Quantitative trait loci detection for three tiller-related traits and the effects on wheat (Triticum aestivum L.) yields.

KEY MESSAGE: A total of 38 putative additive QTLs and 55 pairwise putative epistatic QTLs for tiller-related traits were reported, and the candidate genes underlying qMtn-KJ-5D, a novel major and stable QTL for maximum tiller number, were characterized. Tiller-related traits play an important role in determining the yield potential of wheat. Therefore, it is important to elucidate the genetic basis for tiller number when attempting to use genetic improvement as a tool for enhancing wheat yields. In this study, a quantitative trait locus (QTL) analysis of three tiller-related traits was performed on the recombinant inbred lines (RILs) of a mapping population, referred to as KJ-RILs, that was derived from a cross between the Kenong 9204 (KN9204) and Jing 411 (J411) lines. A total of 38 putative additive QTLs and 55 pairwise putative epistatic QTLs for spike number per plant (SNPP), maximum tiller number (MTN), and ear-bearing tiller rate (EBTR) were detected in eight different environments. Among these QTLs with additive effects, three major and stable QTLs were first documented herein. Almost all but two pairwise epistatic QTLs showed minor interaction effects accounting for no more than 3.0% of the phenotypic variance. The genetic effects of two colocated major and stable QTLs, i.e., qSnpp-KJ-5D.1 and qMtn-KJ-5D, for yield-related traits were characterized. The breeding selection effect of the beneficial allele for the two QTLs was characterized, and its genetic effects on yield-related traits were evaluated. The candidate genes underlying qMtn-KJ-5D were predicted based on multi-omics data, and TraesKN5D01HG00080 was identified as a likely candidate gene. Overall, our results will help elucidate the genetic architecture of tiller-related traits and can be used to develop novel wheat varieties with high yields.

Tailoring therapeutics via a systematic beneficial elements comparison between photosynthetic bacteria-derived OMVs and extruded nanovesicles.

Photosynthetic bacteria (PSB) has shown significant potential as a drug or drug delivery system owing to their photothermal capabilities and antioxidant properties. Nevertheless, the actualization of their potential is impeded by inherent constraints, including their considerable size, heightened immunogenicity and compromised biosafety. Conquering these obstacles and pursuing more effective solutions remains a top priority. Similar to extracellular vesicles, bacterial outer membrane vesicles (OMVs) have demonstrated a great potential in biomedical applications. OMVs from PSB encapsulate a rich array of bioactive constituents, including proteins, nucleic acids, and lipids inherited from their parent cells. Consequently, they emerge as a promising and practical alternative. Unfortunately, OMVs have suffered from low yield and inconsistent particle sizes. In response, bacteria-derived nanovesicles (BNVs), created through controlled extrusion, adeptly overcome the challenges associated with OMVs. However, the differences, both in composition and subsequent biological effects, between OMVs and BNVs remain enigmatic. In a groundbreaking endeavor, our study meticulously cultivates PSB-derived OMVs and BNVs, dissecting their nuances. Despite minimal differences in morphology and size between PSB-derived OMVs and BNVs, the latter contains a higher concentration of active ingredients and metabolites. Particularly noteworthy is the elevated levels of lysophosphatidylcholine (LPC) found in BNVs, known for its ability to enhance cell proliferation and initiate downstream signaling pathways that promote angiogenesis and epithelialization. Importantly, our results indicate that BNVs can accelerate wound closure more effectively by orchestrating a harmonious balance of cell proliferation and migration within NIH-3T3 cells, while also activating the EGFR/AKT/PI3K pathway. In contrast, OMVs have a pronounced aptitude in anti-cancer efforts, driving macrophages toward the M1 phenotype and promoting the release of inflammatory cytokines. Thus, our findings not only provide a promising methodological framework but also establish a definitive criterion for discerning the optimal application of OMVs and BNVs in addressing a wide range of medical conditions.

GSTM3 enhances radiosensitivity of nasopharyngeal carcinoma by promoting radiation-induced ferroptosis through USP14/FASN axis and GPX4.

