PHLDA2 overexpression facilitates senescence and apoptosis via the mitochondrial route in human nucleus pulposus cells by regulating Wnt/ß-catenin signalling pathway.

Low back pain is a common clinical symptom of intervertebral disc degeneration (IVDD), which seriously affects the quality of life of the patients. The abnormal apoptosis and senescence of nucleus pulposus cells (NPCs) play important roles in the pathogenesis of IVDD. PHLDA2 is an imprinted gene related to cell apoptosis and tumour progression. However, its role in NPC degeneration is not yet clear. Therefore, this study was set to explore the effects of PHLDA2 on NPC senescence and apoptosis and the underlying mechanisms. The expression of PHLDA2 was examined in human nucleus pulposus (NP) tissues and NPCs. Immunohistochemical staining, magnetic resonance imaging imaging and western blot were performed to evaluate the phenotypes of intervertebral discs. Senescence and apoptosis of NPCs were assessed by SA-ß-galactosidase, flow cytometry and western blot. Mitochondrial function was investigated by JC-1 staining and transmission electron microscopy. It was found that the expression level of PHLDA2 was abnormally elevated in degenerated human NP tissues and NPCs. Furthermore, knockdown of PHLDA2 can significantly inhibit senescence and apoptosis of NPCs, whereas overexpression of PHLDA2 can reverse senescence and apoptosis of NPCs in vitro. In vivo experiment further confirmed that PHLDA2 knockdown could alleviate IVDD in rats. Knockdown of PHLDA2 could also reverse senescence and apoptosis in IL-1ß-treated NPCs. JC-1 staining indicated PHLDA2's knockdown impaired disruption of the mitochondrial membrane potential and also ameliorated superstructural destruction of NPCs as showed by transmission electron microscopy. Finally, we found the PHLDA2 knockdown promoted Collagen-II expression and suppressed MMP3 expression in NPCs by repressing wnt/ß-catenin pathway. In conclusion, the results of the present study showed that PHLDA2 promotes IL-1ß-induced apoptosis and senescence of NP cells via mitochondrial route by activating the Wnt/ß-catenin pathway, and suggested that therapy targeting PHLDA2 may provide valuable insights into possible IVDD therapies.

Prioritization of organic contaminants in China's groundwater based on national-scale monitoring data and their persistence, bioaccumulation, and toxicity.

There has been increasing concern regarding the adverse environmental and health effects of organic pollutants. A list of priority control organic pollutants (PCOPs) can provide regulatory frameworks for the use and monitoring of organic compounds in the environment. In this study, 20,010 groundwater samples were collected from 15 "first level" groundwater resource zones in China. Fifty (50) organic compounds were analyzed based on their prevalence, occurrence, and physicochemical properties (persistence, bioaccumulation, and toxicity). Results showed that 16 PCOPs, including 12 pesticides, 3 aromatic hydrocarbons (AHs), and 1 phthalate ester, were recognized. Pesticides and AHs accounted for 75 % and 18.75 % of the high-priority pollutants, respectively. There were significant differences in PCOPs between confined and phreatic groundwater. Higher concentrations of pesticides were mainly detected in phreatic groundwater. PCOPs detected in samples from the 15 groundwater resource zones were mainly pesticides and AHs. The groundwater data indicate that the organic compounds detected in the Yellow River Basin (YRB), Yangtze River Basin (YZB), Liaohe River Basin (LRB), and Songhua River Basin (SRB) are mainly categorized as Q1 (high priority) and Q2 (medium priority) pollutants based on the contaminants ranking system in China. The findings from this study offer a snapshot of the wide distribution of PCOPs in the surveyed regions, and are expected to establishing treatment and prevention measures at both the regional and national levels in China.

Development and validation of a nomogram to predict the risk of residual low back pain after tubular microdiskectomy of lumbar disk herniation.

