Genome and Transcriptome Analysis of the Torreya grandis WRKY Gene Family during Seed Development.

Torreya grandis, an economically significant evergreen tree species exclusive to subtropical China, is highly valued for its seeds. However, the seed development process of T. grandis remains relatively unexplored. Given the pivotal role WRKY transcription factors (TFs) play in coordinating diverse cellular and biological activities, as well as crucial signaling pathways essential for plant growth and development, and the lack of comprehensive investigation into their specific functions in T. grandis, our study investigated its genome and successfully isolated 78 WRKY genes and categorized them into three distinct clades. A conserved motif analysis unveiled the presence of the characteristic WRKY domain in each identified TgWRKY protein. The examination of gene structures revealed variable numbers of introns (ranging from zero to eight) and exons (ranging from one to nine) among TgWRKY genes. A chromosomal distribution analysis demonstrated the presence of TgWRKY across eight chromosomes in T. grandis. Tissue-specific expression profiling unveiled distinctive patterns of these 78 TgWRKY genes across various tissues. Remarkably, a co-expression analysis integrating RNA-seq data and morphological assessments pinpointed the pronounced expression of TgWRKY25 during the developmental stages of T. grandis seeds. Moreover, a KEGG enrichment analysis, focusing on genes correlated with TgWRKY25 expression, suggested its potential involvement in processes such as protein processing in the endoplasmic reticulum, starch, and sucrose metabolism, thereby modulating seed development in T. grandis. These findings not only underscore the pivotal role of WRKY genes in T. grandis seed development but also pave the way for innovative breeding strategies.

The interaction of RELN-DNMT genes involving in neurotrophin signaling pathway contributes to schizophrenia susceptibility.

OBJECTIVE: Schizophrenia belongs to a severe mental illness with complicated clinical presentations, an ill-defined pathogenesis, and no known cause. Many genetic studies imply that polygenic interaction is important in the development of schizophrenia. The main mechanism of the RELN-BDNF-CREB-DNMT signaling pathway in neurodevelopment involves RELN, brain-derived neurotrophic factor (BDNF), transcription factor cyclic adenosine monophosphate response element binding protein (CREB), DNA methyltransferase 1 (DNMT1), as well as DNA methyltransferase 3B (DNMT3B). An early case-control research on 15 polymorphisms in the RELN, CREB, BDNF, DNMT1, and DNMT3B genes was done. A single gene variation has little effect on the pathogenesis of schizophrenia, but the combination of intergenic variation loci has a bigger impact because schizophrenia is a complex polygenic disorder. The objective of the current study sought to explore the impact of genetic interactions between RELN, BDNF, CREB, DNMT1, and DNMT3B on schizophrenia in order to further highlight the genetic factors influencing the risk of schizophrenia. METHODS: Taking the case-control study design, with the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5) to be the evaluation norm, 134 individuals suffering from schizophrenia hospitalized in the Third People's Hospital of Zhongshan City within January 2018 to April 2020 (case group) were selected, and 64 healthy individuals (control group) from the same geographical area had been chosen as well. MassArray identified DNMT1 gene single nucleotide polymorphisms (rs2114724 and rs2228611) and DNMT3B gene SNPs (rs2424932, rs1569686, rs6119954, and rs2424908). Using the generalized multifactor dimensionality reduction (GMDR), the RELN-BDNF-CREB-DNMT pathway's gene interactions were examined for their impact on schizophrenia. RESULTS: GMDR analysis showed that the three-order interaction model RELN (rs2073559, rs2229864)-DNMT3B (rs2424908) was the optimal model (p = 0.001), with the consistency of cross-validation of 10/10 and the test accuracy of 0.8711. CONCLUSION: The interaction between the RELN (rs2073559, rs2229864)-DNMT3B (rs2424908) may be related to schizophrenia, and large sample sizes should be verified in different population.

A stratospheric precursor of East Asian summer droughts and floods.

