Growth hormone-receptor disruption in mice reduces osteoarthritis and chondrocyte hypertrophy.

Excessive growth hormone (GH) has been shown to promote joint degeneration in both preclinical and clinical studies. Little is known about the effect of disrupted GH or GH receptor (GHR) on joint health. The goal of this study is to investigate joint pathology in mice with either germline (GHR-/-) or adult inducible (iGHR-/-) GHR deficiency. Knee joints from male and female GHR-/- and WT mice at 24 months of age were processed for histological analysis. Also, knee joints from male and female iGHR-/- and WT mice at 22 months of age were scanned by micro-CT (µCT) for subchondral bone changes and characterized via histology for cartilage degeneration. Joint sections were also stained for the chondrocyte hypertrophy marker, COLX, and the cartilage degeneration marker, ADAMTS-5, using immunohistochemistry. Compared to WT mice, GHR-/- mice had remarkably smooth articular joint surfaces and an even distribution of proteoglycan with no signs of degeneration. Quantitatively, GHR-/- mice had lower OARSI and Mankin scores compared to WT controls. By contrast, iGHR-/- mice were only moderately protected from developing aging-associated OA. iGHR-/- mice had a significantly lower Mankin score compared to WT. However, Mankin scores were not significantly different between iGHR-/- and WT when males and females were analyzed separately. OARSI scores did not differ significantly between WT and iGHR-/- in either individual or combined sex analyses. Both GHR-/- and iGHR-/- mice had fewer COLX+ hypertrophic chondrocytes compared to WT, while no significant difference was observed in ADAMTS-5 staining. Compared to WT, a significantly lower trabecular thickness in the subchondral bone was observed in the iGHR-/- male mice but not in the female mice. However, there were no significant differences between WT and iGHR-/- mice in the bone volume to total tissue volume (BV/TV), bone mineral density (BMD), and trabecular number in either sex. This study identified that both germline and adult-induced GHR deficiency protected mice from developing aging-associated OA with more effective protection in GHR-/- mice.

CRHR1 antagonist alleviated depression-like behavior by downregulating p62 in a rat model of post-stroke depression.

Post-stroke depression (PSD) is a complication of cerebrovascular disease, which can increase mortality after stroke. CRH is one of the main signaling peptides released after activation of the hypothalamic-pituitary-adrenal (HPA) axis in response to stress. It affects synaptic plasticity by regulating inflammation, oxidative stress and autophagy in the central nervous system. And the loss of spines exacerbates depression-like behavior. Therefore, synaptic deficits induced by CRH may be related to post-stroke depression. However, the underlying mechanism remains unclear. The Keap1-Nrf2 complex is one of the core components of the antioxidant response. As an autophagy associated protein, p62 participates in the Keap1-NrF2 pathway through its Keap1 interaction domain. Oxidative stress is involved in the feedback regulation between Keap1-Nrf2 pathway and p62.However, whether the relationship between CRH and the Keap1-Nrf2-p62 pathway is involved in PSD remains unknown. This study found that serum levels of CRH in 22 patients with PSD were higher than those in healthy subjects. We used MCAO combined with CUMS single-cage SD rats to establish an animal model of PSD. Animal experiments showed that CRHR1 antagonist prevented synaptic loss in the hippocampus of PSD rats and alleviated depression-like behavior. CRH induced p62 accumulation in the prefrontal cortex of PSD rats through CRHR1. CRHR1 antagonist inhibited Keap1-Nrf2-p62 pathway by attenuating oxidative stress. In addition, we found that abnormal accumulation of p62 induces PSD. It alleviates depression-like behavior by inhibiting the expression of p62 and promoting the clearance of p62 in PSD rats. These findings can help explore the pathogenesis of PSD and design targeted treatments for PSD.

Gut microbiota and D-ribose mediate the anti-colitic effect of punicalagin in DSS-treated mice.