OBJECTIVE: Tubular microdiskectomy (tMD) is one of the most commonly used for treating lumbar disk herniation. However, there still patients still complain of persistent postoperative residual low back pain (rLBP) postoperatively. This study attempts to develop a nomogram to predict the risk of rLBP after tMD. METHODS: The patients were divided into non-rLBP (LBP VAS score < 2) and rLBP (LBP VAS score ≥ 2) group. The correlation between rLBP and these factors were analyzed by multivariate logistic analysis. Then, a nomogram prediction model of rLBP was developed based on the risk factors screened by multivariate analysis. The samples in the model are randomly divided into training and validation sets in a 7:3 ratio. The Receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) were used to evaluate the diskrimination, calibration and clinical value of the model, respectively. RESULTS: A total of 14.3% (47/329) of patients have persistent rLBP. The multivariate analysis suggests that higher preoperative LBP visual analog scale (VAS) score, lower facet orientation (FO), grade 2-3 facet joint degeneration (FJD) and moderate-severe multifidus fat atrophy (MFA) are risk factors for postoperative rLBP. In the training and validation sets, the ROC curves, calibration curves, and DCAs suggested the good diskrimination, predictive accuracy between the predicted probability and actual probability, and clinical value of the model, respectively. CONCLUSION: This nomogram including preoperative LBP VAS score, FO, FJD and MFA can serve a promising prediction model, which will provide a reference for clinicians to predict the rLBP after tMD.

Transcutaneous auricular vagus nerve stimulation for post-stroke depression: A double-blind, randomized, placebo-controlled trial.

BACKGROUND: It is a well-established fact that post-stroke depression (PSD) is a prevalent condition that affects a significant proportion of individuals who have suffered a stroke. Hence, our research endeavors to explore the safety, efficacy and the potential molecular mechanism of transcutaneous auricular vagus nerve stimulation (ta-VNS) for the treatment of depression in PSD patients by conducting a double-blind, sham-controlled, randomized trial. METHODS: Patients who had experienced strokes and exhibited depressive symptoms, with a Hamilton Depression Scale (HAMD-17) score of ≥8 and met the DSM-IV criteria, were diagnosed with PSD. A volunteer sample of participants (N = 80) were randomly divided into either the ta-VNS group (which received ta-VNS in addition to conventional treatment) or the control group (which received conventional treatment only), in a 1:1 ratio. The effectiveness of the interventions was evaluated using the 17-item Hamilton Rating Scale for Depression (HAMD-17), Zung Self-Rating Depression Scale (SDS), and Barthel Index (BI) scores. Furthermore, Plasma BDNF, CREB1, and 5-HT levels were measured before and after treatment. RESULTS: The concomitant application of ta-VNS demonstrated a remarkable reduction in HAMD-17 and SDS scores, leading to noteworthy enhancements in patients' daily functioning, as evidenced by improved activities of daily living, at all assessed time points, in contrast to the control group (p < 0.0001). Notably, the ta-VNS group exhibited superior effects in modulating the measured neurotrophic biomarkers when compared to the control group (p < 0.05). CONCLUSIONS: The synergistic approach of combining ta-VNS with conventional treatment has demonstrated remarkable efficacy and tolerability in managing depression following a stroke.

[Hydrochemical Characteristics and Genesis Mechanism of Groundwater in the Dry Period in the Zhangjiakou Area].

In order to better support the construction of the capital water conservation functional area and ecological environment support area， research on the chemical characteristics of groundwater and its formation mechanism in the dry period in the Zhangjiakou area can provide a great reference for the rational development and utilization of groundwater resources. A total of 41 groups of groundwater samples were collected， and the hydrochemical types， composition characteristics， and control factors of groundwater in the study area were analyzed by using the combined method of descriptive statistical analysis， Piper triplot， correlation analysis， Gibbs plot， and ion ratio. The results showed that the groundwater in the study area was weakly alkaline， with the total hardness and ρ（TDS） ranging from 105.00 mg·L-1 to 1 433.00 mg·L-1 and 137.00 mg·L-1 to 2 286.00 mg·L-1， respectively. The total hardness and TDS mass concentrations of groundwater in the Bashang area were higher than those in the Baxia area. HCO3- and Na+ were the main dominant anions and cations in the groundwater in the study area. The highest overstandard rate of the main components in groundwater was that of total hardness （36.59%）. The overstandard rate and maximum excess multiple of each component in groundwater in the Bashang area were greater than those in the Baxia area. HCO3-Ca·Mg·Na was the main type of groundwater hydrochemistry in the study area， and there was little difference between the Bashang area and the Baxia area. SO42-， Cl-， HCO3-， Na+， and Mg2+ contributed the most to TDS. The chemical characteristics of groundwater were affected by weathering and filtration of rock minerals such as salt rock， albite， and dolomite； cation exchange； and human activities. Evaporative crystallization and atmospheric precipitation contributed to a small part of the main ion source of groundwater in the area. The effect of human activities on groundwater in the Bashang area was greater than that in the Baxia area， and NO3- mainly originated from agricultural activities.