East Asian floods and droughts in summer show a typical dipole pattern with a north-south oscillation centered near 30°N, called the southern drought-northern flood (SDNF) pattern, which has caused significant economic losses and casualties in the past three decades. However, effective explanations and predictions are still challenging, making suitable disaster prevention more difficult. Here, we find that a key predictor of this dipole pattern is the Quasi-Biennial Oscillation (QBO, tropical winds above 10 km). The QBO can modulate precipitation in East Asia, contributing the largest explained variation of this dipole pattern. A QBO-included statistical model can effectively predict summer floods and droughts at least three months in advance and explain at least 75.8% of precipitation variation. More than 30% of the SDNF pattern is attributed to the QBO in July-August 2020 and 2021. This result suggests a good prospect for using the tropical mid- to upper atmosphere in seasonal forecasts for summer.

Berberine hydrochloride-loaded dung beetle chitosan/sodium alginate microspheres ameliorate DSS-induced colitis and regulate gut microorganisms in mice.

Berberine hydrochloride (BH) has long been known for its therapeutic efficacy. In the present study, we aimed to treat mice with colitis using dung beetle chitosan (DCS) -transported BH. To achieve this, BH-loaded DCS/sodium alginate microspheres (SA-DCS-BH) were prepared. The SA-DCS-BH was characterized using SEM, DLS, FT-IR, and XRD, then was used for administration and anti-inflammatory examination in mice. SEM and DLS confirmed the surface morphology of the microspheres, and the particle size was relatively uniform. FT-IR and XRD results confirmed that BH was successfully loaded. In vitro and in vivo studies showed that SA-DCS-BH had slow-release ability. After treatment with SA-DCS-BH, DAI was significantly reduced, colon weight and length increased, spleen length and weight reduced, concentrations of pro-inflammatory cytokines in colonic tissues were reduced, and gut microbiota species abundance was modulated. In addition, this study found a correlation between specific microbes and colitis indicators, Muribaculaceae showed sequential growth after receiving BH, SA-CS-BH, and SA-DCS-BH treatments, respectively. It was concluded that SA-DCS-BH effectively delivered the BH to the intestine with slow-release ability and exhibited anti-inflammatory effects by immune response. Compared to commercial chitosan, DCS has potential for modulating intestinal microorganisms and more suitable carrier for intestinal drug delivery systems.

DNMT1 SNPs (rs2114724 and rs2228611) associated with positive symptoms in Chinese patients with schizophrenia.

OBJECTIVE: Schizophrenia is a serious mental disorder with complex clinical manifestations, while its pathophysiological mechanism is not fully understood. Accumulated evidence suggested the alteration in epigenetic pathway was associated with clinical features and brain dysfunctions in schizophrenia. DNA methyltransferases (DNMTs), a key enzyme for DNA methylation, are related to the development of schizophrenia, whereas the current research evidence is not sufficient. The aim of study was to explore the effects of gene polymorphisms of DNMTs on the susceptibility and symptoms of schizophrenia. METHODS: The study was case-control study that designed and employed the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5) as the diagnostic standard. 134 hospitalized patients with schizophrenia in the Third People's Hospital of Zhongshan City from January 2018 to April 2020 (Case group) as well as 64 healthy controls (Control group) from the same region were involved. Single nucleotide polymorphisms (SNPs) of DNMT1 genes (r s2114724 and rs 2228611) and DNMT3B genes (rs 2424932, rs 1569686, rs 6119954 and rs 2424908) were determined with massARRAY. Linkage disequilibrium analysis and haplotype analysis were performed, and genotype and allele frequencies were compared. The Hardy-Weinberg equilibrium was tested by the Chi-square test in SPSS software (version 20.0, SPSS Inc., USA). The severity of clinical symptoms was assessed by the Positive and Negative Syndrome Scale (PANSS). The correlation between DNMT1 genes (rs 2114724 and rs 2228611) and DNMT3B genes (rs2424932, rs1569686, rs6119954 and rs2424908) and clinical features was analyzed. RESULTS: There were no significant differences in genotype, allele frequency and haplotype of DNMT1 genes (rs 2114724 and rs 2228611) and DNMT3B genes (rs 2424932, rs 1569686, rs 6119954 and rs 2424908) between the case and healthy control group. There were significant differences in the PANSS total positive symptom scores, P3 (hallucinatory behavior), P6 (suspicious/persecution), G7 (motor retardation), and G15 (preoccupation) in patients with different DNMT1 gene rs 2114724 and rs 2228611 genotypes. The linkage disequilibrium analysis of gene polymorphic loci revealed that rs 2114724-rs 2228611 was complete linkage disequilibrium, and rs 1569686-rs 2424908, rs 2424932-rs 1569696 and rs 2424932-rs 2424908 were strongly linkage disequilibrium. CONCLUSION: The polymorphisms alteration in genetic pathway may be associated with development of specific clinical features in schizophrenia.