Background: Inflammatory bowel disease (IBD) is an increasing health burden worldwide. Punicalagin, a bioactive component rich in pomegranate rind, has been shown to attenuate chemical or bacteria-induced experimental colitis in mice, but whether punicalagin exerts its function through modulating gut microbiota and metabolites remains unexplored. Results: Punicalagin (100 mg per kg per day) administered orally to mice alleviated dextran-sodium sulfate (DSS)-induced colitis. Gut microbiota analyzed by 16S rRNA sequencing showed that punicalagin altered gut microbiota by increasing the Lachnospiraceae_NK4A136_group and Bifidobacterium abundance. To evaluate the effect of punicalagin-modulated microbiota and its metabolites in colitis mice, we transplanted fecal microbiota and sterile fecal filtrate (SFF) to mice treated with oral antibiotics. The results of fecal microbiota transplantation (FMT) demonstrated that punicalagin's anti-colitic effect is transferable by transplanting punicalagin-modulated gut microbiota and its metabolites. Additionally, we discovered that punicalagin-modulated sterile fecal filtrate also exhibits anti-colitis effects, as evidenced by improved intestinal barrier integrity and decreased inflammation. Subsequently, fecal metabolites were analyzed using liquid chromatography-mass spectrometry (LC-MS). The analysis revealed that punicalagin significantly increased the level of D-ribose. In vitro experiments showed that D-ribose has both anti-inflammatory and antioxidant properties. Furthermore, D-ribose significantly mitigated DSS-induced colitis symptoms in mice. Conclusions: Overall, this study demonstrated that gut microbiota and its metabolites partly mediate the protective effect of punicalagin against DSS-induced colitis in mice. D-ribose is a key metabolite that contributes to the anti-colitic effect of punicalagin in mice.

Microbial etch: A novel construction method of functionalized biochar for enhanced uranium extraction in radioactive wastewater.

Nuclear energy is playing an increasingly important role on the earth, but the nuclear plants leaves a legacy of radioactive waste pollution, especially uranium-containing pollution. Straw biochar with wide sources, large output, low cost, and easy availability, has emerged as a promising material for uranium extraction from radioactive wastewater, but the natural biomass with suboptimal structure and low content of functional groups limits the efficiency. In this work, microbial etch was first came up to regulate the biochar's structure and function. The surface of the biochar becomes rougher and more microporous, and the mineral contents (Ca, P) indirectly increased by microbial etch. The biochar was modified by calcium phosphate and exhibited a remarkable uranium extraction capacity of 590.8 mg g-1 (fitted value). This work provides a cost-effective and sustainable method for preparing functionalized biochar via microbial etch, which has potential for application to uranium extraction from radioactive wastewater.

Integration of C3H15-mediated transcriptional and post-transcriptional regulation confers plant thermotolerance in Arabidopsis.

Heat stress is an environmental factor that significantly threatens crop production worldwide. Nevertheless, the molecular mechanisms governing plant responses to heat stress are not fully understood. Plant zinc finger CCCH proteins have roles in stress responses as well as growth and development through protein-RNA, protein-DNA, and protein-protein interactions. Here, we reveal an integrated multi-level regulation of plant thermotolerance that is mediated by the CCCH protein C3H15 in Arabidopsis. Heat stress rapidly suppressed C3H15 transcription, which attenuated C3H15-inhibited expression of its target gene HEAT SHOCK TRANSCRIPTION FACTOR A2 (HSFA2), a central regulator of heat stress response (HSR), thereby activating HEAT SHOCK COGNATE 70 (HSC70.3) expression. The RING-type E3 ligase MED25-BINDING RING-H2 PROTEIN 2 (MBR2) was identified as an interacting partner of C3H15. The mbr2 mutant was susceptible to heat stress compared to wild-type plants, whereas plants overexpressing MBR2 showed increased heat tolerance. MBR2-dependent ubiquitination mediated the degradation of phosphorylated C3H15 protein in the cytoplasm, which was enhanced by heat stress. Consistently, heat sensitivities of C3H15 overexpression lines increased in MBR2 loss-of-function and decreased in MBR2 overexpression backgrounds. Heat stress-induced accumulation of HSC70.3 promoted MBR2-mediated degradation of C3H15 protein, implying that an auto-regulatory loop involving C3H15, HSFA2, and HSC70.3 regulates HSR. Heat stress also led to the accumulation of C3H15 in stress granules (SGs), a kind of cytoplasmic RNA granule. This study advances our understanding of the mechanisms plants use to respond to heat stress, which will facilitate technologies to improve thermotolerance in crops.

