Modulation Of Responsiveness Research Articles

Paracellular Delivery of Protein Drugs with Smart EnteroPatho Nanoparticles.

A general platform for the safe and effective oral delivery of biologics would revolutionize the administration of protein-based drugs, improving access for patients and lowering the financial burden on the health-care industry. Because of their dimensions and physiochemical properties, nanomaterials stand as promising vehicles for navigating the complex and challenging environment in the gastrointestinal (GI) tract. Recent developments have led to materials that protect protein drugs from degradation and enable controlled release in the small intestine, the site of absorption for most proteins. Yet, once present in the small intestine, the protein must transit through the secreted mucus and epithelial cells of the intestinal mucosa into systemic circulation, a process that remains a bottleneck for nanomaterial-based delivery. One attractive pathway through the intestinal mucosa is the paracellular route, which avoids cell trafficking and other degradative processes in the interior of cells. Direct flux between cells is regulated by epithelial tight junctions (TJs) that seal the paracellular space and prevent protein flux. Here, we describe a smart nanoparticle system that directly and transiently disrupts TJs for improved protein delivery, an unrealized goal to-date. We take inspiration from enteropathogenic bacteria that adhere to intestinal epithelia and secrete inhibitors that block TJ interactions in the local environment. To mimic these natural mechanisms, we engineer nanoparticles (EnteroPatho NPs) that attach to the epithelial glycocalyx and release TJ modulators in response to the intestinal pH. We show that EnteroPatho NPs lead to TJ disruption and paracellular protein delivery, giving rise to a general platform for oral delivery.

Revealing the impact of modified modules flexibility on gemcitabine prodrug nanoassemblies for effective cancer therapy

Prodrug nanoassemblies combine the advantages of prodrug strategies and nanotechnology have been widely utilized for delivering antitumor drugs. These prodrugs typically comprise active drug modules, response modules, and modification modules. Among them, the modification modules play a critical factor in improving the self-assembly ability of the parent drug. However, the impact of the specific structure of the modification modules on prodrug self-assembly remains elusive. In this study, two gemcitabine (GEM) prodrugs are developed using 2-octyl-1-dodecanol (OD) as flexible modification modules and cholesterol (CLS) as rigid modification modules. Interestingly, the differences in the chemical structure of modification modules significantly affect the assembly performance, drug release, cytotoxicity, tumor accumulation, and antitumor efficacy of prodrug nanoassemblies. It is noteworthy that the prodrug nanoassemblies constructed with flexible modifying chains (OD) exhibit improved stability, faster drug release, and enhanced antitumor effects. Our findings elucidate the significant impact of modification modules on the construction of prodrug nanoassemblies.

Optimization of such strategy as frequency modulation for grid-side energy storage control-terminal in response to frequency fluctuations in the new power system grid

Abstract This paper focuses on the refinement of the control strategy for grid-side energy storage systems as they engage in primary and secondary frequency modulation within an emerging smart grid. To attain an optimal outcome, traditional frequency modulation methods, which often require high-precision operations and extended adjustment periods, fall short of the stringent demands posed by modern power systems for swift and responsive frequency modulation. Under such circumstances, the grid-side energy storage control-terminal system presents a viable solution for managing energy storage, thereby providing rapid and precise assistance to the power system’s frequency modulation. By implementing a control mechanism that can adaptively switch between ARR signal-based and ACE signal-based frequency adjustments, a segmented parallel control approach ensures that the energy storage system can promptly and effectively modify the power within the grid system, facilitating swift frequency modulation.

Structurally-constrained encoding framework using a multi-voxel reduced-rank latent model for human natural vision

Objective. Voxel-wise visual encoding models based on convolutional neural networks (CNNs) have emerged as one of the prominent predictive tools of human brain activity via functional magnetic resonance imaging signals. While CNN-based models imitate the hierarchical structure of the human visual cortex to generate explainable features in response to natural visual stimuli, there is still a need for a brain-inspired model to predict brain responses accurately based on biomedical data. Approach. To bridge this gap, we propose a response prediction module called the Structurally Constrained Multi-Output (SCMO) module to include homologous correlations that arise between a group of voxels in a cortical region and predict more accurate responses. Main results. This module employs all the responses across a visual area to predict individual voxel-wise BOLD responses and therefore accounts for the population activity and collective behavior of voxels. Such a module can determine the relationships within each visual region by creating a structure matrix that represents the underlying voxel-to-voxel interactions. Moreover, since each response module in visual encoding tasks relies on the image features, we conducted experiments using two different feature extraction modules to assess the predictive performance of our proposed module. Specifically, we employed a recurrent CNN that integrates both feedforward and recurrent interactions, as well as the popular AlexNet model that utilizes feedforward connections. Significance. We demonstrate that the proposed framework provides a reliable predictive ability to generate brain responses across multiple areas, outperforming benchmark models in terms of stability and coherency of features.