Chitosan microspheres-based controlled-release nitrogen fertilizers improve the biological characteristics of Brassica rapa ssp. pekinensis and the soil.

Present study investigates the impact of chitosan microspheres-based controlled-release nitrogen fertilizer (Cm-CRNFs) on biological characteristics of Brassica rapa ssp. pekinensis (Chinese cabbage) and soil. The study was carried out under various four treatments, urea (0.8033 g), blank chitosan microspheres (without urea), Cm-CRNFs (0.8033 g), and a control group (CK). The results indicated that Cm-CRNFs significantly prolonged the nitrogen release and enhanced the plant shoot length, shoot diameter, number of branches, pods, total amino acids, and vitamin C of Brassica rapa ssp. pekinensis as well as increased the soil nutrient availability. Chao index of bacterial diversity analysis showed a significant reduction of 15.89 % in Cm-CRNFs, but the Shannon index value in Cm-CRNFs was increased by 23.55 % compared to CK. Furthermore, Cm-CRNFs treatment significantly influenced genus richness level of Arthrobacter, Archangium, Bacillus, and Flavihumibacter. Moreover, relative abundance of bacteria significantly enhanced Cm-CRNFs, including Acidobacteriota, Acitinobacteriota, Cloroflexi, Cyanobacteria, and Patescibacteria. Soil enzyme activity such as: urease, acid phosphatase, and catalase enzymes in Cm-CRNFs and urea treatment significantly increased. Besides, other enzymes such as: cellulase and ß-glucosidase activity decreased in the Cm-CRNFs treatment. It was concluded that Cm-CRNFs potentially prolonged discharge of micro/macronutrients and improved soil bacterial diversity, which ultimately enhanced the soil fertility and improved the soil enzyme activity.

Genome-Wide Identification of SPX Family Genes and Functional Characterization of PeSPX6 and PeSPX-MFS2 in Response to Low Phosphorus in Phyllostachys edulis.

Moso bamboo (Phyllostachys edulis) is the most widely distributed bamboo species in the subtropical regions of China. Due to the fast-growing characteristics of P. edulis, its growth requires high nutrients, including phosphorus. Previous studies have shown that SPX proteins play key roles in phosphorus signaling and homeostasis. However, the systematic identification, molecular characterization, and functional characterization of the SPX gene family have rarely been reported in P. edulis. In this study, 23 SPXs were identified and phylogenetic analysis showed that they were classified into three groups and distributed on 13 chromosomes. The analysis of conserved domains indicated that there was a high similarity between PeSPXs among SPX proteins in other species. RNA sequencing and qRT-PCR analysis indicated that PeSPX6 and PeSPX-MFS2, which were highly expressed in roots, were clearly upregulated under low phosphorus. Co-expression network analysis and a dual luciferase experiment in tobacco showed that PeWRKY6 positively regulated the PeSPX6 expression, while PeCIGR1-2, PeMYB20, PeWRKY6, and PeWRKY53 positively regulated the PeSPX-MFS2 expression. Overall, these results provide a basis for the identification of SPX genes in P. edulis and further exploration of their functions in mediating low phosphorus responses.

Ti3C2Tx MXene nanosheets enhance the tolerance of Torreya grandis to Pb stress.