BACKGROUND: Radiotherapy is a critical treatment modality for nasopharyngeal carcinoma (NPC). However, the mechanisms underlying radiation resistance and tumour recurrence in NPC remain incompletely understood. METHODS: Oxidised lipids were assessed through targeted metabolomics. Ferroptosis levels were evaluated using cell viability, clonogenic survival, lipid peroxidation, and transmission electron microscopy. We investigated the biological functions of glutathione S-transferase mu 3 (GSTM3) in cell lines and xenograft tumours. Co-immunoprecipitation, mass spectrometry, and immunofluorescence were conducted to explore the molecular mechanisms involving GSTM3. Immunohistochemistry was performed to investigate the clinical characteristics of GSTM3. RESULTS: Ionising radiation (IR) promoted lipid peroxidation and induced ferroptosis in NPC cells. GSTM3 was upregulated following IR exposure and correlated with IR-induced ferroptosis, enhancing NPC radiosensitivity in vitro and in vivo. Mechanistically, GSTM3 stabilised ubiquitin-specific peptidase 14 (USP14), thereby inhibiting the ubiquitination and subsequent degradation of fatty acid synthase (FASN). Additionally, GSTM3 interacted with glutathione peroxidase 4 (GPX4) and suppressed GPX4 expression. Combining IR treatment with ferroptosis inducers synergistically improved NPC radiosensitivity and suppressed tumour growth. Notably, a decrease in GSTM3 abundance predicted tumour relapse and poor prognosis. CONCLUSIONS: Our findings elucidate the pivotal role of GSTM3 in IR-induced ferroptosis, offering strategies for the treatment of radiation-resistant or recurrent NPC.

MRI-Based Interstitial Fluid Velocity Analysis for Drug Delivery Efficiency Evaluation in Tumor.

There are many flow behaviors in solid tumors, including intravascular, bloodstream, and interstitial convection. Studies have shown that tumor interstitial fluid (TIF) is an important part of tumor microenvironment regulation and affects drug delivery and metabolism between tumor cells. Magnetic resonance imaging (MRI) is suitable for detecting the flow rates of liquids in tissues. Clinical phase contrast PC-MRI technology has been designed to observe the blood flow in large vessels such as arteries and veins; however, it is not sensitive enough to deal with slow flow velocity. Our previously developed vertical plane echo PC-MRI technology, the Velocity Mapping sequence, improved the signal-to-noise ratio (SNR) for measuring slow interstitial fluid rate. In this study, this sequence was used to determine the TIF flow rate in MDA-MB-231 human breast tumor cells used in BALB/c nude male mice. Two different sizes of contrast agents were intravenously injected, and the relationship between their distribution and the TIF flow rate was studied for the first time. Combining the results of clinical scanning showed that small-molecule DTPA-Gd (diethylenetriaminepentaacetic acid-gadolinium) was distributed immediately around the tumor margin after the injection. This distribution was positively correlated to the high flow rate area of the TIF before administration. In contrast, nanoparticles NaGdF4-PEG (polyethylene glycol) entered the tumor and reached their peak at 3 h. Drug distribution was negatively correlated with the high-flow-rate region of the TIF. Investigation of the TIF velocity can help better understand the fluid behavior in tumors and its role in drug delivery.

Low sucrose availability reduces basal spikelet fertility by inducing ABA and JA synthesis in wheat.

Within a spike of wheat, central spikelet usually generates 3-4 fertile florets, while basal spikelet hardly achieves it; in fact, the physiological and transcriptional mechanism behind the difference in fertility between basal and central spikelet is unclear. This study reports a high temporal-resolution investigation of transcriptomes, number and morphology of floret primordia and physiological traits. The W6.5-W7.5 stage was regarded as a boundary domain to distinguish between fertile and abortive potential of floret primordia; those floret primordia reaching the W6.5-7.5 stage during differentiation phase (3-9 days after terminal spikelet stage, DAT) usually developed into fertile florets in the next dimorphism phase (12-27 DAT), whereas the others aborted. Central spikelet had a greater number of fertile florets than basal spikelet, which was associated with more floret primordia reaching the W6.5-7.5 stage. Physiological and transcriptional results demonstrated that central spikelet had a higher sucrose content, lower abscisic acid (ABA) and jasmonic acid (JA) accumulation than basal spikelet due to down-regulation of genes involved in ABA and JA synthesis. Collectively, we proposed a model in which ABA and JA accumulation was induced under limiting sucrose availability (basal spikelet) through up-regulating genes involved in ABA and JA synthesis; this led to floret primordia in basal spikelet hardly to reach fertile potential (W6.5-7.5 stage) during differentiation phase and then aborted. This fertility repression module may also regulate spikelet fertility in other cereal crops and potentially provide genetic resources to improve spikelet fertility.