Intravenous immunoglobulin protects the integrity of the intestinal epithelial barrier and inhibits ferroptosis induced by radiation exposure by activating the mTOR pathway.

Radiation exposure often leads to serious health problems in humans. The intestinal epithelium is sensitive to radiation damage, and radiation causes destruction of the intestinal epithelial barrier, which leads to radiation enteritis (RE), the loss of fluids, and the translocation of intestinal bacteria and toxins; radiation can even threaten survival. In this study, we aimed to explore the influence of IVIg on the integrity of the intestinal epithelial barrier after RE. Using a RE mouse model, we investigated the protective effects of intravenous immunoglobulin (IVIg) on the epithelial junctions of RE mice and validated these findings with intestinal organoids cultured in vitro. In addition, transmission electron microscopy (TEM), western blotting (WB) and immunostaining were used to further investigate changes in intestinal epithelial ferroptosis and related signaling pathways. When RE occurs, the intestinal epithelial barrier is severely damaged. IVIg treatment significantly ameliorated this damage to epithelial tight junctions both in vivo and in vitro. Notably, IVIg alleviated RE by inhibiting intestinal epithelial ferroptosis in RE mice. Mechanistically, IVIg promoted activation of the mTOR pathway and inhibited ferroptosis in the intestinal epithelium of mice. Rapamycin, which is a potent inhibitor of the mTOR protein, significantly abolished the protective effect of IVIg against radiation-induced damage to intestinal epithelial tight junctions. Overall, IVIg can prevent RE-induced damage to the intestinal epithelial barrier and inhibit ferroptosis by activating the mTOR pathway; this study provides a new treatment strategy for patients with RE caused by radiotherapy or accidental nuclear exposure.

Out-of-Plane Single-Copper-Site Catalysts for Room-Temperature Benzene Oxidation.

Crafting single-atom catalysts (SACs) that possess "just right" modulated electronic and geometric structures, granting accessible active sites for direct room-temperature benzene oxidation is a coveted objective. However, achieving this goal remains a formidable challenge. Here, we introduce an innovative in situ phosphorus-immitting strategy using a new phosphorus source (phosphorus nitride, P3N5) to construct the phosphorus-rich copper (Cu) SACs, designated as Cu/NPC. These catalysts feature locally protruding metal sites on a nitrogen (N)-phosphorus (P)-carbon (C) support (NPC). Rigorous analyses, including X-ray absorption spectroscopy (XAS) and X-ray photoelectron spectroscopy (XPS), validate the coordinated bonding of nitrogen and phosphorus with atomically dispersed Cu sites on NPC. Crucially, systematic first-principles calculations, coupled with the climbing image nudged-elastic-band (CI-NEB) method, provide a comprehensive understanding of the structure-property-activity relationship of the distorted Cu-N2P2 centers in Cu/NPC for selective oxidation of benzene to phenol production. Interestingly, Cu/NPC has shown more energetically favorable C-H bond activation compared to the benchmark Cu/NC SACs in the direct oxidation of benzene, resulting in outstanding benzene conversion (50.3 %) and phenol selectivity (99.3 %) at room temperature. Furthermore, Cu/NPC achieves a remarkable turnover frequency of 263 h-1 and mass-specific activity of 35.2 mmol g-1 h-1, surpassing the state-of-the-art benzene-to-phenol conversion catalysts to date.