Comparative Transcriptome Analysis of Hepatopancreas Reveals Sexual Dimorphic Response to Methyl Farnesoate Injection in Litopenaeus vannamei.

Sexually dimorphic traits such as growth and body size are often found in various crustaceans. Methyl farnesoate (MF), the main active form of sesquiterpenoid hormone in crustaceans, plays vital roles in the regulation of their molting and reproduction. However, understanding on the sex differences in their hormonal regulation is limited. Here, we carried out a comprehensive investigation on sexual dimorphic responses to MF in the hepatopancreas of the most dominant aquacultural crustacean-the white-leg shrimp (Litopenaeus vannamei). Through comparative transcriptomic analysis of the main MF target tissue (hepatopancreas) from both female and male L. vannamei, two sets of sex-specific and four sets of sex-dose-specific differentially expressed transcripts (DETs) were identified after different doses of MF injection. Functional analysis of DETs showed that the male-specific DETs were mainly related to sugar and lipid metabolism, of which multiple chitinases were significantly up-regulated. In contrast, the female-specific DETs were mainly related to miRNA processing and immune responses. Further co-expression network analysis revealed 8 sex-specific response modules and 55 key regulatory transcripts, of which several key transcripts of genes related to energy metabolism and immune responses were identified, such as arginine kinase, tropomyosin, elongation of very long chain fatty acids protein 6, thioredoxin reductase, cysteine dioxygenase, lysosomal acid lipase, estradiol 17-beta-dehydrogenase 8, and sodium/potassium-transporting ATPase subunit alpha. Altogether, our study demonstrates the sex differences in the hormonal regulatory networks of L. vannamei, providing new insights into the molecular basis of MF regulatory mechanisms and sex dimorphism in prawn aquaculture.

Two-tailed modification module tuned steric-hindrance effect enabling high therapeutic efficacy of paclitaxel prodrug nanoassemblies

Self-assembled prodrug nanomedicine has emerged as an advanced platform for antitumor therapy, mainly comprise drug modules, response modules and modification modules. However, existing studies usually compare the differences between single types of modification modules, neglecting the impact of steric-hindrance effect caused by chemical structure. Herein, single-tailed modification module with low-steric-hindrance effect and two-tailed modification module with high-steric-hindrance effect were selected to construct paclitaxel prodrugs (P-LAC18 and P-BAC18), and the in-depth insights of the steric-hindrance effect on prodrug nanoassemblies were explored. Notably, the size stability of the two-tailed prodrugs was enhanced due to improved intermolecular interactions and steric hindrance. Single-tailed prodrug nanoassemblies were more susceptible to attack by redox agents, showing faster drug release and stronger antitumor efficacy, but with poorer safety. In contrast, two-tailed prodrug nanoassemblies exhibited significant advantages in terms of pharmacokinetics, tumor accumulation and safety due to the good size stability, thus ensuring equivalent antitumor efficacy at tolerance dose. These findings highlighted the critical role of steric-hindrance effect of the modification module in regulating the structure-activity relationship of prodrug nanoassemblies and proposed new perspectives into the precise design of self-assembled prodrugs for high-performance cancer therapeutics.

Interaction-and-Response Network for Distantly Supervised Relation Extraction.

Distantly supervised relation extraction (DSRE) aims to identify semantic relations from massive plain texts. A broad range of the prior research has leveraged a series of selective attention mechanisms over sentences in a bag to extract relation features without considering dependencies among the relation features. As a result, potential discriminative information existed in the dependencies is ignored, causing a decline in the performance of extracting entity relations. In this article, we focus on going beyond the selective attention mechanisms and propose a new framework termed interaction-and-response network (IR-Net) that adaptively recalibrates the features of sentence, bag, and group levels by explicitly modeling interdependencies among the features on each level. The IR-Net consists of a series of interactive and responsive modules throughout feature hierarchy, seeking to strengthen its power of learning salient discriminative features for distinguishing entity relations. We conduct extensive experiments on three benchmark DSRE datasets, including NYT-10, NYT-16, and Wiki-20m. The experimental results demonstrate that the IR-Net brings obvious improvements in performance when comparing ten state-of-the-art DSRE methods for entity relation extraction.

