Prenatal LPS leads to increases in RAS expression within the PVN and overactivation of sympathetic outflow in offspring rats.

The renin-angiotensin system (RAS) and the sympathetic nervous system (SNS) are two major blood pressure-regulating systems. The link between the renal and cerebral RAS axes was provided by reflex activation of renal afferents and efferent sympathetic nerves. There is a self-sustaining enhancement of the brain and the intrarenal RAS. In this study, prenatal exposure to lipopolysaccharide (LPS) led to increased RAS activity in the paraventricular nucleus (PVN) and overactivation of sympathetic outflow, accompanied by increased production of reactive oxygen species (ROS) and disturbances between inhibitory and excitatory neurons in PVN. The AT1 receptor blocker losartan and α2 adrenergic receptor agonist clonidine in the PVN significantly decreased renal sympathetic nerve activity (RSNA) and synchronously reduced systolic blood pressure. Prenatal LPS stimulation caused H3 acetylation at H3K9 and H3K14 in the PVN, which suggested that epigenetic changes are involved in transmitting the prenatal adverse stimulative information to the next generation. Additionally, melatonin treatment during pregnancy reduced RAS activity and ROS levels in the PVN; balanced the activity of inhibitory and excitatory neurons in the PVN; increased urine sodium secretion; reduced RSNA and blood pressure. In conclusion, prenatal LPS leads to increased RAS expression within the PVN and overactivation of the sympathetic outflow, thereby contributing to hypertension in offspring rats. Melatonin is expected to be a promising agent for preventing prenatal LPS exposure-induced hypertension.

SERS and electrochemical dual-mode detection of miRNA-141 by using single Au@Ag nanowire as a new platform.

As biomarkers of cancer, the accurate and sensitive detection of microRNAs is of great significance. Therefore, we proposed a surface-enhanced Raman scattering (SERS)/electrochemical (EC) dual-mode nanosensor for sensitively detecting miRNA-141. The nanosensor uses Au@Ag nanowires as a novel SERS/EC sensing platform, which has the advantages of good biocompatibility, fast response, and high sensitivity. The dual-mode nanosensor can not only effectively overcome the problem of insufficient reliability of single signal, but also realize the amplification and stable output of the detection signal, to ensure the reliability and repeatability of miRNA detection. With this sensing strategy, the target miRNA-141 can be detected over a wide linear range (100 fM to 50 nM) (LOD of 18.4 fM for SERS and 16.0 fM for electrochemical methods). In addition, the process shows good selectivity and can distinguish miRNA-141 from other interfering miRNAs. The actual analysis of human serum samples also proves that our strategy has good reliability, repeatability, and has broad application prospects in the field of analysis and detection.

A Blood Hepatocellular Carcinoma Signature Recognizes Very Small Tumor Nodules with Metastatic Traits.

Background and Aims: Hepatocellular carcinoma (HCC) cases with small nodules are commonly treated with radiofrequency ablation (RFA), but the recurrence rate remains high. This study aimed to establish a blood signature for identifying HCC with metastatic traits pre-RFA. Methods: Data from HCC patients treated between 2010 and 2017 were retrospectively collected. A blood signature for metastatic HCC was established based on blood levels of alpha-fetoprotein and des-γ-carboxy-prothrombin, cell-free DNA (cfDNA) mutations, and methylation changes in target genes in frozen-stored plasma samples that were collected before RFA performance. The HCC blood signature was validated in patients prospectively enrolled in 2021. Results: Of 251 HCC patients in the retrospective study, 33.9% experienced recurrence within 1 year post-RFA. The HCC blood signature identified from these patients included des-γ-carboxy-prothrombin ≥40 mAU/mL with cfDNA mutation score, where cfDNA mutations occurred in the genes of TP53, CTNNB1, and TERT promoter. This signature effectively predicted 1-year post-RFA recurrence of HCC with 92% specificity and 91% sensitivity in the retrospective dataset, and with 87% specificity and 76% sensitivity in the prospective dataset (n=32 patients). Among 14 cases in the prospective study with biopsy tissues available, positivity for the HCC blood signature was associated with a higher HCC tissue score and shorter distance between HCC cells and microvasculature. Conclusions: This study established an HCC blood signature in pre-RFA blood that potentially reflects HCC with metastatic traits and may be valuable for predicting the disease's early recurrence post-RFA.