Leveraging circulating microbiome signatures to predict tumor immune microenvironment and prognosis of patients with non-small cell lung cancer.

BACKGROUND: Accumulating evidence supports the significant role of human microbiome in development and therapeutic response of tumors. Circulating microbial DNA is non-invasive and could show a general view of the microbiome of host, making it a promising biomarker for cancers. However, whether circulating microbiome is associated with prognosis of non-small cell lung cancer (NSCLC) and its potential mechanisms on tumor immune microenvironment still remains unknown. METHODS: The blood microbiome data and matching tumor RNA-seq data of TCGA NSCLC patients were obtained from Poore's study and UCSC Xena. Univariate and multivariate Cox regression analysis were used to identify circulating microbiome signatures associated with overall survival (OS) and construct the circulating microbial abundance prognostic scoring (MAPS) model. Nomograms integrating clinical characteristics and circulating MAPS scores were established to predict OS rate of NSCLC patients. Joint analysis of blood microbiome data and matching tumor RNA-seq data was used to deciphered the tumor microenvironment landscape of patients in circulating MAPS-high and MAPS-low groups. Finally, the predictive value of circulating MAPS on the efficacy of immunotherapy and chemotherapy were assessed. RESULTS: A circulating MAPS prediction model consisting of 14 circulating microbes was constructed and had an independent prognostic value for NSCLC. The integration of circulating MAPS into nomograms may improve the prognosis predictive power. Joint analysis revealed potential interactions between prognostic circulating microbiome and tumor immune microenvironment. Especially, intratumor plasma cells and humoral immune response were enriched in circulating MAPS-low group, while intratumor CD4 + Th2 cells and proliferative related pathways were enriched in MAPS-high group. Finally, drug sensitivity analysis indicated the potential of circulating MAPS as a predictor of chemotherapy efficacy. CONCLUSION: A circulating MAPS prediction model was constructed successfully and showed great prognostic value for NSCLC. Our study provides new insights of interactions between microbes, tumors and immunity, and may further contribute to precision medicine for NSCLC.

Diverse regulated cell death modes predict the immune microenvironment and drug sensitivity in lung adenocarcinoma.

Integrated action modes of regulated cell death (RCD) in lung adenocarcinoma (LUAD) have not been comprehensively dissected. Here, we adopted 15 RCD modes, including 1350 related genes, and established RCD signature scores. We found that LUAD patients with high RCD scores had a significantly worse prognosis in all four different cohorts (TCGA, KM-plotter, GSE31210, and GSE30219). Our nomogram established based on the RCD score and clinical characteristics performed well in both the discovery and validation sets. There was a close correlation between the RCD scores and LUAD molecular subtypes identified by unsupervised consensus clustering. Furthermore, we profiled the tumor microenvironment via deconvolution and found significant differences in immune activity, transcription factor activity and molecular pathway enrichment between the RCD-high and RCD-low groups. More importantly, we revealed that the regulation of antigen presentation is the crucial mechanism underlying RCD. In addition, higher RCD scores predict poorer sensitivity to multiple therapeutic drugs, which indicates that RCD scores may serve as a promising predictor of chemotherapy and immunotherapy outcomes. In summary, this work is the first to reveal the internal links between RCD modes, LUAD, and cancer immunity and highlights the necessity of RCD scores in personalizing treatment plans.

Association between host nitrogen absorption and root-associated microbial community in field-grown wheat.