As a 2D nanomaterial, MXene (Ti3C2Tx) has shown enormous potential for use in fields such as biomedical and environmental pollution. However, the utilization of MXene materials in plants has received little attention thus far. The efficient use of MXene materials in agriculture and forestry is first highlighted in this study. Phenotypic and physiological analyses indicated that MXene application significantly enhanced the tolerance of Torreya grandis to Pb stress by reducing Pb accumulation. Furthermore, we illustrated two independent mechanisms of MXene material in reducing Pb accumulation in T. grandis: 1) MXene converted the available form of Pb into stable forms via its strong Pb adsorption ability, resulting in a decrease of the available form of Pb in soils, and 2) MXene application obviously increased the cell wall pectin content to restrict more Pb in the cell wall by regulating the expression of pectin synthesis/metabolism-related genes (TgPLL2, TgPLL11, TgPG5, TgPG30, TgGAUT3 and TgGAUT12) in T. grandis roots. Overall, this finding provides insight into the application of MXene material in modern agriculture and forestry, which will facilitate the rapid development of nanotechnology in sustainable agriculture and forestry.

A bibliometric and visualization analysis of global research on vestibular schwannoma.

BACKGROUND: Vestibular schwannoma is the most common benign tumor in the pontocerebellar horn region. As the tumor grows, it often causes severe hearing loss due to compression of nearby nerves, resulting in a lower quality of life. This study examined vestibular schwannoma-related research through a bibliometric and visualization analysis, and it explored current trends and research hot spots. METHODS: Research related to vestibular schwannoma published from 2002 to 2021 was searched using the Web of Science Core Collection. The processing and visualization analysis of the data were conducted using R software, VOSviewer, and CiteSpace. RESULTS: A total of 3,909 publications were included in this study, and an overall increasing trend in the annual output of publications was found. The United States, Germany, and the United Kingdom were the most prolific countries, publishing the most articles. Germany had the most frequent international cooperation and the highest centrality score. The Mayo Clinic, University of California, and Harvard University were the three most productive institutions. Otology & Neurotology was the most prolific journal, and MJ Link was the most productive and highest scoring author for centrality. Current frontier topics mainly focused on "hearing preservation" and "radiosurgery". A map of trends in topics and a thematic graph revealed that "hearing loss", "vertigo", "magnetic resonance imaging", "radiosurgery", "stereotactic radiosurgery", and "gamma knife" were the topics of focus of current discussions. CONCLUSION: Hearing preservation is a current frontier topic in this area. Radiosurgery has a promising future in the field of vestibular schwannoma, and stereotactic radiosurgery is a focus of global attention. Bibliometric and visualization analysis offer a unique and objective perspective of the field of vestibular schwannoma and may assist scholars in the identification of new research directions.

MicroRNAs in POI, DOR and POR.

PURPOSE: Premature ovarian insufficiency (POI) is a clinical syndrome defined by loss of ovarian activity before the age of 40 years. However, the etiology of approximately 90% patients remains unknown. Diminished ovarian reserve (DOR) and poor ovarian response (POR) are related to POI in clinic. The main purpose of this review was to evaluate the roles of microRNAs (miRNAs) in the pathogenesis and therapeutic potential for POI, DOR and POR. METHODS: A literature search was conducted using six databases (PubMed, EMBASE, Web of Science, Cochrane Library, CNKI and Wangfang Data) to obtain relevant studies. RESULTS: This review enlightens expression profiles and functional studies of miRNAs in ovarian insufficiency in animal models and humans. Functional studies emphasized the role of miRNAs in steroidogenesis, granulosa cell proliferation/apoptosis, autophagy and follicular development by regulating target genes in specific pathways, such as the PI3K/AKT/mTOR, TGFß, MAPK and Hippo pathways. Differentially expressed circulating miRNAs provided novel biomarkers for diagnosis and prediction, such as miR-22-3p and miR-21. Moreover, exosomes derived from stem cells restored ovarian function through miRNAs in chemotherapy-induced POI models. CONCLUSION: Differential miRNA expression profiles in patients and animal models uncovered the underlying mechanisms and biomarkers of ovarian insufficiency. Exosomal miRNAs can restore ovarian function against chemotherapy-induced POI, which needs further investigation to develop novel preventive and therapeutic strategies in clinical practice.