Circulating exosomal circRNA-miRNA-mRNA network in a familial partial lipodystrophy type 3 family with a novel PPARG frameshift mutation c.418dup.

Familial Partial Lipodystrophy 3 (FPLD3) is a rare genetic disorder caused by loss-of-function mutations in the PPARG gene, characterized by a selective absence of subcutaneous fat and associated metabolic complications. However, the molecular mechanisms of FPLD3 remain unclear. In this study, we recruited a 17-year-old Chinese female with FPLD3 and her family, identifying a novel PPARG frameshift mutation (exon 4: c.418dup: p.R140Kfs*7) that truncates the PPARγ protein at the 7th amino acid, significantly expanding the genetic landscape of FPLD3. By performing next generation sequencing of circular RNAs (circRNAs), microRNAs (miRNAs), and mRNAs in plasma exosomes, we discovered 59 circRNAs, 57 miRNAs, and 299 mRNAs were significantly altered in the mutation carriers in the comparison of healthy controls. Integration analysis highlighted that the circ_0001597-miR-671-5p pair and 18 mRNAs might be incorporated into the metabolic regulatory networks of the FPLD3 induced by the novel PPARG mutation. Functional annotation suggested that these genes were significantly enriched in glucose and lipid metabolism related pathways. Among the circRNA-miRNA-mRNA network, we identified two critical regulators, EGR1, a key transcription factor known for its role in insulin signaling pathways and lipid metabolism, and AGPAT3, which gets involved in the biosynthesis of triglycerides and lipolysis. Circ_0001597 regulates the expression of these genes through miR-671-5p, potentially contributing to the pathophysiology of FPLD3. Overall, this study clarified a circulating exosomal circRNA-miRNA-mRNA network in a FPLD3 family with a novel PPARG mutation, providing evidence for exploring promising biomarkers and developing novel therapeutic strategies for this rare genetic disorder.

RHOF activation of AKT/ß-catenin signaling pathway drives acute myeloid leukemia progression and chemotherapy resistance.

Acute myeloid leukemia (AML) is a clonal malignancy originating from leukemia stem cells, characterized by a poor prognosis, underscoring the necessity for novel therapeutic targets and treatment methodologies. This study focuses on Ras homolog family member F, filopodia associated (RHOF), a Rho guanosine triphosphatase (GTPase) family member. We found that RHOF is overexpressed in AML, correlating with an adverse prognosis. Our gain- and loss-of-function experiments revealed that RHOF overexpression enhances proliferation and impedes apoptosis in AML cells in vitro. Conversely, genetic suppression of RHOF markedly reduced the leukemia burden in a human AML xenograft mouse model. Furthermore, we investigated the synergistic effect of RHOF downregulation and chemotherapy, demonstrating significant therapeutic efficacy in vivo. Mechanistically, RHOF activates the AKT/ß-catenin signaling pathway, thereby accelerating the progression of AML. Our findings elucidate the pivotal role of RHOF in AML pathogenesis and propose RHOF inhibition as a promising therapeutic approach for AML management.

Sex- and age-specific associations of serum essential elements with diabetes among the Chinese adults: a community-based cross-sectional study.