Plant roots and rhizosphere soils assemble diverse microbial communities, and these root-associated microbiomes profoundly influence host development. Modern wheat has given rise to numerous cultivars for its wide range of ecological adaptations and commercial uses. Variations in nitrogen uptake by different wheat cultivars are widely observed in production practices. However, little is known about the composition and structure of the root-associated microbiota in different wheat cultivars, and it is not sure whether root-associated microbial communities are relevant in host nitrogen absorption. Therefore, there is an urgent need for systematic assessment of root-associated microbial communities and their association with host nitrogen absorption in field-grown wheat. Here, we investigated the root-associated microbial community composition, structure, and keystone taxa in wheat cultivars with different nitrogen absorption characteristics at different stages and their relationships with edaphic variables and host nitrogen uptake. Our results indicated that cultivar nitrogen absorption characteristics strongly interacted with bacterial and archaeal communities in the roots and edaphic physicochemical factors. The impact of host cultivar identity, developmental stage, and spatial niche on bacterial and archaeal community structure and network complexity increased progressively from rhizosphere soils to roots. The root microbial community had a significant direct effect on plant nitrogen absorption, while plant nitrogen absorption and soil temperature also significantly influenced root microbial community structure. The cultivar with higher nitrogen absorption at the jointing stage tended to cooperate with root microbial community to facilitate their own nitrogen absorption. Our work provides important information for further wheat microbiome manipulation to influence host nitrogen absorption. KEY POINTS: • Wheat cultivar and developmental stage affected microbiome structure and network. • The root microbial community strongly interacted with plant nitrogen absorption. • High nitrogen absorption cultivar tended to cooperate with root microbiome.

A robust MRI contrast agent for specific display of the interstitial stream.

Experimental and clinical studies have reported phenomena of long-range fluid flow in interstitial space. However, its behaviours and functions are yet to be addressed. The imaging of the interstitial stream in vivo can clarify its transportation route and allow further understanding of physiological mechanisms and clinical relevance. Here to illustrate the route of the interstitial stream leading to the kidney, we design and synthesize a magnetic resonance imaging (MRI) contrast agent PAA-g-(DTPA-gadolinium). This MRI agent has a high longitudinal relaxivity for higher MRI contrast and large size to avoid leakage across the interstitial space. Using dynamic contrast enhanced MRI, histochemical staining, and trace element analysis of gadolinium, we track the nano-scale PAA-g-(DTPA-gadolinium) transported in the interstitial stream. The agent can be applied for a wide range of imaging and analysis of tissues and organs, thereby enabling advances in the fields of physiology, pathology, and pharmacology.

High-Sensitivity, Low-Field 19F-MRI Approach Using High Manganese Ferrite Concentrations.

Fluorine-19 (19F) MRI (19F-MRI) is a promising method for quantifying biomedical research and clinical applications without background interference. Nevertheless, dependency on high-field MRI systems limits the applicability of 19F-MRI. Low-field MRI systems are more common than high-field MRI systems. Hence, developing 19F-MRI at low-field MRI devices can promote the 19F-MRI translation in medical diagnosis. The detection sensitivity of fluorine agents is critical in 19F-MRI. Reduction of the 19F spin-lattice relaxation time (T1) enables an improved detection sensitivity while requiring ultrashort echo time (UTE) imaging methods to reduce the negative spin-spin relaxation (T2) decay effect. However, conventional UTE sequences require hardware with high performance. Herein, we introduce the k-space scaling imaging (KSSI) MRI sequence that accomplishes sampling k-space with variable scales to implement hardware-friendly UTE 19F-MRI compatible with low-field MRI systems. We implemented experiments with swine bone, a perfluorooctyl bromide (PFOB) phantom, and one tumor-bearing mouse on two self-customized low-field MRI systems. The swine bone imaging validated the ultrashort TE of KSSI. Under high concentrations of manganese ferrite, a high signal-to-noise ratio was shown in the imaging of a fluorine atom concentration of 658 mM, which indicated high-sensitivity detection of KSSI. Moreover, the KSSI sequence exhibited a 7.1 times signal-to-noise ratio of spin echo sequence on the PFOB phantom imaging with a fluorine atom concentration of 3.29 M. Additionally, the various concentrations of the PFOB phantom imaging revealed quantifiable capacity. Finally, the 1H/19F imaging was implemented with KSSI on one tumor-bearing mouse. This method provides the potential for clinical translation of fluorine probes at low-field MRI systems.