The association of ambient temperature variability with blood pressure in southern China.

OBJECTIVES: Numerous studies have shown a positive relationship between temperature variability and mortality, but few studies have investigated the effect of temperature variability on blood pressure (BP). We aimed to estimate the effect of temperature variability on BP in Guangdong Province, southern China. METHODS: Data on meteorological factors were obtained from the Guangdong Meteorological Center, and BP was collected from a series of cross-sectional surveys conducted in Guangdong Province, China, from 2004 to 2015. There were 38 088 participants aged 18 years and over. A generalized additive model was used to estimate the association between temperature variability and BP after adjusting for confounding variables. RESULTS: Our study found a significant positive association between temperature variability and SBP, and this effect increased with the increment of exposure days in total population. The highest estimate was for temperature variability at 7 days lag (TV 0-7 ) with a 0.497 (95% confidence interval, 0.335-0.660) mmHg rise of SBP for each 1°C increase of TV 0-7 . The effects of TV 0-1 and TV 0-2 on SBP were higher for hypertensives than that for normotensives, and in warm season higher than that in cold season. However, we did not observe statistical significance between temperature variability and DBP. CONCLUSIONS: There was a positive association between temperature variability and SBP in Guangdong Province, which should be considered in clinical management and epidemiological survey of hypertension.

Catalytically Active Metal-Organic Frameworks Elicit Robust Immune Response to Combination Chemodynamic and Checkpoint Blockade Immunotherapy.

Chemodynamic therapy (CDT) strategies rely on the generation of reactive oxygen species (ROS) to kill tumor cells, with hydroxyl radicals (•OH) serving as the key mediators of cytotoxicity in this setting. However, the efficacy of CDT approaches is often hampered by the properties of the tumor microenvironment (TME) and associated limitations to the Fenton reaction that constrains ROS generation. As such, there is a pressing need for the design of new nanoplatforms capable of improving CDT outcomes. In this study, an Fc-based metal-organic framework (MOF) vitamin k3 (Vk3)-loaded cascade catalytic nanoplatform (Vk3@Co-Fc) was developed. This platform was capable of undergoing TME-responsive degradation without impacting normal cells. After its release, Vk3 was processed by nicotinamide adenine dinucleotide hydrogen phosphate (NAD(P)H) quinone oxidoreductase-1 (NQO1), which is highly expressed in tumor cells, thereby yielding large quantities of H2O2 that in turn interact with Fe ions via the Fenton reaction to facilitate in situ cytotoxic •OH production. This process leads to immunogenic cell death (ICD) of the tumor, which then promotes dendritic cell maturation and ultimately increases T cell infiltration into the tumor site. When this nanoplatform was combined with programmed death 1 (PD-1) checkpoint blockade approaches, it was sufficient to enhance tumor-associated immune responses in breast cancer as evidenced by increases in the frequencies of CD45+ leukocytes and CD8+ cytotoxic T lymphocytes, thereby inhibiting tumor metastasis to the lungs and improving murine survival outcomes. Together, this Vk3@Co-Fc cascading catalytic nanoplatform enables potent cancer immunotherapy for breast cancer regression and metastasis prevention.

Brain Activation During Working Memory Task in Amnestic Mild Cognitive Impairment Patients and Its Association with Memory and Attention.