Assessing the Response Mechanisms of Elevated CO2 Concentration on Various Forms of Nitrogen Losses in the Golden Corn Belt

AbstractNitrogen (N) loss is a significant source of water quality pollution in alluvial watersheds. However, the mechanisms linking N loss and elevated CO2 concentration (eCO2) are not well recognized. In this study, we comprehensively calibrated the SWAT model equipped with a dynamic CO2 input and response module to investigate the response mechanisms between multiform N losses and eCO2 in a representative large‐scale watershed. Results revealed nitrate loss under eCO2 exceeding 100% in some upstream zones under the SSP5‐8.5 scenario (P < 0.05) compared to the constant CO2 concentration. This was directly related to the great increase in hydrological variables, which were the carriers of N losses, and the intensive inputs of N fertilizer. Results also found that nitrate leaching was greater than the other two processes for future periods, peaking at 309.3%, as compared to the baseline period. The findings suggested reducing fertilizer inputs by 10%–20% was promising, especially for reducing nitrate loss through runoff and leaching by up to 17.7% and 12.2%. This study explored the mechanisms of increased N loss in response to eCO2 and provided scientific evidence for early warning and making decisions to improve water quality at a large watershed scale.

Fuzzy evaluation and obstacle factors of urban ecological health changes in the Wei River Basin, northwest China

BackgroundUrban ecological health is crucial for the long-term sustainable development of watershed. Accurately evaluating the health level of the ecological environment helps to develop reasonable strategies for ecological environment restoration and resource management. This paper constructed a comprehensive evaluation index system based on the Pressure-State-Response (PSR) framework and evaluated the ecological health of eleven administrative regions in the Wei River Basin (WRB), northwest China in 1980, 2000, and 2020 using an evaluation model established by fuzzy mathematics. Further, obstacle degrees were used to quantify the contribution of pressure, state, and response modules, as well as individual indicators to ecological health.ResultsThe comprehensive evaluation system constructed based on the PSR framework could effectively reflect the ecological health conditions of different regions in the WRB. During the study period, the ecological health went through a process of first deterioration and then improvement. By 2020, the ecological health of seven administrative regions reached healthy levels. The state module was the main obstacle module of the PSR framework to the ecological health of the most regions. The population density (P1), patch density of construction land (S5), comprehensive elasticity index (S8), soil erosion index (R1), and per capital GDP (R3) were the most crucial individual indicators affecting the ecological health. For different cities, the main obstacle factors varied. In economically developed cities, the limiting effect of P1 was more significant, while in economically underdeveloped cities, the limiting effect of R3 was stronger.ConclusionsIn response to the special natural environment and socio-economic conditions of arid and semi-arid areas in the WRB, an ecological health evaluation index system suitable for the characteristics of the basin was constructed. The results indicated that, to improve the levels of urban ecological health, it is necessary to restore the natural ecological environment and control population size while accelerating economic construction. Our results can provide scientific support for the ecological health evaluation and protection of the WRB and even the arid and semi-arid areas in northwest China.

Chemically Programmed Hydrogels for Spatiotemporal Modulation of the Cardiac Pathological Microenvironment.

After myocardial infarction (MI), sustained ischemic events induce pathological microenvironments characterized by ischemia-hypoxia, oxidative stress, inflammatory responses, matrix remodeling, and fibrous scarring. Conventional clinical therapies lack spatially targeted and temporally responsive modulation of the infarct microenvironment, leading to limited myocardial repair. Engineered hydrogels have a chemically programmed toolbox for minimally invasive localization of the pathological microenvironment and personalized responsive modulation over different pathological periods. Chemically programmed strategies for crosslinking interactions, interfacial binding, and topological microstructures in hydrogels enable minimally invasive implantation and in situ integration tailored to the myocardium. This enhances substance exchange and signal interactions within the infarcted microenvironment. Programmed responsive polymer networks, intelligent micro/nanoplatforms, and biological therapeutic cues contribute to the formation of microenvironment-modulated hydrogels with precise targeting, spatiotemporal control, and on-demand feedback. Therefore, this review summarizes the features of the MI microenvironment and chemically programmed schemes for hydrogels to conform, integrate, and modulate the cardiac pathological microenvironment. Chemically programmed strategies for oxygen-generating, antioxidant, anti-inflammatory, provascular, and electrointegrated hydrogels to stimulate iterative and translational cardiac tissue engineering are discussed.