Immunogenetic polymorphisms predict therapeutic efficacy and survival outcomes in tumor patients receiving PD-1/PD-L1 blockade.

BACKGROUND: While immune checkpoint inhibitors (ICIs) demonstrate remarkable clinical responses, only a small subset of patients obtains benefits. Genes linked to the tumor immune system are confirmed to be critical for the treatment of ICIs, and their polymorphisms can contribute to ICI efficacy. Here, we examined the potential of immunogenetic variations to predict the efficacy and survival of the PD-1/PD-L1 blockade. METHODS: Cancerous patients receiving PD-1/PD-L1 blockade were recruited and followed up. Pivotal genes related to tumor-immunity were filtered through a protein-protein interaction network and the degree algorithm in Cytoscape. Finally, 39 genetic variants were genotyped through multiplex genotyping assays. Association analyses between variants and ICI efficacy and progression-free survival (PFS) were performed. RESULTS: Overall, 318 patients were ultimately enrolled. Hence, three immunogenetic variants were identified as predictors of PD-1/PD-L1 blockade response. Mutant alleles from ATG7 rs7625881, CD274 rs2297136, and TLR4 rs1927911 were all at increased risk of tumor progression following ICI therapy (OR: 1.475, 1.641, 1.462, respectively; P value: 0.028, 0.017, 0.027, respectively). Significant immunogenetic variants also attained similar trends in the PD-1 blockade, lung cancer, or lung cancer using PD-1 blockade subgroups. Furthermore, the mutant genotypes of CD274 rs2297136 (GG as the reference: HR: 0.50 (95%CI: 0.29-0.88), P value: 0.015) and TLR4 rs1927911 (AA as the reference: HR: 0.65 (95%CI: 0.47-0.91), P value: 0.012) indicated poorer PFS and were both independent prognostic factors. CONCLUSION: Immunogenetic polymorphisms, including ATG7 rs7625881, CD274 rs2297136, and TLR4 rs1927911, were first identified as potential predictors of response to PD-1/PD-L1 blockade in tumor patients.

Repeated Photobiomodulation Induced Reduction of Bilateral Cortical Hemodynamic Activation During a Working Memory Task in Healthy Older Adults.

Transcranial photobiomodulation (tPBM) is an emerging non-invasive light-based neuromodulation technique that shows promising potential for improving working memory (WM) performance in older adults. However, the neurophysiological mechanisms associated with tPBM that underlie the improvement of WM and the persistence of such improvement have not been investigated. Sixty-one healthy older adults were recruited to receive a baseline sham stimulation, followed by one-week active tPBM (12 min daily, 1064-nm laser, 250 mW/cm2) and three-week follow-ups. N-back WM task was conducted on post-stimulation of the baseline, the first (Day 1) and seventh (Day 7) days of the active treatment, and at the follow-ups. During the task, functional near-infrared spectroscopy (fNIRS) imaging was employed to record the cortical hemodynamic changes. Brain activations during the active and follow-up sessions were compared with the baseline to determine how tPBM had changed cortical hemodynamic activity and how long these changes persisted. We found that tPBM stimulation on Day 1 induced significantly decreased activation in the right hemisphere during the 3-back. The decreased activation expanded from only the right hemisphere on Day 1 to both hemispheres on Day 7. The decreased activation persisted for one week in the right supramarginal gyrus and the left angular gyrus and two weeks in the left somatosensory association cortex. These activation changes were accompanied by significantly improved task accuracy during the N-back. These findings provide important evidence for understanding neural mechanisms underlying cognitive enhancement after tPBM.

Machine learning versus crop growth models: an ally, not a rival.