BACKGROUND: Amnestic mild cognitive impairment (aMCI) is regarded as a transitional state of Alzheimer's disease, with working memory (WM) impairment. OBJECTIVE: To investigate the brain activity in aMCI patients during WM tasks with the functional near-infrared spectroscopy (fNIRS) technique, as well as explore the association between brain activity and cognitive function in multiple domains. METHODS: This study is a case-control study of 54 aMCI patients and 33 cognitively healthy elderly (NC). All participants underwent neuropsychological assessments. fNIRS was applied to examine the brain activation during the WM task. Multivariable linear regression analysis was applied to evaluate associations between brain activation and cognitive function in multiple domains. RESULTS: Compared to NC subjects, aMCI patients had lower activation in the bilateral prefrontal, parietal, and occipital cortex during the WM task. Additionally, activation in the left prefrontal, bilateral parietal, and occipital cortex during the encoding and maintenance phase was positively associated with memory function. During memory retrieval, higher activity in the left prefrontal, parietal, and occipital cortex were correlated with higher memory scores. Besides, a positive association also formed between attention function and the activation in the left prefrontal, parietal, and occipital cortex during the WM task. CONCLUSION: These findings demonstrated that reduced activation in the prefrontal, parietal and occipital cortex during WM might reflect the risk of cognitive impairment, especially memory and attention function in aMCI patients. Given the brain activation visualization, fNIRS may be a convenient and alternative tool for screening the risk of Alzheimer's disease.

Bas-relief modeling from RGB monocular images with regional division characteristics.

Traditional Bas-relief modeling methods are often limited to inefficient and difficult to be altered after the product is formed. This paper presents a novel method for bas-relief modeling from RGB monocular images with regional division characteristics. The problem discussed in this paper involves edge detection, region division, height value recovery and three-dimensional reconstruction of image. In our framework, we can automatically obtain the pixel height of each area in the image and can adjust the concave-convex relationship of each image area to obtain a bas-relief modeling which can be printed directly in 3D. The edge detection algorithm used Gaussian difference pyramid to combine the luminance information and chrominance information of digital image; the regions of the RGB monocular image are divided by the improved connected-component labeling algorithm;and the 3D pixel point cloud of each region is calculated by the shape-from-shading algorithm. Different from previous work, our method can fully obtain the image height field data and completely restored the depth information,which makes it possible to use any RGB monocular image for bas-relief modeling. Experiments with groups of images show that our method can effectively generate bas-relief modeling.

Global trends in the research on benign paroxysmal positional vertigo: A 20-year bibliometric and visualization analysis.

Background: Benign paroxysmal positional vertigo (BPPV) is the most common cause of peripheral vestibular vertigo. Although BPPV is benign, its underlying mechanisms are complicated, and patients diagnosed with BPPV are significantly affected by it in their daily lives. Hence, this study's purpose was to investigate global trends and frontiers in the field of BPPV. Methods: We searched the research literature published from 2002 to 2021 on BPPV using two databases from the Web of Science Core Collection, and we conducted a bibliometric and visualization analysis. Bibliometric tools were used to perform co-authorship, co-citation, and co-occurrence analyses of countries or regions, institutions, authors, journals, keywords, and references. Results: In all, 1,419 publications from 4,594 authors, 1,542 institutions, and 65 countries or regions with 71 subject categories were included in the study. The number of articles increased gradually from 2002 to 2021. Seoul National University, the University of Munich, and Osaka University were among the leading institutions with the most publications, while United States of America, South Korea, and China were the leading countries. JS Kim was the most prolific author, Otology & Neurotology was the most prolific journal, and Otorhinolaryngology was the most published subject category. The five most frequently occurring keywords were BPPV, vertigo, dizziness, nystagmus, and management and the top research hot spots were osteoporosis and vitamin D. Conclusion: This study systematically analyzed trends in global scientific research on BPPV. The academic understanding of BPPV has improved significantly over the last two decades, with osteoporosis and vitamin D the two main research hot spots in the field of BPPV in recent years. These findings provide direction for current research to grasp the trends and research frontiers of current research.

Diagnostic accuracy of multi-component spatial-temporal gait parameters in older adults with amnestic mild cognitive impairment.