Transcriptome Analysis of Sesame (Sesamum indicum L.) Reveals the LncRNA and mRNA Regulatory Network Responding to Low Nitrogen Stress.

Nitrogen is one of the important factors restricting the development of sesame planting and industry in China. Cultivating sesame varieties tolerant to low nitrogen is an effective way to solve the problem of crop nitrogen deficiency. To date, the mechanism of low nitrogen tolerance in sesame has not been elucidated at the transcriptional level. In this study, two sesame varieties Zhengzhi HL05 (ZZ, nitrogen efficient) and Burmese prolific (MD, nitrogen inefficient) in low nitrogen were used for RNA-sequencing. A total of 3964 DEGs (differentially expressed genes) and 221 DELs (differentially expressed lncRNAs) were identified in two sesame varieties at 3d and 9d after low nitrogen stress. Among them, 1227 genes related to low nitrogen tolerance are mainly located in amino acid metabolism, starch and sucrose metabolism and secondary metabolism, and participate in the process of transporter activity and antioxidant activity. In addition, a total of 209 pairs of lncRNA-mRNA were detected, including 21 pairs of trans and 188 cis. WGCNA (weighted gene co-expression network analysis) analysis divided the obtained genes into 29 modules; phenotypic association analysis identified three low-nitrogen response modules; through lncRNA-mRNA co-expression network, a number of hub genes and cis/trans-regulatory factors were identified in response to low-nitrogen stress including GS1-2 (glutamine synthetase 1-2), PAL (phenylalanine ammonia-lyase), CHS (chalcone synthase, CHS), CAB21 (chlorophyll a-b binding protein 21) and transcription factors MYB54, MYB88 and NAC75 and so on. As a trans regulator, lncRNA MSTRG.13854.1 affects the expression of some genes related to low nitrogen response by regulating the expression of MYB54, thus responding to low nitrogen stress. Our research is the first to provide a more comprehensive understanding of DEGs involved in the low nitrogen stress of sesame at the transcriptome level. These results may reveal insights into the molecular mechanisms of low nitrogen tolerance in sesame and provide diverse genetic resources involved in low nitrogen tolerance research.

Systematic evaluation of the elderly care industry based on energy factor inputs

The energy factor is the foundation of economic and social development, and it is also an important prerequisite for the effective operation of the elderly care industry. Based on the perspective of energy factor input, this paper constructs the DPSR mechanism model of the energy-elderly care industry system. Taking Shanghai as an example, through its 2010–2019 15 index data such as energy factors and industrial economy, the Entropy-TOPSIS method is comprehensively used to evaluate the energy-elderly care industry system. Finally, the following conclusions are drawn: (1) The energy factor has an important impact on the operation of the elderly care industry through its effect on the driving force module, the pressure module and the state module; (2) The elderly care industry has an important impact on the energy factor through the conduction of the response module; (3) The evaluation results of the Shanghai energy-elderly care industry system showed a continuous improvement trend from 2010 to 2019.

The ZmbHLH47-ZmSnRK2.9 Module Promotes Drought Tolerance in Maize.

Drought stress globally poses a significant threat to maize (Zea mays L.) productivity and the underlying molecular mechanisms of drought tolerance remain elusive. In this study, we characterized ZmbHLH47, a basic helix-loop-helix (bHLH) transcription factor, as a positive regulator of drought tolerance in maize. ZmbHLH47 expression was notably induced by both drought stress and abscisic acid (ABA). Transgenic plants overexpressing ZmbHLH47 displayed elevated drought tolerance and ABA responsiveness, while the zmbhlh47 mutant exhibited increased drought sensitivity and reduced ABA sensitivity. Mechanistically, it was revealed that ZmbHLH47 could directly bind to the promoter of ZmSnRK2.9 gene, a member of the subgroup III SnRK2 kinases, activating its expression. Furthermore, ZmSnRK2.9-overexpressing plants exhibited enhanced ABA sensitivity and drought tolerance, whereas the zmsnrk2.9 mutant displayed a decreased sensitivity to both. Notably, overexpressing ZmbHLH47 in the zmsnrk2.9 mutant closely resembled the zmsnrk2.9 mutant, indicating the importance of the ZmbHLH47-ZmSnRK2.9 module in ABA response and drought tolerance. These findings provided valuable insights and a potential genetic resource for enhancing the environmental adaptability of maize.