The rapid increases of the global population and climate change pose major challenges to a sustainable production of food to meet consumer demands. Process-based models (PBMs) have long been used in agricultural crop production for predicting yield and understanding the environmental regulation of plant physiological processes and its consequences for crop growth and development. In recent years, with the increasing use of sensor and communication technologies for data acquisition in agriculture, machine learning (ML) has become a popular tool in yield prediction (especially on a large scale) and phenotyping. Both PBMs and ML are frequently used in studies on major challenges in crop production and each has its own advantages and drawbacks. We propose to combine PBMs and ML given their intrinsic complementarity, to develop knowledge- and data-driven modelling (KDDM) with high prediction accuracy as well as good interpretability. Parallel, serial and modular structures are three main modes can be adopted to develop KDDM for agricultural applications. The KDDM approach helps to simplify model parameterization by making use of sensor data and improves the accuracy of yield prediction. Furthermore, the KDDM approach has great potential to expand the boundary of current crop models to allow upscaling towards a farm, regional or global level and downscaling to the gene-to-cell level. The KDDM approach is a promising way of combining simulation models in agriculture with the fast developments in data science while mechanisms of many genetic and physiological processes are still under investigation, especially at the nexus of increasing food production, mitigating climate change and achieving sustainability.

Separable Microneedles with Photosynthesis-Driven Oxygen Manufactory for Diabetic Wound Healing.

Oxygen plays an important role in diabetic chronic wound healing by regulating various life activities such as cell proliferation, migration, and angiogenesis. Therefore, oxygen-delivering systems have drawn much attention and evolved continuously. Here, we propose that an active Chlorella vulgaris (Cv)-loaded separable microneedle (MN) can be used to control oxygen delivery, which then promotes wound healing. The Cv-loaded microneedles (CvMN) consist of a polyvinyl acetate (PVA) substrate and gelatin methacryloyl (GelMA) tips with encapsulated Cv. Once CvMN is applied to diabetic wound, the PVA basal layer is rapidly dissolved in a short time, while the noncytotoxic and biocompatible GelMA tips remain in the skin. By taking advantage of the photosynthesis of Cv, oxygen would be continuously produced in a green way and released from CvMN in a controlled manner. Both in vitro and in vivo results showed that CvMN could promote cell proliferation, migration, and angiogenesis and enhance wound healing in diabetic mice effectively. The remarkable therapeutic effect is mainly attributed to the continuous generation of dissolved oxygen in CvMN and the presence of antioxidant vitamins, γ-linolenic acid, and linoleic acid in Cv. Thus, CvMN provides a promising strategy for diabetic wound healing with more possibility of clinical transformations.

KNSTRN, a Poor Prognostic Biomarker, Affects the Tumor Immune Microenvironment and Immunotherapy Outcomes in Pan-Cancer.

Kinetochore-localized astrin- (SPAG5-) binding protein (KNSTRN) is mainly involved in mitosis. Somatic mutations in KNSTRN are known to lead to the occurrence and development of certain tumors. However, the role of KNSTRN in the tumor immune microenvironment (TIME) as a tumor prognostic biomarker and potential therapeutic target has not been clarified. Accordingly, in this study, we aimed to investigate the role of KNSTRN in the TIME. mRNA expression, cancer patient prognosis, and correlations between KNSTRN expression and immune component infiltration were analyzed using Genotype-Tissue Expression, The Cancer Genome Atlas, Cancer Cell Line Encyclopedia, Human Protein Atlas, ImmuCellAI, TIMER2.0, and KM-Plotter. The Genomics of Drug Sensitivity in Cancer database was used to evaluate the relationship between KNSTRN expression and the half maximal inhibitory concentration (IC50) of several anticancer drugs, and gene set variation analysis was performed. Data were visualized using R version 4.1.1. KNSTRN expression was upregulated in the majority of cancers and was associated with a worse prognosis. Additionally, KNSTRN expression was highly correlated with the infiltration of multiple immune components in the TIME and was related to a poor prognosis in tumor patients receiving immunotherapy. KNSTRN expression was also positively correlated with the IC50 of various anticancer drugs. In conclusion, KNSTRN may be a significant prognostic biomarker and promising target for oncotherapy in numerous cancers.