Objective: This study aimed to develop a diagnostic model of multi-kinematic parameters for patients with amnestic mild cognitive impairment (aMCI). Method: In this cross-sectional study, 94 older adults were included (33 cognitively normal, CN; and 61 aMCI). We conducted neuropsychological battery tests, such as global cognition and cognitive domains, and collected gait parameters by an inertial-sensor gait analysis system. Multivariable regression models were used to identify the potential diagnostic variables for aMCI. Receiver operating characteristic (ROC) curves were applied to assess the diagnostic accuracy of kinematic parameters in discriminating aMCI from healthy subjects. Results: Multivariable regression showed that multi-kinematic parameters were the potential diagnostic variables for aMCI. The multi-kinematic parameter model, developed using Timed Up and Go (TUG) time, stride length, toe-off/heel stride angles, one-leg standing (OLS) time, and braking force, showed areas under ROC (AUC), 0.96 [95% confidence interval (CI), 0.905-0.857]; sensitivity, 0.90; and specificity, 0.91. In contrast, a single kinematic parameter's sensitivity was 0.26-0.95 and specificity was 0.21-0.90. Notably, the separating capacity of multi-kinematic parameters was highly similar to Montreal Cognitive Assessment (MoCA; AUC: 0.96 vs. 0.95). Compared to cognitive domain tests, the separating ability was comparable to Auditory Verbal Learning Test (AVLT) and Boston Naming Test (BNT; AUC: 0.96 vs. 0.97; AUC: 0.96 vs. 0.94). Conclusion: We developed one diagnostic model of multi-kinematic parameters for patients with aMCI in Foshan.

Collagenase-Loaded H-TiO2 Nanoparticles Enhance Ultrasound Imaging-Guided Sonodynamic Therapy in a Pancreatic Carcinoma Xenograft Model via Digesting Stromal Barriers.

Sonodynamic therapy (SDT), a noninvasive therapy that relies on sonosensitizers and generates reactive oxygen species (ROS), has attracted considerable attention in the treatment of pancreatic cancer. However, being surrounded by dense stromal barriers, pancreatic cancer exhibits high interstitial fluid pressure (IFP) and hypoxia in the tumor microenvironment (TME), resulting in poor SDT efficacy. Collagenase-loaded hollow TiO2 (Col-H-TiO2) nanoparticles (NPs) capable of degrading stromal barriers and producing sufficient ROS production were synthesized in this study. After administration of NPs in the patient-derived xenograft (PDX) model, ultrasonic irradiation-released collagenase degraded tumor matrix fibers, decreased intratumoral IFP, and enhanced the penetration and retention of NPs within tumor tissues. Moreover, the NPs accumulated within the tumor not only generate abundant ROS under the influence of ultrasound irradiation but also improve intratumoral ultrasound signal, providing ultrasonic imaging-guided highly effective SDT for pancreatic cancer. In conclusion, this research improves the SDT technique and enhances the visualization of pancreatic cancer by remodeling the TME and is a promising strategy for further clinical applications.

Ultrasound improved immune adjuvant delivery to induce DC maturation and T cell activation.

Tumor immunotherapy has emerged as a promising approach to tumor treatment. Currently, immune adjuvant-based therapeutic modalities are rarely curative in solid tumors owing to challenges including the low permeability and extremely poor water solubility of these adjuvants, limiting their ability to effectively promote dendritic cell (DC) maturation. Herein, we employed ultrasound-mediated cavitation (UMC) to promote the delivery of Toll-like receptor agonist (R837)-loaded pH-responsive liposomes (PEOz-Lip@R837) to tumors. The tumor-associated antigens (TAAs) produced by UMC treatment exhibited vaccinal activity, particularly in the presence of immune adjuvants, together promoting the maturation of DC and inducing cytokine production. Importantly, UMC can down-regulate immune checkpoint molecules, like Cd274, Foxp3 and Ctla4, synergistically stimulating the activation and proliferation of T cells in the body to facilitate tumor treatment. This UMC-enhanced PEOz-Lip@R837 approach was able to induce a robust antitumor immune response capable of arresting primary and distant tumor growth, while also developing immunological memory, protecting against tumor rechallenge following initial tumor clearance. Overall, these results highlight a promising UMC- and pH-sensitive immune adjuvant delivery-based treatment for tumors with the potential for clinical application.

High Fall Risk Associated With Memory Deficit and Brain Lobes Atrophy Among Elderly With Amnestic Mild Cognitive Impairment and Mild Alzheimer's Disease.