BACKGROUND: Although several studies have found the relationship between essential elements and diabetes, the studies about the association of essential elements with diabetes diagnosed according to an oral glucose tolerance test (OGTT) and glycated hemoglobin (HbA1c) in a sex- and age-specific manner were limited. To investigate the linear and nonlinear relationship of five essential elements including iron (Fe), copper (Cu), Zinc (Zn), magnesium (Mg), and calcium (Ca) with diabetes, fasting plasma glucose (FPG), 2-h postprandial plasma glucose (PPG), and HbA1c and to evaluate the sex- and age-specific heterogeneities in these relationships. METHODS: A total of 8392 community-dwelling adults were recruited to complete a questionnaire and undergo checkups of anthropometric parameters and serum levels of five metals (Fe, Cu, Zn, Mg, and Ca). The multivariable logistic and linear regression, the restricted cubic spline (RCS) analysis, and subgroup analysis were applied to find the associations between the essential elements and the prevalence of diabetes as well as FPG, PPG, and HbA1c. RESULTS: In the multivariable logistic regression and multivariable linear regression, serum Cu was positively associated with FPG, PPG, and HbA1c while serum Mg was significantly inversely correlated with FPG, PPG, HbA1c, and diabetes (all P < 0.001). In the RCS analysis, the non-linear relationship of Cu and diabetes (P < 0.001) was found. In the subgroup analysis, stronger positive associations of Cu with diabetes (P for interaction = 0.027) and PPG (P for interaction = 0.002) were found in younger women. CONCLUSIONS: These findings may lead to more appropriate approaches to essential elements supplementation in people with diabetes of different ages and sexes. However, more prospective cohort and experimental studies are needed to probe the possible mechanism of sex- and age-specific associations between serum essential elements and diabetes.

ZbMYB111 Expression Positively Regulates ZbUFGT-Mediated Anthocyanin Biosynthesis in Zanthoxylum bungeanum with the Involvement of ZbbHLH2.

Anthocyanin (ACN)-derived pigmentation in the red Zanthoxylum bungeanum peel is an essential commercial trait. Therefore, exploring the metabolic regulatory networks involved in peel ACN levels in this species is crucial for improving its quality. However, its underlying transcriptional regulatory mechanisms are still unknown. This transcriptomic and bioinformatics study not only discovered a new TF (ZbMYB111) as a potential regulator for ACN biosynthesis in Z. bungeanum peel, but also deciphered the underlying molecular mechanisms of ACN biosynthesis. Overexpression of ZbMYB111 and flavonoid 3-O-glucosyltransferase (ZbUFGT) induced ACN accumulation in both Z. bungeanum peels and callus along with Arabidopsis thaliana and tobacco flowers, whereas their silencing impaired ACN biosynthesis. Therefore, the dual-luciferase reporter, yeast-one-hybrid, and electrophoretic mobility shift assays showed that ZbMYB111 directly interacted with the ZbUFGT promoter to activate its expression. This diverted the secondary metabolism toward the ACN pathway, thereby promoting ACN accumulation.

Information disclosure, multifaceted collaborative governance, and carbon total factor productivity---an evaluation of the effects of the 'environmental information disclosure pilot' policy based on double machine learning.

As an environmental institutional arrangement related to the information factor of the diversified participation of the government, enterprises, the media and the public, the environmental information disclosure pilot policy, can and how to affect the carbon emission efficiency through multiple collaborative governance? This study uses the Environmental Information Disclosure Pilot Policy implemented in China in 2007 as a quasi-natural experiment. It examines 284 prefecture-level cities from 2004 to 2021 and A-share listed companies from 2004 to 2021, constructing an evolutionary game dynamic model involving government, public, enterprises, and media. Through mathematical derivation and assignment analysis, it explores how environmental information impacts carbon emission efficiency under multifaceted collaborative governance, assessing the strategic choices and evolutionary paths of stakeholders before and after policy implementation, using methods like double machine learning for empirical testing. The study highlights several key findings: First, the implementation of the Environmental Information Disclosure Pilot Policy significantly enhanced carbon total factor productivity in pilot cities, as revealed through Double Machine Learning (DML) policy effect evaluation. Second, adjustments for potential estimation biases using Doubly Debiased LASSO (DDL) regression indicated that environmental information disclosure impacts carbon productivity via a governance mechanism involving government, public, media, and enterprises. Third, a causal pathway analysis suggested a sequential logic in governance effectiveness, starting from governmental environmental focus to corporate environmental responsibility. Lastly, integrating DML with a moderation effect model revealed a regulatory role for environmental legislation construction, offering new insights for achieving dual carbon goals and enriching empirical evidence on information's impact on carbon emission efficiency.