Haematococcus pluvialis polysaccharides improve microbiota-driven gut epithelial and vascular barrier and prevent alcoholic steatohepatitis development.

Algal polysaccharides possess many biological activities and health benefits, such as antioxidant, anti-tumor, anti-coagulant, and immunomodulatory potential. Gut microbiota has emerged as one of the major contributor in mediating the health benefits of algal polysaccharides. In this study we showed that Haematococcus pluvialis polysaccharides (HPP) decreased serum transaminase levels and hepatic triglyceride content, alleviated inflammation and oxidative stress in the liver of chronic and binge ethanol diet-fed mice. Furthermore, HPP reduced endotoxemia, improved gut microbiota dysbiosis, inhibited epithelial barrier disruption and gut vascular barrier (GVB) damage in ethanol diet-fed mice. Co-housing vehicle-fed mice with HPP-fed mice alleviated ethanol-induced liver damage and endotoxemia. Moreover, fecal microbiota transplantation from HPP-fed mice into antibiotic-induced microbiota-depleted recipients also alleviated ethanol-induced liver injury and improved gut epithelial and vascular barrier. Our study demonstrated that HPP ameliorated ethanol-induced gut epithelial and vascular barrier dysfunction through alteration of gut microbiota, therefore preventing alcoholic liver damage.

Repurposing indocyanine green: exploring the potential of an old drug in modern medicine.

The repurposing of existing drugs, referred to as theranostics, has made profound impacts on precision medicine. Indocyanine green (ICG), a well-established and clinical dye, has continued to be a star agent, described as a multifunctional molecule with concurrent photo- or sono-sensitiveness capabilities and co-delivery accessibility, showing remarkable potential in the area of unimodal or multimodal imaging-guided therapy of various diseases, leading to the extensive consideration of immediate clinical translations. In this review, we strive to bring the understanding of repurposing performance assessment for ICG into practice by clarifying the relationships between its features and applicability. Specifically, we address the obstacles encountered in the process of developing an ICG repurposing strategy, as well as the noteworthy advancements made in the field of ICG repurposing. We also go into detail about the structure-function correlations of drugs containing ICG and how different structural groups significantly affect the physicochemical properties.

Phase 2 Study of Preoperative Tislelizumab in Combination with Low-dose Nab-Paclitaxel in Patients with Muscle-invasive Bladder Cancer.

BACKGROUND AND OBJECTIVE: Combinations of immune checkpoint inhibitors and nab-paclitaxel have achieved significant therapeutic effects in the treatment of advanced urothelial carcinoma. Our aim was to assess the efficacy and safety of tislelizumab combined with low-dose nab-paclitaxel in patients with muscle-invasive bladder cancer (MIBC). METHODS: TRUCE-01 was a single-arm phase 2 study that included 62 patients with T2-4a N0/X M0 MIBC tumors with predominant urothelial carcinoma histology. Eligible patients received three 21-d cycles of intravenous 200 mg tislelizumab on day 1 plus intravenous 200 mg nab-paclitaxel on day 2, followed by surgical assessment. The primary study endpoint was a clinical complete response (cCR). Treatment-related adverse event (TRAE) profiles were recorded according to Common Terminology Criteria for Adverse Events version 5.0. KEY FINDINGS AND LIMITATIONS: The safety analysis included all 62 patients and the efficacy analysis included 48 patients. The primary efficacy endpoint (cCR) was met by 25 patients (52%) patients. Among the 62 patients in the safety analysis, six (9.7%) had grade ≥3 TRAEs. CONCLUSIONS: Tislelizumab combined with low-dose nab-paclitaxel showed promising antitumor effectiveness and was generally well tolerated, which makes it an excellent preoperative therapy option for MIBC. PATIENT SUMMARY: We found that a combination of the drugs tislelizumab and low-dose nab-paclitaxel had satisfactory efficacy and safety for preoperative treatment of muscle-invasive bladder cancer.

