ameliorated the aberrant down-regulation of the PI3K-AKT signaling pathway induced by HFD. Furthermore, the five highest-ranked genes were obtained by PPI network analysis. Moreover, our findings suggest that TRCA may impede the progression of HFD-induced NASH by regulating the expression of PPARG, MMP9, ALB, CCL2, and EGFR. CONCLUSIONS: TRCA can ameliorate HFD-induced liver injury by modulating aberrant downregulation of the PI3K-AKT signaling pathway. Key proteins such as PPARG, MMP9, ALB, CCL2, and EGFR may be critical targets for TRCA to ameliorate NASH. This finding supports using Rhizoma Coptidis, a well-known herbal medicine, as a potential therapeutic agent for NASH.

Collaborative governance effects of carbon market on GHG and air pollutants emission reduction in 3E model -- analysis based on System Dynamics.

The carbon market is regarded as one of the important means to achieve China's dual carbon target. It has ancillary effect for reducing air pollution while regulating carbon emissions since climate change and air pollution share the same origin and homology. Research on how to design the carbon market mechanism in order to maximize the synergistic effect of reducing greenhouse gas and air pollution will have a very important practical impact for China. This study conducts a theoretical analysis of the collaborative emission reduction path of China's carbon market, and constructs an Energy-Economy-Environment (3E) model of the collaborative emission reduction effect of carbon trading system based on System Dynamics. After analyzing the feedback path of the core cycle of the model and verifying its performance, three main policy factors in the carbon market are explored, and their effects under the dual objectives of emission control and economic development are comprehensively evaluated. This study suggests that the exploration of the potential of carbon market for collaborative governance should be accelerated, and ensure the orderly expansion of coverage and precise setting of limits, so as to ensure the smooth achievement of carbon reduction targets while guaranteeing the social and economic development.

The pyramid representation of the functional network using resting-state fMRI.

Background: Resting-state functional magnetic resonance imaging (RS-fMRI) has been proved to be a useful tool to study the brain mechanism in the quest to probe the distinct pattern of inter-region interactions in the brain. As an important application of RS-fMRI, the graph-based approach characterizes the brain as a complex network. However, the network is susceptible to its scale that determines the trade-off between sensitivity and anatomical variability. Objective: To balance sensitivity and anatomical variability, a pyramid representation of the functional network is proposed, which is composed of five individual networks reconstructed at multiple scales. Methods: The pyramid representation of the functional network was applied to two groups of participants, including patients with Alzheimer's disease (AD) and normal elderly (NC) individuals, as a demonstration. Features were extracted from the multi-scale networks and were evaluated with their inter-group differences between AD and NC, as well as the discriminative power in recognizing AD. Moreover, the proposed method was also validated by another dataset from people with autism. Results: The different features reflect the highest sensitivity to distinguish AD at different scales. In addition, the combined features have higher accuracy than any single scale-based feature. These findings highlight the potential use of multi-scale features as markers of the disrupted topological organization in AD networks. Conclusion: We believe that multi-scale metrics could provide a more comprehensive characterization of the functional network and thus provide a promising solution for representing the underlying functional mechanism in the human brain on a multi-scale basis.

Effect of jet lag on brain white matter functional connectivity.

Background: A long-haul flight across more than five time zones may produce a circadian rhythm sleep disorder known as jet lag. Little is known about the effect of jet lag on white matter (WM) functional connectivity (FC). Objective: The present study is to investigate changes in WM FC in subjects due to recovery from jet lag after flying across six time zones. Methods: Here, resting-state functional magnetic resonance imaging was performed in 23 participants within 24 hours of flying and again 50 days later. Gray matter (GM) and WM networks were identified by k-means clustering. WM FC and functional covariance connectivity (FCC) were analyzed. Next, a sliding window method was used to establish dynamic WM FC. WM static and dynamic FC and FCC were compared between when participants had initially completed their journey and 50 days later. Emotion was assessed using the Positive and Negative Affect Schedule and the State Anxiety Inventory. Results: All participants were confirmed to have jet lag symptoms by the Columbian Jet Lag Scale. The static FC strengthes of cingulate network (WM7)- sensorimotor network and ventral frontal network- visual network were lower after the long-haul flight compared with recovery. Corresponding results were obtained for the dynamic FC analysis. The analysis of FCC revealed weakened connections between the WM7 and several other brain networks, especially the precentral/postcentral network. Moreover, a negative correlation was found between emotion scores and the FC between the WM7 and sensorimotor related regions. Conclusions: The results of this study provide further evidence for the existence of WM networks and show that jet lag is associated with alterations in static and dynamic WM FC and FCC, especially in sensorimotor networks. Jet lag is a complex problem that not only is related to sleep rhythm but also influences emotion.