The MdVQ37-MdWRKY100 complex regulates salicylic acid content and MdRPM1 expression to modulate resistance to Glomerella leaf spot in apples.

Glomerella leaf spot (GLS), caused by the fungus Colletotrichum fructicola, is considered one of the most destructive diseases affecting apples. The VQ-WRKY complex plays a crucial role in the response of plants to biotic stresses. However, our understanding of the defensive role of the VQ-WRKY complex on woody plants, particularly apples, under biotic stress, remains limited. In this study, we elucidated the molecular mechanisms underlying the defensive role of the apple MdVQ37-MdWRKY100 module in response to GLS infection. The overexpression of MdWRKY100 enhanced resistance to C. fructicola, whereas MdWRKY100 RNA interference in apple plants reduced resistance to C. fructicola by affecting salicylic acid (SA) content and the expression level of the CC-NBS-LRR resistance gene MdRPM1. DAP-seq, Y1H, EMSA, and RT-qPCR assays indicated that MdWRKY100 inhibited the expression of MdWRKY17, a positive regulatory factor gene of SA degradation, upregulated the expression of MdPAL1, a key enzyme gene of SA biosynthesis, and promoted MdRPM1 expression by directly binding to their promotors. Transient overexpression and silencing experiments showed that MdPAL1 and MdRPM1 positively regulated GLS resistance in apples. Furthermore, the overexpression of MdVQ37 increased the susceptibility to C. fructicola by reducing the SA content and expression level of MdRPM1. Additionally, MdVQ37 interacted with MdWRKY100, which repressed the transcriptional activity of MdWRKY100. In summary, these results revealed the molecular mechanism through which the apple MdVQ37-MdWRKY100 module responds to GLS infection by regulating SA content and MdRPM1 expression, providing novel insights into the involvement of the VQ-WRKY complex in plant pathogen defence responses.

DNA nanodevice as a multi-module co-delivery platform for combination cancer immunotherapy

A major challenge in combining cancer immunotherapy is the efficient delivery of multiple types of immunological stimulators to elicit a robust anti-tumor immune response and reprogram the immunosuppressive tumor microenvironment (TME). Here, we developed a DNA nanodevice that was generated by precisely assembling three types of immunological stimulators. The doxorubicin (Dox) component induced immunogenic cell death (ICD) in tumor cells and enhanced phagocytosis of antigen-presenting cells (APCs). Exogenous double-stranded DNA (dsDNA) could act as a molecular adjuvant to activate the stimulator of interferon genes (STING) signaling in APCs by engulfing dying tumor cells. Interleukin (IL)-12 and small hairpin programmed cell death-ligand 1 (shPD-L1) transcription templates were designed to regulate TME. Additionally, for targeted drug delivery, multiple cyclo[Arg-Gly-Asp-(d-Phe)-Cys] (cRGD) peptide units on DNA origami were employed. The incorporation of disulfide bonds allowed the release of multiple modules in response to intracellular glutathione (GSH) in tumors. The nanodevice promoted the infiltration of CD8+ and CD4+ cells into the tumor and generated a highly inflamed TME, thereby enhancing the effectiveness of cancer immunotherapy. Our research results indicate that the nanodevice we constructed can effectively inhibit tumor growth and prevent lung metastasis without obvious systemic toxicity, providing a promising strategy for cancer combination treatment.

Synthetic protein protease sensor platform.