DAPK1 mediates cognitive dysfunction and neuronal apoptosis in PSD rats through the ERK/CREB/BDNF signaling pathway.

Post-stroke depression (PSD) is one of the most common mental sequelae after a stroke and can damage the brain. Although PSD has garnered increasing attention in recent years, the precise mechanism remains unclear. Studies have indicated that the expression of DAPK1 is elevated in various neurodegenerative conditions, including depression, ischemic stroke, and Alzheimer's disease. However, the specific molecular mechanism of DAPK1-mediated cognitive dysfunction and neuronal apoptosis in PSD rats is unclear. In this study, we established a rat model of PSD, and then assessed depression-like behaviors and cognitive dysfunction in rats using behavioral tests. In addition, we detected neuronal apoptosis and analyzed the expression of DAPK1 protein and proteins related to the ERK/CREB/BDNF signaling pathway. The findings revealed that MCAO combined with CUMS can induce more severe depression-like behaviors and cognitive dysfunction in rats, while overexpression of DAPK1 may hinder the downstream ERK/CREB/BDNF signaling pathways, resulting in neuronal loss and exacerbation of brain tissue damage. In this study, we will focus on DAPK1 and explore its role in PSD.

Precise regulation of phosphorus in nitrogen-coordinated porous carbon spheres for tunable CO2 electroreduction to syngas.

The production of high-demand syngas with tunable ratios by CO2 electroreduction has attracted considerable research interest. However, it is challenging to balance the evolution performance of H2 and CO with wide H2/CO ratios, while maintaining high efficiency. Herein, nitrogen-coordinated hierarchical porous carbon spheres with varying phosphorus content (PxNC-T) are assembled to regulate syngas production performance. The precise introduction of P modulates the local charge distribution of nitrogen-coordinated carbons, thereby accelerating the protonation process of ∗CO2-to-∗COOH and promoting moderate H∗ adsorption. Specifically, syngas with wide H2/CO ratios (0.60-4.98) is obtained over a low potential range (-0.46 to -0.86 V vs. RHE). As a representative, P1.0NC-900 presents a remarkable current density (-152 mA cm-2) at -1.0 V vs. RHE in flow cells and delivers a decent peak power density (1.93 mW cm-2) in reversible Zn-CO2 batteries. Our work provides valuable insights into the rational design of carbon-based catalysts for CO2 reduction.

Construction of Risk Prediction Model of Type 2 Diabetic Kidney Disease Based on Deep Learning.

Background: This study aimed to develop a diabetic kidney disease (DKD) prediction model using long short term memory (LSTM) neural network and evaluate its performance using accuracy, precision, recall, and area under the curve (AUC) of the receiver operating characteristic (ROC) curve. Methods: The study identified DKD risk factors through literature review and physician focus group, and collected 7 years of data from 6,040 type 2 diabetes mellitus patients based on the risk factors. Pytorch was used to build the LSTM neural network, with 70% of the data used for training and the other 30% for testing. Three models were established to examine the impact of glycosylated hemoglobin (HbA1c), systolic blood pressure (SBP), and pulse pressure (PP) variabilities on the model's performance. Results: The developed model achieved an accuracy of 83% and an AUC of 0.83. When the risk factor of HbA1c variability, SBP variability, or PP variability was removed one by one, the accuracy of each model was significantly lower than that of the optimal model, with an accuracy of 78% (P<0.001), 79% (P<0.001), and 81% (P<0.001), respectively. The AUC of ROC was also significantly lower for each model, with values of 0.72 (P<0.001), 0.75 (P<0.001), and 0.77 (P<0.05). Conclusion: The developed DKD risk predictive model using LSTM neural networks demonstrated high accuracy and AUC value. When HbA1c, SBP, and PP variabilities were added to the model as featured characteristics, the model's performance was greatly improved.