Objectives: This study aimed to primarily examine the association between memory deficit and increased fall risk, second, explore the underlying neuroanatomical linkage of this association in the elderly with aMCI and mild AD. Methods: In this cross-sectional study, a total of 103 older adults were included (55 cognitively normal, CN; 48 cognitive impairment, CI, elderly with aMCI, and mild AD). Memory was assessed by the Auditory Verbal Learning Test (AVLT). Fall risk was evaluated by the Timed Up and Go (TUG) Test, heel strike angles, and stride speed, which were collected by an inertial-sensor-based wearable instrument (the JiBuEn™ gait analysis system). Brain volumes were full-automatic segmented and quantified using AccuBrain® v1.2 from three-dimensional T1-weighted (3D T1W) MR images. Multivariable regression analysis was used to examine the extent of the association between memory deficit and fall risk, the association of brain volumes with memory, and fall risk. Age, sex, education, BMI, and HAMD scores were adjusted. Sensitivity analysis was conducted. Results: Compared to CN, participants with aMCI and mild AD had poorer cognitive performance (p < 0.001), longer TUG time (p = 0.018), and smaller hippocampus and medial temporal volumes (p = 0.037 and 0.029). In the CI group, compared to good short delayed memory (SDM) performance (AVLT > 5), the elderly with bad SDM performance (AVLT ≤ 3) had longer TUG time, smaller heel strike angles, and slower stride speed. Multivariable regression analysis showed that elderly with poor memory had higher fall risk than relative good memory performance among cognitive impairment elderly. The TUG time increased by 2.1 s, 95% CI, 0.54∼3.67; left heel strike angle reduced by 3.22°, 95% CI, -6.05 to -0.39; and stride speed reduced by 0.09 m/s, 95% CI, -0.19 to -0.00 for the poor memory elderly among the CI group, but not found the association in CN group. In addition, serious medial temporal atrophy (MTA), small volumes of the frontal lobe and occipital lobe were associated with long TUG time and small heel strike angles; small volumes of the temporal lobe, frontal lobe, and parietal lobe were associated with slow stride speed. Conclusion: Our findings suggested that memory deficit was associated with increased fall risk in the elderly with aMCI and mild AD. The association might be mediated by the atrophy of medial temporal, frontal, and parietal lobes. Additionally, increased fall risk, tested by TUG time, heel stride angles, and stride speed, might be objective and convenient kinematics markers for dynamic monitoring of both memory function and fall risk.

Enhancement of antitumor immunotherapy using mitochondria-targeted cancer cell membrane-biomimetic MOF-mediated sonodynamic therapy and checkpoint blockade immunotherapy.

Immunotherapeutic interventions represent a promising approach to treating cancer, with strategies such as immune checkpoint blockade (ICB), immunogenic sonodynamic therapy (SDT), and immune adjuvant T cell delivery having exhibited clinical promise. In this report, we describe the use of cancer cell membrane-coated triphenylphosphonium (TPP) decorated nano-metal-organic framework (nMOF) constructs [Zr-TCPP(TPP)/R837@M] that were used to generate homologous, mitochondria-targeted platforms with a high rate of sonosensitizer loading. This construct was utilized to simultaneously promote tumor antigen presentation via enhancing SDT while synergistically promoting dendritic cell (DC) maturation through the delivery of the Toll-like receptor agonist R837. In vitro, these functionalized nMOFs were readily internalized by homologous tumor cells in which they were efficiently targeted to the mitochondria, promoting DC activation through the induction of immunogenic cell death (ICD) following ultrasound exposure. Moreover, this nanoplatform was able to achieve in vivo synergy with anti-CTLA-4 ICB to reverse immunosuppression tumor microenvironment (TME), thus achieving more robust antitumor efficacy capable of suppressing metastatic disease progression and facilitating the development of durable antitumor memory responses. Together, these results highlight a promising approach to achieving enhanced SDT activity while overcoming an immunosuppressive TME, thereby achieving more robust antitumor immunity.