Anti-CRMP2 antibody induces anxiety-like behavior and increases pyramidal neuron excitability in mice.

BACKGROUND: We have previously identified auto-antibody (Ab) to collapsin response mediator protein 2 (CRMP2) in patients with encephalitis. The present study aims to evaluate the pathogenic effects of anti-CRMP2 Ab. METHODS: Recombinant CRMP2 protein was injected subcutaneously into mice to establish an active immune mouse model with anti-CRMP2 Ab. Behavioral assessments, histopathological staining, and electrophysiological testing were performed to identify any pathogenic changes. RESULTS: The mice exhibited signs of impaired motor coordination four weeks post-immunization of CRMP2 protein. Moreover, CRMP2 immunized mice for eight weeks showed anxiety-like behaviors indicating by tests of open field and the elevated plus maze. After incubating the CA1 region of hippocampal brain section with the sera from CRMP2 immunized mice, the whole-cell path-clamp recordings showed increased excitability of pyramidal neurons. However, no obvious inflammation and infiltration of immune cells were observed by histopathological analysis. Western blot showed that the phosphorylation levels of CRMP2-Thr514 and -Ser522 were not affected. CONCLUSION: In an active immunization model with CRMP2 protein, impaired coordination and anxiety-like behaviors were observed. Also, anti-CRMP2 Abs containing sera heightened the excitability of hippocampal pyramidal neurons in vitro, which imply the pathogenic effects of anti-CRMP2 Ab.

Site-recognition boosted the sensing performance of terbium-based organic frameworks for UO22+ detection.

A unique fluorescent sensing probe for UO22+ detection was fabricated with terbium-based metal organic frameworks via introducing specific recognition sites (denoted as Tb-TDPAT). The newly formed Tb-TDPAT presented remarkable detection sensitivity and selectivity towards UO22+, surpassing the need for complex post-modification methods.

A comprehensive analysis of the WRKY family in soybean and functional analysis of GmWRKY164-GmGSL7c in resistance to soybean mosaic virus.

BACKGROUND: Soybean mosaic disease caused by soybean mosaic virus (SMV) is one of the most devastating and widespread diseases in soybean producing areas worldwide. The WRKY transcription factors (TFs) are widely involved in plant development and stress responses. However, the roles of the GmWRKY TFs in resistance to SMV are largely unclear. RESULTS: Here, 185 GmWRKYs were characterized in soybean (Glycine max), among which 60 GmWRKY genes were differentially expressed during SMV infection according to the transcriptome data. The transcriptome data and RT-qPCR results showed that the expression of GmWRKY164 decreased after imidazole treatment and had higher expression levels in the incompatible combination between soybean cultivar variety Jidou 7 and SMV strain N3. Remarkably, the silencing of GmWRKY164 reduced callose deposition and enhanced virus spread during SMV infection. In addition, the transcript levels of the GmGSL7c were dramatically lower upon the silencing of GmWRKY164. Furthermore, EMSA and ChIP-qPCR revealed that GmWRKY164 can directly bind to the promoter of GmGSL7c, which contains the W-box element. CONCLUSION: Our findings suggest that GmWRKY164 plays a positive role in resistance to SMV infection by regulating the expression of GmGSL7c, resulting in the deposition of callose and the inhibition of viral movement, which provides guidance for future studies in understanding virus-resistance mechanisms in soybean.

Comparison of the chemical constituents of Saposhnikoviae Radix associated with three different growth patterns and its therapeutic effect against atopic dermatitis.