Ecological and health risk assessments of heavy metals and their accumulation in a peanut-soil system.

Heavy metals pollution is a notable threat to environment and human health. This study evaluated the potential ecological and health risks of heavy metals (Cu, Cr, Cd, Pb, Zn, Ni, and As) and their accumulation in a peanut-soil system based on 34 soil and peanut kernel paired samples across China. Soil As and Cd posed the greatest pollution risk with 47.1% and 17.6% of soil samples exceeding the risk screen levels, respectively, with 26.5% and 20.6% of the soil sites at relatively strong potential ecological risk level, respectively, and with the geo-accumulation levels at several soil sites in the uncontaminated to moderately contaminated categories. About 35.29% and 2.94% of soil sites were moderately and severely polluted based on Nemerow comprehensive pollution index, respectively, and a total of 32.4% of samples were at moderate ecological hazard level based on comprehensive potential ecological risk index values. The Cd, Cr, Ni, and Cu contents exceeded the standard in 11.76, 8.82, 11.76 and 5.88% of the peanut kernel samples, respectively. Soil metals posed more health risks to children than adults in the order As > Ni > Cr > Cu > Pb > Zn > Cd for non-carcinogenic health risks and Ni > Cr â‰« Cd > As > Pb for carcinogenic health risks. The soil As non-cancer risk index for children was greater than the permitted limits at 14 sites, and soil Ni and Cr posed the greatest carcinogenic risk to adults and children at many soil sites. The metals in peanut did not pose a non-carcinogenic risk according to standard. Peanut kernels had strong enrichment ability for Cd with an average bio-concentration factor (BCF) of 1.62. Soil metals contents and significant soil properties accounted for 35-74% of the variation in the BCF values of metals based on empirical prediction models.

A comparison study of dynamic [18F]Alfatide II imaging and [11C]MET in orthotopic rat models of glioblastoma.

PURPOSE: To investigate and compare the dynamic positron emission tomography (PET) imaging with [18F]Alfatide II Imaging and [11C]Methionine ([11C]MET) in orthotopic rat models of glioblastoma multiforme (GBM), and to assess the utility of [18F]Alfatide II in detecting and evaluating neoangiogenesis in GBM. METHODS: [18F]Alfatide II and [11C]MET were injected into the orthotopic GBM rat models (n = 20, C6 glioma cells), followed by dynamic PET/MR scans 21 days after surgery of tumor implantation. On the PET image with both radiotracers, the MRI-based volume-of-interest (VOI) was manually delineated encompassing glioblastoma. Time-activity curves were expressed as tumor-to-normal brain ratio (TNR) parameters and PET pharmacokinetic modeling (PKM) performed using 2-tissue-compartment models (2TCM). Immunofluorescent staining (IFS), western blotting and blocking experiment of tumor tissue were performed for the validation. RESULTS: Compared to 11C-MET, [18F]Alfatide II presented a persistent accumulation in the tumor, albeit with a slightly lower SUVmean of 0.79 ± 0.25, and a reduced uptake in the contralateral normal brain tissue, respectively. This resulted in a markedly higher tumor-to-normal brain ratio (TNR) of 18.22 ± 1.91. The time-activity curve (TACs) showed a significant increase in radioactive uptake in tumor tissue, followed by a plateau phase up to 60 min for [18F]Alfatide II (time to peak:255 s) and 40 min for [11C]MET (time to peak:135 s) post injection. PKM confirmed significantly higher K1 (0.23/0.07) and K3 (0.26/0.09) in the tumor region compared to the normal brain with [18F]Alfatide II. Compared to [11C]MET imaging, PKM confirmed both significantly higher K1/K2 (1.24 ± 0.79/1.05 ± 0.39) and K3/K4 (11.93 ± 4.28/3.89 ± 1.29) in the tumor region with [18F]Alfatide II. IFS confirmed significant expression of integrin and tumor vascularization in tumor region. CONCLUSION: [18F]Alfatide II demonstrates potential in imaging tumor-associated neovascularization in the context of glioblastoma multiforme (GBM), suggesting its utility as a tool for further exploration in neovascular characterization.