Combined removal of SO3 and HCl by modified Ca(OH)2 from coal-fired flue gas.

As treatments for mainstream pollutants in coal-fired power plants have been established, the control of non-conventional pollutants, such as SO3 and HCl, is gradually gaining attention. In this study, combined SO3 and HCl removal is proposed based on SO3 removal by absorber injection. However, it is challenging to selectively absorb SO3 and HCl from SO2-rich atmospheres. Therefore, Ca(OH)2 was modified via ball milling and doping with CuO for the combined removal of SO3 and HCl. The results showed that ball milling reduced the particle and grain sizes of Ca(OH)2, which increased the active sites of Ca(OH)2 and prolonged reaction time. After modification by ball milling, SO3 absorption per mg of Ca(OH)2 increased by 40 %. However, HCl removal efficiency was difficult to improve by modifying Ca(OH)2 using only ball milling under SO3 and SO2 atmospheres. Therefore, the dechlorination capacity of Ca(OH)2 was improved by adding ions during the ball milling process. Doping of Ca(OH)2 with Cu2+ changed its crystal structure, weakened the diffusion resistance of HCl, and improved Ca(OH)2 utilization. Additionally, it increased the energy of Ca(OH)2 to adsorb HCl.

Parental Psychological Flexibility and Children's Behavior Problems in Rural Areas in Northeast China: The Mediation of Children's Emotion Regulation.

Children's behavior problems are not conducive to their sustainable development. Therefore, it is of great value to explore the mechanism of relevant influencing factors on the behavior problems of rural preschoolers. This study aimed to reveal the direct effect of parental psychological flexibility on children's behavior problems and the mediating effect of children's emotion regulation. Based on simple random sampling, 355 caregivers (male = 31.25 years, SD = 9.78; 74.08% females; 9.01% bachelor degree) were recruited from eight rural kindergartens in three provinces in northeast China. With questionnaires, caregivers reported their parental psychological flexibility and assessed their children's emotion regulation and behavior problems. SPSS 25.0 software was used for statistical data analysis. The results support our hypotheses, suggesting that parental psychological flexibility, emotional stability, and emotional regulation negatively predicted children's externalizing and internalizing behavior problems. Meanwhile, emotional stability and regulation partially mediated the relationship between parental psychological flexibility and children's externalizing and internalizing behavior problems. These findings provide a new perspective for preventing and intervening in preschoolers' behavior problems.

Repeated transcranial photobiomodulation improves working memory of healthy older adults: behavioral outcomes of poststimulation including a three-week follow-up.

Significance: Decline in cognitive ability is a significant issue associated with healthy aging. Transcranial photobiomodulation (tPBM) is an emerging non-invasive neuromodulation technique and has shown promise to overcome this challenge. Aim: This study aimed to investigate the effects of seven-day repeated tPBM, compared to those of single tPBM and baseline, on improving N -back working memory in healthy older adults and to evaluate the persistent efficacy of repeated tPBM. Approach: In a sham-controlled and within-subject design, 61 healthy older adults were recruited to participate in a longitudinal study involving an experimental baseline, seven days of tPBM treatment (12 min daily, 1064-nm laser, 250 mW / cm 2 ) in the left dorsolateral prefrontal cortex and three weeks of follow-ups. Behavioral performance in the N -back ( N = 1,2 , 3 ) was recorded poststimulation during the baseline, the first and seventh days of the tPBM session, and the three weekly follow-ups. A control group with 25 participants was included in this study to rule out the practice and placebo effects. The accuracy rate and response time were used in the statistical analysis. Results: Repeated and single tPBM significantly improved accuracy rate in 1- and 3-back tasks and decreased response time in 3-back compared to the baseline. Moreover, the repeated tPBM resulted in a significantly higher improvement in accuracy rate than the single tPBM. These improvements in accuracy rate and response time lasted at least three weeks following repeated tPBM. In contrast, the control group showed no significant improvement in behavioral performance. Conclusions: This study demonstrated that seven-day repeated tPBM improved the working memory of healthy older adults more efficiently, with the beneficial effect lasting at least three weeks. These findings provide fundamental evidence that repeated tPBM may be a potential intervention for older individuals with memory decline.