Comparison of minimally invasive transforaminal lumbar interbody fusion (Mis-TLIF) with bilateral decompression via unilateral approach and open-TLIF with bilateral decompression for degenerative lumbar diseases: a retrospective cohort study.

OBJECTIVE: Presently, no study has compared the clinical outcomes of minimally invasive transforaminal lumbar interbody fusion (Mis-TLIF) with bilateral decompression via the unilateral approach (BDUA) and Open-TLIF with bilateral decompression for degenerative lumbar diseases (DLD). We aimed to compare the clinical outcomes of through Mis-TLIF combined with BDUA and Open-TLIF with bilateral decompression for the treatment of DLD, and reported the learning curve of the procedure of MIS-TLIF with BDUA. METHODS: We retrospectively analyzed the prospectively collected data of consecutive DLD patients in the two groups from January 2016 to January 2020. RESULTS: The operative time (OT) was significantly longer in the Mis-TLIF group (n = 113) than in the Open-TLIF group (n = 135). The postoperative drainage volume (PDV) and length of stay (LOS) were significantly higher in the Open-TLIF group than in the Mis-TLIF group. Additionally, the complication rate was significantly higher in the Open-TLIF group than in the Mis-TLIF group (14.8% vs. 6.2%, P = 0.030), while there was no significant difference in the reoperation and adjacent segment disease rates between the two groups. There were no significant differences in back pain and leg pain Numerical Rating Scale (NRS) scores and Oswestry Disability Index (ODI) between the two groups preoperatively, at discharge, and 2 years postoperatively. Patients in both groups showed significant improvements in NRS scores and ODI scores after surgery. OT was negatively correlated with the number of surgeries performed (P < 0.001, r = -0.43). The learning curve of Mis-TLIF with BDUA was steep, with OT tapered to steady state in 43 cases. CONCLUSION: Compared with Open-TLIF with bilateral decompression, Mis-TLIF with BDUA can achieve equivalent clinical outcomes, lower PDV and LOS, and lower complication rates. Although this procedure took longer, it could be a viable alternative for the treatment of DLD after a steep learning curve.

Dynamics of N6-methyladenosine modification during aging and their potential roles in the degeneration of intervertebral disc.

Background: The N6-methyladenosine (m6A) dynamics in the progression of intervertebral disc (IVD) aging remain largely unknown. This study aimed to explore the distribution and pattern of m6A modification in nucleus pulpous (NP) tissues of rats at different ages. Methods: Histological staining and MRI were performed to evaluate the degeneration of IVD. The expression of m6A modifiers was analyzed using qRT-PCR and western blot. Subsequently, methylated RNA immunoprecipitation next generation sequencing and RNA-seq were conducted to identify differences in m6A methylome and transcriptome of NP tissues. Results: Compared to 2-month-old rats, we found significant changes in the global m6A level and the expression of Mettl3 and FTO in NP tissues from 20-month-old rats. During the progression of NP aging, there were 1126 persistently differentially m6A peaks within 931 genes, and 51 persistently differentially expressed genes. GO and KEGG analyses showed that these m6A peaks and m6A modified genes were mainly engaged in the biological processes and pathways of intervertebral disc degermation (IDD), such as extracellular matrix metabolism, angiogenesis, inflammatory response, mTOR and AMPK signaling pathways. Meanwhile, conjoint analyses and Venn diagram revealed a total of 405 aging related genes contained significant methylation and expression levels in 20-month-old rats in contrast to 2-month-old and 10-month-old rats. Moreover, it was found that four aging related genes with hypermethylated modification including BUB1, CA12, Adamts1, and Adamts4 depicted differentially expressed at protein level, of which BUB1 and CA12 were decreased, while Adamts1 and Adamts4 were increased during the progression of NP aging. Conclusion: Collectively, this study elucidated the distribution and pattern of m6A modification during the aging of IVD. Furthermore, the m6A modified genes were involved in the IDD related biological processes and pathways. These findings may provide novel insights into the mechanisms and therapies of IDD from the perspective of aging.

Lactic acid promotes nucleus pulposus cell senescence and corresponding intervertebral disc degeneration via interacting with Akt.