Bio-functional hydroxyapatite-coated 3D porous polyetherketoneketone scaffold for enhanced osteogenesis and osteointegration in orthopedic applications.

Polyetherketoneketone (PEKK), a high-performance thermoplastic special engineering material, maintains bone-like mechanical properties and has received considerable attention in the biomedical field. The 3D printing technique enables the production of porous scaffolds with a honeycomb structure featuring precisely controlled pore size, porosity and interconnectivity, which holds significant potential for applications in tissue engineering. The ideal pore architecture of porous PEKK scaffolds has yet to be elucidated. Porous PEKK scaffolds with five pore sizes P200 (225 ± 9.8 µm), P400 (411 ± 22.1 µm), P600 (596 ± 23.4 µm), P800 (786 ± 24.2 µm) and P1000 (993 ± 26.0 µm) were produced by a 3D printer. Subsequently, the optimum pore size, the P600, for mechanical properties and osteogenesis was selected based on in vitro experiments. To improve the interfacial bioactivity of porous PEKK scaffolds, hydroxyapatite (HAp) crystals were generated via in situ biomimetic mineralization induced by the phase-transited lysozyme coating. Herein, a micro/nanostructured surface showing HAp crystals on PEKK scaffold was developed. In vitro and in vivo experiments confirmed that the porous PEKK-HAp scaffolds exhibited highly interconnected pores and functional surface structures that were favorable for biocompatibility and osteoinductivity, which boosted bone regeneration. Therefore, this work not only demonstrates that the pore structure of the P600 scaffold is suitable for PEKK orthopedic implants but also sheds light on a synergistic approach involving 3D printing and biomimetic mineralization, which has the potential to yield customized 3D PEKK-HAp scaffolds with enhanced osteoinductivity and osteogenesis, offering a promising strategy for bone tissue engineering.

Analysis and prediction of interactions between transmembrane and non-transmembrane proteins.

BACKGROUND: Most of the important biological mechanisms and functions of transmembrane proteins (TMPs) are realized through their interactions with non-transmembrane proteins(nonTMPs). The interactions between TMPs and nonTMPs in cells play vital roles in intracellular signaling, energy metabolism, investigating membrane-crossing mechanisms, correlations between disease and drugs. RESULTS: Despite the importance of TMP-nonTMP interactions, the study of them remains in the wet experimental stage, lacking specific and comprehensive studies in the field of bioinformatics. To fill this gap, we performed a comprehensive statistical analysis of known TMP-nonTMP interactions and constructed a deep learning-based predictor to identify potential interactions. The statistical analysis describes known TMP-nonTMP interactions from various perspectives, such as distributions of species and protein families, enrichment of GO and KEGG pathways, as well as hub proteins and subnetwork modules in the PPI network. The predictor implemented by an end-to-end deep learning model can identify potential interactions from protein primary sequence information. The experimental results over the independent validation demonstrated considerable prediction performance with an MCC of 0.541. CONCLUSIONS: To our knowledge, we were the first to focus on TMP-nonTMP interactions. We comprehensively analyzed them using bioinformatics methods and predicted them via deep learning-based solely on their sequence. This research completes a key link in the protein network, benefits the understanding of protein functions, and helps in pathogenesis studies of diseases and associated drug development.