ETHNOPHARMACOLOGICAL RELEVANCE: Saposhnikoviae Radix (SR) was initially documented in Shennong Bencao Jing classics for its properties in dispelling wind, dissolving surface, relieving pain, and alleviating spasms. This herb is commonly used in traditional Chinese medicine to address conditions that affect the body's surface, by aiding in the expulsion of pathogens from the surface and alleviating pain associated with the immune response. Atopic dermatitis (AD) is a prevalent allergic skin disorder, and the therapeutic effects of SR in dispelling wind and relieving the body's surface are consistent with the clinical symptoms commonly observed in AD. AIM OF THE STUDY: The anti-AD effects of SR were examined under three different growth patterns to identify active pharmacodynamic compounds. The results provide insight into the clinical efficacy of wild and cultivated SR. MATERIALS AND METHODS: The efficacy of wild, wild-simulated, and cultivated SR was assessed in a mouse model of AD. In addition, the effects of wild and varying doses of cultivated SR were evaluated in mice with short-term AD symptoms. GC-MS and UPLC-MS/MS were used to analyze the chemical components of the three SR treatments and molecular docking was used to identify active components. RESULTS: A mouse model of AD was used to assess the pharmacodynamic effects of SR prepared by three different cultivation methods. The study found that all three SR preparations improved phenotypic markers and histopathological features in the AD mouse model. The efficacy of wild SR and wild-simulated SR was similar, although there was a significant difference between wild and cultivated SR. Both wild SR and various doses of cultivated SR ameliorated skin injuries and reduced inflammation in serum and skin tissues. Furthermore, skin thickness, inflammatory cells, mast cell infiltration, and IL-33 expression improved following treatment. Notably, wild SR, double-cultivated SR, and triple-cultivated SR demonstrated significant therapeutic effects. An analysis using GC-MS revealed the presence of 55, 52, and 43 volatile oils in the three SR preparations, with more common components observed between wild and wild-simulated SR. Fewer common components were evident between cultivated and wild SR. UPLC-MS/MS analysis identified a total of 37 compounds, with larger relative peak areas observed for the chromogenic ketones. Molecular docking studies revealed that certain compounds, such as n-propyl 9,12-octadecadienoate, (E)-9-octadecenoic acid ethyl ester, and various chromogenic ketones, such as cimifugin, 5-O-methyIvisamminol, hamaudol, 3'-O-acetylhamaudol, 3'-O-angeloyhamandol, adenosine and farnesylaceton, may be the major substances that distinguish the activities of SR with three different growth patterns. CONCLUSION: Variations in the anti-AD efficacy of SR with three growth patterns were identified, and their chemical composition differences were determined. These findings suggest that increasing the dosage of cultivated SR could potentially be a viable clinical alternative for atopic dermatitis treatment.

scHolography: a computational method for single-cell spatial neighborhood reconstruction and analysis.

Spatial transcriptomics has transformed our ability to study tissue complexity. However, it remains challenging to accurately dissect tissue organization at single-cell resolution. Here we introduce scHolography, a machine learning-based method designed to reconstruct single-cell spatial neighborhoods and facilitate 3D tissue visualization using spatial and single-cell RNA sequencing data. scHolography employs a high-dimensional transcriptome-to-space projection that infers spatial relationships among cells, defining spatial neighborhoods and enhancing analyses of cell-cell communication. When applied to both human and mouse datasets, scHolography enables quantitative assessments of spatial cell neighborhoods, cell-cell interactions, and tumor-immune microenvironment. Together, scHolography offers a robust computational framework for elucidating 3D tissue organization and analyzing spatial dynamics at the cellular level.

Three new flavonoids from the roots of Sophora tonkinensis.

Three new flavonoids including two isoflavanones sophortones A and B (1 and 2), and one chalcone sophortone C (3) were isolated from the roots of Sophora tonkinensis. Their structures were established by UV, IR, HRESIMS, and NMR data. The absolute configurations of 1 and 2 were determined by electronic circular dichroism (ECD) calculations.

Ginkgo biloba for Tardive Dyskinesia and Plasma MnSOD Activity: Association with MnSOD Ala-9Val Variant.