The accumulation of metabolites in the intervertebral disc is considered an important cause of intervertebral disc degeneration (IVDD). Lactic acid, which is a metabolite that is produced by cellular anaerobic glycolysis, has been proven to be closely associated with IVDD. However, little is known about the role of lactic acid in nucleus pulposus cells (NPCs) senescence and oxidative stress. The aim of this study was to investigate the effect of lactic acid on NPCs senescence and oxidative stress as well as the underlying mechanism. A puncture-induced disc degeneration (PIDD) model was established in rats. Metabolomics analysis revealed that lactic acid levels were significantly increased in degenerated intervertebral discs. Elimination of excessive lactic acid using a lactate oxidase (LOx)-overexpressing lentivirus alleviated the progression of IVDD. In vitro experiments showed that high concentrations of lactic acid could induce senescence and oxidative stress in NPCs. High-throughput RNA sequencing results and bioinformatic analysis demonstrated that the induction of NPCs senescence and oxidative stress by lactic acid may be related to the PI3K/Akt signaling pathway. Further study verified that high concentrations of lactic acid could induce NPCs senescence and oxidative stress by interacting with Akt and regulating its downstream Akt/p21/p27/cyclin D1 and Akt/Nrf2/HO-1 pathways. Utilizing molecular docking, site-directed mutation and microscale thermophoresis assays, we found that lactic acid could regulate Akt kinase activity by binding to the Lys39 and Leu52 residues in the PH domain of Akt. These results highlight the involvement of lactic acid in NPCs senescence and oxidative stress, and lactic acid may become a novel potential therapeutic target for the treatment of IVDD.

Genome-Wide Association Study Identifies Rice Panicle Blast-Resistant Gene Pb4 Encoding a Wall-Associated Kinase.

Rice blast is one of the most devastating diseases, causing a significant reduction in global rice production. Developing and utilizing resistant varieties has proven to be the most efficient and cost-effective approach to control blasts. However, due to environmental pressure and intense pathogenic selection, resistance has rapidly broken down, and more durable resistance genes are being discovered. In this paper, a novel wall-associated kinase (WAK) gene, Pb4, which confers resistance to rice blast, was identified through a genome-wide association study (GWAS) utilizing 249 rice accessions. Pb4 comprises an N-terminal signal peptide, extracellular GUB domain, EGF domain, EGF-Ca2+ domain, and intracellular Ser/Thr protein kinase domain. The extracellular domain (GUB domain, EGF domain, and EGF-Ca2+ domain) of Pb4 can interact with the extracellular domain of CEBiP. Additionally, its expression is induced by chitin and polygalacturonic acid. Furthermore, transgenic plants overexpressing Pb4 enhance resistance to rice blast. In summary, this study identified a novel rice blast-resistant gene, Pb4, and provides a theoretical basis for understanding the role of WAKs in mediating rice resistance against rice blast disease.

Advances in bi-directional relationships for EZH2 and oxidative stress.

Over the past two decades, polycomb repressive complex 2(PRC2) has emerged as a vital repressive complex in overall cell fate determination. In mammals, enhancer of zeste homolog 2 (EHZ2), which is the core component of PRC2, has also been recognized as an important regulator of inflammatory, redox, tumorigenesis and damage repair signalling networks. To exert these effects, EZH2 must regulate target genes epigenetically or interact directly with other gene expression-regulating factors, such as LncRNAs and microRNAs. Our review provides a comprehensive summary of research advances, discoveries and trends regarding the regulatory mechanisms between EZH2 and reactive oxygen species (ROS). First, we outline novel findings about how EZH2 regulates the generation of ROS at the molecular level. Then, we summarize how oxidative stress controls EHZ2 alteration (upregulation, downregulation, or phosphorylation) via various molecules and signalling pathways. Finally, we address why EZH2 and oxidative stress have an undefined relationship and provide potential future research ideas.

An individualized criterion for left bundle branch capture in patients with a narrow QRS complex.