Effect of electroacupuncture on proBDNF/mBDNF and synaptic plasticity in rats with learning and memory impairment after cerebral ischemia-reperfusion. / ç”µé’ˆå¯¹è„‘ç¼ºè¡€å†çŒæ³¨å­¦ä¹ è®°å¿†éšœç¢å¤§é¼ æµ·é©¬è„‘æºæ€§ç¥žç»è¥å »å› å­è½¬åŒ–å’Œçªè§¦å¯å¡‘æ€§çš„å½±å“.

OBJECTIVES: To observe the effect of electroacupuncture (EA) at "Baihui" (GV20) and "Shenting" (GV24) on the rats' behavior and the transforming precursor of brain-derived neurotrophic factor (proBDNF) into mature brain-derived neurotrophic factor (mBDNF) in the hippocampus of rats with learning and memory impairment induced by cerebral ischemia-reperfusion (IR), so as to explore its mechanisms underlying improvement of learning and memory ability. METHODS: SD rats were randomly divided into blank, sham operation, model, and EA groups, with 6 rats in each group. The model of IR was established by occlusion of the middle cerebral artery. EA (1 Hz/20 Hz) was applied to GV24 and GV20 for 30 min, once daily for 14 days. The neurological function was evaluated according to the Zea Longa's score criteria 24 h after modeling and after intervention. Morris water maze test was used to detect the learning and memory function of the rats. TTC staining was used to evaluate the cerebral infarction volume on the affected side. The protein expression levels of proBDNF, mBDNF, tissue plasminogen activator (tPA), tyrosine kinase receptor B (TrkB) and p75 neurotrophin receptor (p75NTR) in hippocampal tissue were detected by Western blot. RESULTS: Compared with the sham operation group, the neurological function score, the percentage of cerebral infarction volume and the expression levels of proBDNF and p75NTR protein in hippocampus were increased (P<0.01), while the times of crossing the original platform and the total distance in the target quadrant, the expression levels of mBDNF, TrkB and tPA protein and the ratio of mBDNF/proBDNF were decreased (P<0.01, P<0.05) in the model group. Compared with the model group, the neurological function score, the percentage of cerebral infarction volume, and the expression levels of proBDNF and p75NTR protein in hippocampus were decreased (P<0.01, P<0.05), while the times of crossing the original platform, the total distance in the target quadrant, and the expression levels of mBDNF, TrkB and tPA protein and the ratio of mBDNF/proBDNF were increased (P<0.05, P<0.01) in the EA group. CONCLUSIONS: EA can alleviate learning and memory impairment in IR rats, which may be related to its function in up-regulating the expression of tPA protein and promoting the transformation of proBDNF to mBDNF, thus improving the synaptic plasticity.

A novel OsHB5-OsAPL-OsMADS27/OsWRKY102 regulatory module regulates grain size in rice.

Grain size, a crucial trait that determines rice yield and quality, is typically regulated by multiple genes. Although numerous genes controlling grain size have been identified, the precise and dynamic regulatory network governing grain size is still not fully understood. In this study, we unveiled a novel regulatory module composed of OsHB5, OsAPL and OsMADS27/OsWRKY102, which plays a crucial role in modulating grain size in rice. As a positive regulator of grain size, OsAPL has been found to interact with OsHB5 both in vitro and in vivo. Through chromatin immunoprecipitation-sequencing, we successfully mapped two potential targets of OsAPL, namely OsMADS27, a positive regulator in grain size and OsWRKY102, a negative regulator in lignification that is also associated with grain size control. Further evidence from EMSA and chromatin immunoprecipitation-quantitative PCR experiments has shown that OsAPL acts as an upstream transcription factor that directly binds to the promoters of OsMADS27 and OsWRKY102. Moreover, EMSA and dual-luciferase reporter assays have indicated that the interaction between OsAPL and OsHB5 enhances the repressive effect of OsAPL on OsMADS27 and OsWRKY102. Collectively, our findings discovered a novel regulatory module, OsHB5-OsAPL-OsMADS27/OsWRKY102, which plays a significant role in controlling grain size in rice. These discoveries provide potential targets for breeding high-yield and high-quality rice varieties.