Exosome transportation-mediated immunosuppression relief through cascade amplification for enhanced apoptotic body vaccination.

Cancer vaccines represent the most promising strategies in the battle against cancers. Eliciting a robust therapeutic effect with vaccines, however, remains a challenge owing to the weak immunogenicity of autologous tumor antigens and highly immunosuppressive microenvironment. In the present study, we constructed CpG oligodeoxyribonucleotide (CpG ODN)-loaded cancer cell apoptotic bodies (Abs) as cancer vaccines for enhanced immunotherapy through cascade amplification-mediated immunosuppression relief. Abs that contain an abundant source of tumor-specific neoantigens and other tumor-associated antigens (TAAs) can be regarded as vaccines with higher immunogenicity. The de novo synthesized Abs-CpG could target and polarize macrophages to improve the immunosuppressive microenvironment. More importantly, we found that the effect of immunosuppression relief was cascade amplified, which was mediated by M1 macrophage-derived exosome transportation. Our results showed that CpG ODN polarized macrophages to M1 type and produced a large amount of TNF-α, which then activated cell division control protein 42 (Cdc42). Interestingly, we found that exosomes from M1 macrophages delivered Cdc42 and CpG to adjacent macrophages and further enhanced the phagocytosis of adjacent macrophages by positive feedback. Through cascade amplification induced by Abs-CpG with macrophage exosomes, the immunogenicity and immunosuppressive microenvironment were greatly improved, which then enhanced the performance of cancer vaccine therapy. Thus, we propose that a strategy of combining the Abs-based vaccine platform with the immunomodulatory approach represents the next generation of cancer immunotherapy. STATEMENT OF SIGNIFICANCE: 1. We discovered a relieving strategy for tumor immunosuppressive microenvironment: Abs-CpG polarized macrophages to M1 type, and M1 macrophage-derived exosomes delivered Cdc42 and CpG to adjacent macrophages, which then further enhanced the phagocytosis of adjacent macrophages by positive feedback. Through cascade amplification induced by the transfer of macrophage exosomes, the immunogenicity and immunosuppressive microenvironment were greatly improved. 2. As a vaccine, Abs contained both tumor-specific neoantigens and other tumor-associated antigens with higher immunogenicity and high clinical transformability.

Near-infrared light and redox dual-activatable nanosystems for synergistically cascaded cancer phototherapy with reduced skin photosensitization.

Currently, activatable photodynamic therapy (PDT) that is precisely regulated by endogenous or exogenous stimuli to selectively produce cytotoxic reactive oxygen species at the tumor site is urgently in demand. Herein, we fabricated a dual-activatable PDT nanosystem regulated by the redox tumor microenvironment and near-infrared (NIR) light-induced photothermal therapy (PTT). In this study, photosensitizer chlorin e6 (Ce6) was conjugated to hyaluronic acid (HA) via a diselenide bond to form an amphiphilic polymer (HSeC) for loading PTT agent IR780 to produce HSeC/IR nanoparticles (NPs). The photoactivity of Ce6 for PDT was "double-locked" by the aggregation-caused quenching (ACQ) effect and the fluorescence resonance energy transfer (FRET) from Ce6 to IR780 during blood circulation. After selective accumulation into tumors, HSeC/IR NPs were subsequently dissociated due to the "double-key", which included diselenide bond dissociation under high redox conditions and IR780 degradation upon NIR laser irradiation, resulting in recovering Ce6. In vitro studies indicated that Ce6 photoactivity in HSeC/IR NPs was significantly suppressed when compared with free Ce6 or in HSeC NPs. Moreover, BALB/c mice treated with HSeC/IR NPs displayed distinctly alleviated skin damage during PDT. Synergetic cascaded PTT-PDT with superior tumor suppression was observed in SCC7 tumor-bearing mice. Therefore, the study findings could provide a promising treatment strategy for PTT-facilitated PDT with high antitumor efficacies and reduced skin phototoxicity levels.