BACKGROUND: Left bundle branch (LBB) pacing (LBBP) is a physiological pacing; however, the accuracy of current electrocardiographic criteria for LBBP remains inadequate. OBJECTIVE: The purpose of this study was to establish a novel individualized criterion to improve the accuracy of LBBP determination in patients with a narrow QRS complex. METHODS: Patients in whom both LBBP and left ventricular septal pacing (LVSP) were acquired during operation were enrolled. LBB conduction time (LBBCT) was measured from LBB potential (LBBpo) to intrinsic QRS onset. LBBpo-V6RWPT, Native-V6RWPT, and Paced-V6RWPT were respectively measured from LBBpo, intrinsic QRS onset, and stimulus to R-wave peak in V6. ΔV6RWPT was the difference value between Paced-V6RWPT and Native-V6RWPT. The accuracy of ΔV6RWPT criterion for determining LBBP was evaluated. RESULTS: In all 71 enrolled patients, ΔV6RWPT was <30 ms during LBBP (21.3 ± 4.6 ms; range 9.3-28.3 ms) but was >30 ms during LVSP (38.5 ± 4.6 ms; range 31.1-47.0 ms). The probability distribution of ΔV6RWPT was well separated between LBBP and LVSP. Sensitivity and specificity of the novel criterion of "ΔV6RWPT <30 ms" for determining LBBP both were 100%. However, the optimal cutoff value of Paced-V6RWPT for validation of LBBP was 64.2 ms, and sensitivity and specificity were 84.5% and 97.2%, respectively. Paced-V6RWPT during LBBP was equivalent to LBBpo-V6RWPT in all patients. There was a strong linear correlation between Native-V6RWPT and LBBpo-V6RWPT (r = 0.796; P <.001). CONCLUSION: ΔV6RWPT could be an accurate individualized criterion for determining LBB capture with high sensitivity and specificity and was superior over the fixed Paced-V6RWPT criterion.

Multiple energy X-ray imaging of metal oxide particles inside gingival tissues.

BACKGROUND: Periodontal disease affects over 50% of the global population and is characterized by gingivitis as the initial sign. One dental health issue that may contribute to the development of periodontal disease is foreign body gingivitis (FBG), which can result from exposure to some kinds of foreign metal particles from dental products or food. OBJECTIVE: We design a novel, portable, affordable, multispectral X-ray and fluorescence optical microscopic imaging system dedicated to detecting and differentiating metal oxide particles in dental pathological tissues. A novel denoising algorithm is applied. We verify the feasibility and optimize the performance of the imaging system with numerical simulations. METHODS: The designed imaging system has a focused X-ray tube with tunable energy spectra and thin scintillator coupled with an optical microscope as detector. A simulated soft tissue phantom is embedded with 2-micron thick metal oxide discs as the imaged object. GATE software is used to optimize the systematic parameters such as energy bandwidth and X-ray photon number. We have also applied a novel denoising method, Noise2Sim with a two-layer UNet structure, to improve the simulated image quality. RESULTS: The use of an X-ray source operating with an energy bandwidth of 5 keV, X-ray photon number of 108, and an X-ray detector with a 0.5 micrometer pixel size in a 100 by 100-pixel array allowed for the detection of particles as small as 0.5 micrometer. With the Noise2Sim algorithm, the CNR has improved substantially. A typical example is that the Aluminum (Al) target's CNR is improved from 6.78 to 9.72 for the case of 108 X-ray photons with the Chromium (Cr) source of 5 keV bandwidth. CONCLUSIONS: Different metal oxide particles were differentiated using Contrast-to-Noise ratio (CNR) by utilizing four different X-ray spectra.

The sonic hedgehog pathway suppresses oxidative stress and senescence in nucleus pulposus cells to alleviate intervertebral disc degeneration via GPX4.