Introduction: Protease activity can serve as a highly specific biomarker for application in health, biotech, and beyond. The aim of this study was to develop a protease cleavable synthetic protein platform to detect protease activity in a rapid cell-free setting. Methods: The protease sensor is modular, with orthogonal peptide tags at the N and C terminal ends, which can be uncoupled via a protease responsive module located in between. The sensor design allows for several different readouts of cleavage signal. A protein 'backbone' [Green fluorescent protein (GFP)] was designed in silico to have both a C-terminal Flag-tag and N-Terminal 6x histidine tag (HIS) for antibody detection. A protease cleavage site, which can be adapted for any known protease cleavage sequence, enables the uncoupling of the peptide tags. Three different proteases-Tobacco, Etch Virus (TEV), the main protease from coronavirus SARS-COV-2 (Mpro) and Matrix Metallopeptidase 9 (MMP9)-a cancer-selective human protease-were examined. A sandwich Enzyme-Linked Immunosorbent Assay (ELISA) was developed based on antibodies against the HIS and Flag tags. As an alternative readout, a C-terminal quencher peptide separable by protease cleavage from the GFP was also included. Purified proteins were deployed in cell-free cleavage assays with their respective protease. Western blots, fluorescence assays and immunoassay were performed on samples. Results: Following the design, build and validation of protein constructs, specific protease cleavage was initially demonstrated by Western blot. The novel ELISA proved to afford highly sensitive detection of protease activity in all cases. By way of alternative readout, activation of fluorescence signal upon protease cleavage was also demonstrated but did not match the sensitivity provided by the ELISA method. Discussion: This platform, comprising a protease-responsive synthetic protein device and accompanying readout, is suitable for future deployment in a rapid, low-cost, lateral flow setting. The modular protein device can readily accommodate any desired protease-response module (target protease cleavage site). This study validates the concept with three disparate proteases and applications-human infectious disease, cancer and agricultural crop infection.

Chronological-Programmed Black Phosphorus Hydrogel for Responsive Modulation of the Pathological Microenvironment in Myocardial Infarction.

Electroactive hydrogels have garnered extensive interest as a promising approach to myocardial tissue engineering. However, the challenges of spatiotemporal-specific modulation of individual pathological processes and achieving nontoxic bioresorption still remain. Herein, inspired by the entire postinfarct pathological processes, an injectable conductive bioresorbable black phosphorus nanosheets (BPNSs)-loaded hydrogel (BHGD) was developed via reactive oxide species (ROS)-sensitive disulfide-bridge and photomediated cross-linking reaction. Significantly, the chronologically programmed BHGD hydrogel can achieve graded modulation during the inflammatory, proliferative, and maturation phases of myocardial infarction (MI). More details, during early infarction, the BHGD hydrogel can effectively reduce ROS levels in the MI area, inhibit cellular oxidative stress damage, and promote macrophage M2 polarization, creating a favorable environment for damaged myocardium repair. Meanwhile, the ROS-responsive structure can protect BPNSs from degradation and maintain good conductivity under MI microenvironments. Therefore, the BHGD hydrogel possesses tissue-matched modulus and conductivity in the MI area, facilitating cardiomyocyte maturation and electrical signal exchange, compensating for impaired electrical signaling, and promoting vascularization in infarcted areas in the maturation phase. More importantly, all components of the hydrogel degrade into nontoxic substances without adverse effects on vital organs. Overall, the presented BPNS-loaded hydrogel offers an expandable and safe option for clinical treatment of MI.

Abstract 4946: ssTimiGP: Equip the TimiGP system with a single-sample module, facilitating the cell-cell interaction inference of the tumor microenvironment in any sample