BACKGROUND: Excessive free radicals are implicated in the pathophysiology of tardive dyskinesia (TD), and Ginkgo biloba extract (EGb761) scavenges free radicals, thereby enhancing antioxidant enzymes such as mitochondrial manganese superoxide dismutase (MnSOD). This study examined whether EGb761 treatment would improve TD symptoms and increase MnSOD activity, particularly in TD patients with specific MnSOD Val-9Ala genotype. METHODS: An EGb761 (240 mg/day) 12-week double-blind clinical trial with 157 TD patients was randomized. The severity of TD was measured by the Abnormal Involuntary Movement Scale (AIMS) and plasma MnSOD activity was assayed before and after 12 weeks of treatment. Further, in an expanded sample, we compared MnSOD activity in 159 TD, 227 non-TD and 280 healthy controls, as well as the allele frequencies and genotypes for the MnSOD Ala-9Val polymorphism in 352 TD, 486 non-TD and 1150 healthy controls. RESULTS: EGb761 significantly reduced TD symptoms and increased MnSOD activity in TD patients compared to placebo (both p < 0.01). Moreover, we found an interaction between genotype and treatment response (p < 0.001). Furthermore, in the EGb761 group, patients carrying the Ala allele displayed a significantly lower AIMS total score than patients with the Val/Val genotype. In addition, MnSOD activity was significantly lower at baseline in TD patients compared with healthy controls or non-TD patients. CONCLUSION: EGb761 treatment enhanced low MnSOD activity in TD patients and produced greater improvement in TD symptoms in patients with the Ala allele of the MnSOD Ala-9Val polymorphism.

The Influence of Piriformospora indica Colonization on the Root Development and Growth of Cerasus humilis Cuttings.

Numerous studies have shown that the endophytic fungus Piriformospora indica has a broad range of promoting effects on root development and plant growth in host plants. However, there are currently no reports on the application of this fungus on Cerasus humilis. This study first compared the colonization ability of P. indica on 11 C. humilis varieties and found that the colonization rate of this fungus on these varieties ranged from 90% to 100%, with the colonization rate of the varieties '09-01' and 'Nongda 7' being as high as 100%. Subsequently, the effect of P. indica on root development and plant growth of C. humilis was investigated using cuttings of '09-01' and 'Nongda 7' as materials. P. indica colonization was found to increase the biomass of '09-01' and 'Nongda 7' plants; root activity, POD enzymes, and chlorophyll content were also significantly increased. In addition, indole-3-acetic acid (IAA) content in the roots of C. humilis plants increased after colonization, while jasmonic acid (JA) and 1-aminocyclopropane-1-car- boxylic acid (ACC) content decreased. In conclusion, it has been demonstrated that P. indica can promote the growth of C. humilis plants by accelerating biomass accumulation, promoting rooting, and enhancing the production of photosynthetic pigments, as well as regulating hormone synthesis.

High-precision all-in-one dual robotic arm strategy in oral implant surgery.

INTRODUCTION: Dental implantation has emerged as an efficient substitute for missing teeth, which is essential for restoring oral function and aesthetics. Compared to traditional denture repair approaches, dental implants offer better stability and sustainability. The position, angle, and depth of dental implants are crucial factors for their long-term success and necessitate high-precision operation and technical support. METHOD: We propose an integrated dual-arm high-precision oral implant surgery navigation positioning system and a corresponding control strategy. Compared with traditional implant robots, the integrated dual-arm design greatly shortens the preparation time before surgery and simplifies the operation process. We propose a novel control flow and module for the proposed structure, including an Occluded Target Tracking Module (OTTM) for occlusion tracking, a Planting Plan Development Module (PPDM) for generating implant plans, and a Path Formulation Module (PFM) for controlling the movement path of the two robot arms. RESULT: Under the coordinated control of the aforementioned modules, the robot achieved excellent accuracy in clinical trials. The average angular error and entry point error for five patients who underwent implant surgery using the proposed robot were 2.1° and 0.39 mm, respectively. CONCLUSION: In essence, our study introduces an integrated dual-arm high-precision navigation system for oral implant surgery, resolving issues like lengthy preoperative preparation and static surgical planning. Clinical results confirm its efficacy, emphasizing its accuracy and precision in guiding oral implant procedures.