Disruption of intervertebral disc (IVD) homeostasis caused by oxidative stress and nucleus pulposus cell (NPC) senescence is a main cause of intervertebral disc degeneration (IDD). The sonic hedgehog (Shh) pathway plays an important role in IVD development, but its roles in IDD are unknown. This study aimed to investigate the effects of the Shh pathway on the alleviation of IDD and the related mechanisms. In vivo, the effect of the Shh pathway on IVD homeostasis was studied by intraperitoneal injection of recombinant Shh (rShh) and GANT61 based on puncture-induced IDD. GANT61, lentivirus-coated sh-Gli1 and rShh were used to investigate the role and mechanism of the Shh pathway in NPCs based on senescence induced by Braco19 and oxidative stress induced by TBHP. Shh pathway expression decreased, and senescence and oxidative stress increased with age. Intraperitoneal injection of rShh activated the Shh pathway to suppress oxidative stress and NPC senescence and consequently alleviated needle puncture-induced IDD. In vitro, the Shh pathway upregulated glutathione peroxidase 4 (GPX4) expression to suppress oxidative stress and senescence in NPCs. Moreover, GPX4 suppression in NPCs by si-GPX4 significantly reduced the protective effect of the Shh pathway on oxidative stress and senescence in NPCs. Our results demonstrate for the first time that the Shh pathway plays a key role in the alleviation of IDD by suppressing oxidative stress and cell senescence in NP tissues. This study provides a new potential target for the prevention and reversal of IDD.

Risk prediction of iron deficiency for plasmapheresis donors in China: Development and validation of a prediction model.

BACKGROUND AND OBJECTIVES: The present study aims to evaluate the iron stores in plasmapheresis donors and develop and validate an iron deficiency (ID) risk prediction model for plasmapheresis donors with potential or existing ID. MATERIALS AND METHODS: We assessed plasmapheresis donors' serum ferritin (SF) and haemoglobin (Hb) levels. The candidate factors showing significant differences in the multivariate logistic regression analysis were used to establish a risk prediction scoring system. The participants were divided into a training cohort and an internal validation cohort in a 7:3 ratio. Additional plasmapheresis donors from a different station were recruited for external validation. RESULTS: The SF levels in both male and female donors in the high-frequency group were significantly lower than those of new donors (male: p < 0.001; female: p = 0.008). The prevalence of ID in female regular donors with a high frequency was significantly higher than that in new donors (33.1% vs. 24.6%; odds ratio = 1.209 [95% CI: 1.035-1.412]). Donation frequency, age, Hb, body mass index and being pre-menopausal were identified as independent risk factors for ID (p < 0.05). The developed model exhibited good discrimination ability (area under the receiver operating characteristic curve >0.7) and calibration (p > 0.05) in development, internal validation cohorts and external validation cohorts. CONCLUSION: A higher donation frequency has been associated with reduced SF levels and an increased risk of ID in women. The developed ID risk prediction model demonstrates moderate discriminative power and good model fitting, suggesting its potential clinical utility.

Do disclosure of ESG information policies inhibit the value of heavily polluting Enterprises?-Evidence from China.

Green governance and high-quality green development are crucial to the growth of enterprises; therefore, this paper examines how environmental, social, and corporate governance (ESG) disclosure policies affect the value of heavily polluting companies. The study's data is from the new version of the Governance Guidelines for Public Companies promulgated by the China Securities Regulatory Commission in 2018. Thus, the data of China's public companies from 2011 to 2021 is used for the study's analysis. The methods applied for our estimation analysis are the differences-in-differences (DID) and the mediation effect model. The findings depict that ESG information disclosure policies can significantly inhibit the corporate value of heavily polluting enterprises (HPE). Enterprise technological innovation plays a mediating effect in this mechanism; that is, after introducing the policy, it effectively alleviates the information asymmetry and promotes enterprise technological innovation, but it also damages the enterprise value. Further analysis shows that the inhibition effect of ESG information disclosure policy on the value of HPE is heterogeneous, and for non-state-owned enterprises, ESG information disclosure policies have a stronger inhibitory effect. Also, there is little difference between the central and western regions and the eastern region in terms of the inhibitory effect of ESG disclosure policies on the value of HPE. The conclusion of this paper is conducive to improving the information disclosure policy of listed companies and promoting the green development of enterprises.

Study on the Treatment of ITP Mice with IVIG Sourced from Distinct Sex-Special Plasma (DSP-IVIG).