Abstract Understanding the tumor microenvironment (TME) is essential in cancer treatment and risk assessment. While single-cell RNA-seq (scRNA-seq) offers in-depth insights into the TME, its expensive cost results in limited data sets and size. In contrast, microarray and RNA-seq provide rich datasets from larger cohorts, but they yield bulk data with lower resolution. To leverage the strengths of both approaches and comprehensively study the TME, we developed the computational framework TimiGP (Tumor Immune Microenvironment Illustration through Gene Pairs). It is inspired by the dynamic balance of the immune system and extended to the entire TME. TimiGP utilizes scRNA-seq to define cell type of interest, and bulk transcriptomic profiles to deduce clinically relevant cell-cell interaction networks and cell functions. Our recent release includes both prognosis and response modules to study the association between TME and the corresponding clinical outcomes. However, their applicability is constrained by the necessity for paired clinical information. In response to this limitation, we present a significant enhancement, a single sample module slightly modified from the TimiGP framework (ssTimiGP). This upgraded version enables TME analysis in any individual sample, requiring only bulk RNA-seq data and cell-type markers. It exports a cell-cell interaction network representing the relative expression of functional markers and the abundance of cells. This optimization expands the utility of TimiGP, making it more accessible across diverse samples and species. We have further expanded the application of ssTimiGP from solid tumors to liquid samples (e.g., peripheral blood). To validate its performance, we conducted a comparative analysis between the interactions of eight immune cell types observed in experimental results using FACS and the computational results derived from ssTimiGP based on paired RNA-seq data. As a result, ssTimiGP not only successfully identified interactions between different cell types that exhibited a significant correlation with experimental findings (e.g., CD4+ naïve T cells → Monocyte, R=0.75, p< 0.001, accuracy = 0.8), but also demonstrated its capability to achieve higher resolution in capturing interactions between immune cell subpopulations (e.g., CD4 naïve T cells → activated CD4+ memory T cells, R=0.57, p=0.008, accuracy = 1.0). In our benchmark analysis, ssTimiGP demonstrated superior performance compared to CIBERSORTx (e.g., CD4+ naïve T cells → Monocyte, R=0, Accuracy=0.3). In summary, ssTimiGP signifies an expansion of the TimiGP system, enabling the inference of the TME in individual solid tumors and liquid samples at various resolutions by integrating the strengths of both scRNA-seq and bulk RNA-seq. This approach offers substantial potential for advancing personalized cancer treatment. Citation Format: Chenyang Li, Jianjun Zhang, Chao Cheng. ssTimiGP: Equip the TimiGP system with a single-sample module, facilitating the cell-cell interaction inference of the tumor microenvironment in any sample [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4946.

Probing the Impact of Surface Functionalization Module on the Performance of Mitoxantrone Prodrug Nanoassemblies: Improving the Effectiveness and Safety.

Prodrug nanoassemblies are emerging as a novel drug delivery system for chemotherapy, comprising four fundamental modules: a drug module, a modification module, a response module, and a surface functionalization module. Among these modules, surface functionalization is an essential process to enhance the biocompatibility and stability of the nanoassemblies. Here, we selected mitoxantrone (MTO) as the drug module and DSPE-PEG2K as surface functionalization module to develop MTO prodrug nanoassemblies. We systematically evaluated the effect of surface functionalization module ratios (10%, 20%, 40%, and 60% of prodrug, WDSPE-mPEG2000/Wprodrug) on the prodrug nanoassemblies. The results indicated that 40% NPs significantly improved the self-assembly stability and cellular uptake of prodrug nanoassemblies. Compared with MTO solution, 40% NPs showed better tumor specificity and pharmacokinetics, resulting in potent antitumor activity with a good safety profile. These findings highlighted the pivotal role of the surface functionalization module in regulating the performance of mitoxantrone prodrug nanoassemblies for cancer treatment.

In Vitro Study of Interleukin-6 when Used at Low Dose and Ultra-Low Dose in Micro-Immunotherapy.

As one of the major cytokines implicated in the orchestration of immune responses, interleukin 6 (IL-6) can either act as a pro- or an anti-inflammatory factor, depending on the micro-environment. In micro-immunotherapy (MI) medicines, IL-6 is employed at low doses (LD) and ultra-low doses (ULD), expressed in centesimal Hahnemannian (CH), and used alone or in combination with other immune regulators to modulate patients' immune responses. The present study focused on assessing the in vitro immune-modulatory effects of two IL-6-containing MI products: (i) the unitary IL-6 (4 CH) and (ii) the complex MI-medicine (MIM) 2LALERG®, which includes IL-6 (17 CH) in association with other actives in its formulation. Our results showed that IL-6 (4 CH) activated granulocytes under basal conditions, and natural killer cells in the presence of an anti-CD3 signal, as assessed by their CD69 expression. In addition, IL-6 (4 CH) balanced the macrophages' differentiation toward a M2a profile. On the other hand, the tested 2LALERG® capsule inhibited the histamine degranulation of rats' peritoneal mast cells and reduced the release of IL-6 itself in inflamed human macrophages. Altogether, these data provide novel pieces of evidence on the double-edged potential of the LD and ULD of IL-6 in immune responses modulation, when employed in MI.