Coordination between two cis-elements of WRKY33, bound by the same transcription factor, confers humid adaption in Arabidopsis thaliana.

To cope with flooding-induced hypoxia, plants have evolved different strategies. Molecular strategies, such as the N-degron pathway and transcriptional regulation, are known to be crucial for Arabidopsis thaliana's hypoxia response. Our study uncovered a novel molecular strategy that involves a single transcription factor interacting with two identical cis-elements, one located in the promoter region and the other within the intron. This unique double-element adjustment mechanism has seldom been reported in previous studies. In humid areas, WRKY70 plays a crucial role in A. thaliana's adaptation to submergence-induced hypoxia by binding to identical cis-elements in both the promoter and intron regions of WRKY33. This dual binding enhances WRKY33 expression and the activation of hypoxia-related genes. Conversely, in arid regions lacking the promoter cis-element, WRKY70 only binds to the intron cis-element, resulting in limited WRKY33 expression during submergence stress. The presence of a critical promoter cis-element in humid accessions, but not in dry accessions, indicates a coordinated regulation enabling A. thaliana to adapt and thrive in humid habitats.

Epigenome-augmented eQTL-hotspots reveal genome-wide transcriptional programs in 36 human tissues.

Expression quantitative trait loci (eQTLs) are used to inform the mechanisms of transcriptional regulation in eukaryotic cells. However, the specificity of genome-wide eQTL identification is limited by stringent control for false discoveries. Here, we described a method based on the non-homogeneous Poisson process to identify 125 489 regions with highly frequent, multiple eQTL associations, or 'eQTL-hotspots', from the public database of 59 human tissues or cell types. We stratified the eQTL-hotspots into two classes with their distinct sequence and epigenomic characteristics. Based on these classifications, we developed a machine-learning model, E-SpotFinder, for augmented discovery of tissue- or cell-type-specific eQTL-hotspots. We applied this model to 36 tissues or cell types. Using augmented eQTL-hotspots, we recovered 655 402 eSNPs and reconstructed a comprehensive regulatory network of 2 725 380 cis-interactions among eQTL-hotspots. We further identified 52 012 modules representing transcriptional programs with unique functional backgrounds. In summary, our study provided a framework of epigenome-augmented eQTL analysis and thereby constructed comprehensive genome-wide networks of cis-regulations across diverse human tissues or cell types.

Polygonatum sibiricum Saponin Prevents Immune Dysfunction and Strengthens Intestinal Mucosal Barrier Function in Cyclophosphamide-Induced Immunosuppressed BALB/c Mice.

The aim of this study was to explore the immunomodulatory effect of Polygonatum sibiricum saponin (PS) in a cyclophosphamide-induced (Cy) immunosuppression mice model. Oral administration of PS by gavage effectively alleviated weight loss caused by Cy and increased the index of immune organs. PS promoted the proliferation of splenic lymphocytes and T cell subsets (CD3+, CD355+, CD4+/CD8+) and relieved the xylene-induced inflammatory response and Cy-induced increase of serum hemolysin. Moreover, PS increased serum levels of lactate dehydrogenase and acid phosphatase. PS elevated serum level of cytokines and immunoglobulins (TNF-α, IFN-γ, IL-4, IL-6, IL-ß, SIgA, and IgG) and the expression of mRNA of IL-10, TNF-α, and IL-6 in the spleen. Increased mRNA expression of tight junction protein (ZO-1, Mucin2, Occludin) expression and protein expression of IL-6/MyD88/TLR4 in the small intestine showed that PS exhibited a restorative effect on intestinal mucosal injury caused by cyclophosphamide. Oral PS prevented Cy-induced decline in leukocytes, red blood cells, lymphocytes, hemoglobin concentrations, and neutrophils, providing evidence for alleviating hematopoietic disorders. In addition, PS increased SOD and NO levels, reduced MDA levels, and improved oxidative damage in the liver. These findings demonstrate that PS has the potential to be developed as a supplemental agent for alleviating immunosuppression caused by chemotherapeutic agents.