Intravenous immunoglobulin (IVIG) is a first-line drug prepared from human plasma for the treatment of autoimmune diseases (AIDs), especially immune thrombocytopenia (ITP). Significant differences exist in protein types and expression levels between male and female plasma, and the prevalence of autoimmune diseases varies between sexes. The present study seeks to explore potential variations in IVIG sourced from distinct sex-specific plasma (DSP-IVIG), including IVIG sourced from female plasma (F-IVIG), IVIG sourced from male plasma (M-IVIG), and IVIG sourced from a blend of male and female plasma (Mix-IVIG). To address this question, we used an ITP mouse model and a monocyte-macrophage inflammation model treated with DSP IVIG. The analysis of proteomics in mice suggested that the pathogenesis and treatment of ITP may involve FcγRs mediated phagocytosis, apoptosis, Th17, cytokines, chemokines, and more. Key indicators, including the mouse spleen index, CD16+ macrophages, M1, M2, IL-6, IL-27, and IL-13, all indicated that the efficacy in improving ITP was highest for M-IVIG. Subsequent cell experiments revealed that M-IVIG exhibited a more potent ability to inhibit monocyte phagocytosis. It induced more necrotic M2 cells and fewer viable M2, resulting in weaker M2 phagocytosis. M-IVIG also demonstrated superiority in the downregulation of surface makers CD36, CD68, and CD16 on M1 macrophages, a weaker capacity to activate complement, and a stronger binding ability to FcγRs on the THP-1 surface. In summary, DSP-IVIG effectively mitigated inflammation in ITP mice and monocytes and macrophages. However, M-IVIG exhibited advantages in improving the spleen index, regulating the number and typing of M1 and M2 macrophages, and inhibiting macrophage-mediated inflammation compared to F-IVIG and Mix-IVIG.

Extracellular vesicle-derived silk fibroin nanoparticles loaded with MFGE8 accelerate skin ulcer healing by targeting the vascular endothelial cells.

BACKGROUND: Reduced supplies of oxygen and nutrients caused by vascular injury lead to difficult-to-heal pressure ulcers (PU) in clinical practice. Rapid vascular repair in the skin wound is the key to the resolution of this challenge, but clinical measures are still limited. We described the beneficial effects of extracellular vesicle-derived silk fibroin nanoparticles (NPs) loaded with milk fat globule EGF factor 8 (MFGE8) on accelerating skin blood vessel and PU healing by targeting CD13 in the vascular endothelial cells (VECs). METHODS: CD13, the specific targeting protein of NGR, and MFGE8, an inhibitor of ferroptosis, were detected in VECs and PU tissues. Then, NPs were synthesized via silk fibroin, and MFGE8-coated NPs (NPs@MFGE8) were assembled via loading purified protein MFGE8 produced by Chinese hamster ovary cells. Lentivirus was used to over-express MFGE8 in VECs and obtained MFGE8-engineered extracellular vesicles (EVs-MFGE8) secreted by these VECs. The inhibitory effect of EVs-MFGE8 or NPs@MFGE8 on ferroptosis was detected in vitro. The NGR peptide cross-linked with NPs@MFGE8 was assembled into NGR-NPs@MFGE8. Collagen and silk fibroin were used to synthesize the silk fibroin/collagen hydrogel. After being loaded with NGR-NPs@MFGE8, silk fibroin/collagen hydrogel sustained-release carrier was synthesized to investigate the repair effect on PU in vivo. RESULTS: MFGE8 was decreased, and CD13 was increased in PU tissues. Similar to the effect of EVs-MFGE8 on inhibiting ferroptosis, NPs@MFGE8 could inhibit the mitochondrial autophagy-induced ferroptosis of VECs. Compared with the hydrogels loaded with NPs or NPs@MFGE8, the hydrogels loaded with NGR-NPs@MFGE8 consistently released NGR-NPs@MFGE8 targeting CD13 in VECs, thereby inhibiting mitochondrial autophagy and ferroptosis caused by hypoxia and accelerating wound healing effectively in rats. CONCLUSIONS: The silk fibroin/collagen hydrogel sustained-release carrier loaded with NGR-NPs@MFGE8 was of great significance to use as a wound dressing to inhibit the ferroptosis of VECs by targeting CD13 in PU tissues, preventing PU formation and promoting wound healing.