Gamma-glutamyl transferase 5 overexpression in cerebrovascular endothelial cells improves brain pathology, cognition, and behavior in APP/PS1 mice.

JOURNAL/nrgr/04.03/01300535-202502000-00030/figure1/v/2024-05-28T214302Z/r/image-tiff In patients with Alzheimer's disease, gamma-glutamyl transferase 5 (GGT5) expression has been observed to be downregulated in cerebrovascular endothelial cells. However, the functional role of GGT5 in the development of Alzheimer's disease remains unclear. This study aimed to explore the effect of GGT5 on cognitive function and brain pathology in an APP/PS1 mouse model of Alzheimer's disease, as well as the underlying mechanism. We observed a significant reduction in GGT5 expression in two in vitro models of Alzheimer's disease (Aß1-42-treated hCMEC/D3 and bEnd.3 cells), as well as in the APP/PS1 mouse model. Additionally, injection of APP/PS1 mice with an adeno-associated virus encoding GGT5 enhanced hippocampal synaptic plasticity and mitigated cognitive deficits. Interestingly, increasing GGT5 expression in cerebrovascular endothelial cells reduced levels of both soluble and insoluble amyloid-ß in the brains of APP/PS1 mice. This effect may be attributable to inhibition of the expression of ß-site APP cleaving enzyme 1, which is mediated by nuclear factor-kappa B. Our findings demonstrate that GGT5 expression in cerebrovascular endothelial cells is inversely associated with Alzheimer's disease pathogenesis, and that GGT5 upregulation mitigates cognitive deficits in APP/PS1 mice. These findings suggest that GGT5 expression in cerebrovascular endothelial cells is a potential therapeutic target and biomarker for Alzheimer's disease.

In-hospital Outcomes and Post Discharge Mortality in Patients with Acute Coronary Syndrome and Atrial Fibrillation.

BACKGROUND: It is unclear whether advances in management of acute coronary syndromes (ACS) and introduction of novel oral anticoagulants (NOAC) have changed outcomes in patients with ACS with concomitant atrial fibrillation (AF) . OBJECTIVE: Examine the incidence of AF in patients admitted for ACS and evaluate its association with adverse outcomes given the recent advances in management of both diseases. METHODS: Natural language processing search algorithms identified AF in patients admitted with ACS across 13 Northwell Health Hospitals from 2015 to 2021. Hierarchical generalized linear mixed modeling was used to assess the association between AF and in-hospital mortality, bleeding, and stroke outcomes; marginal Cox regression modeling was used to assess the association between AF and post-discharge mortality. RESULTS: Of 12,315 patients admitted for ACS, 3,018 (24.5%) had AF with 1,609 (53.3%) newly diagnosed. AF patients more commonly received anticoagulation with an oral anticoagulant (80.4% vs 12.3%) or heparin (61.9% vs 56.9%), had lengthier intensive care unit stay (72 vs 49 hours), and underwent fewer percutaneous coronary interventions (31.9% vs 53.1%). In-hospital bleeding, stroke and mortality were higher in the AF group (15.3% vs 5.0%, 7.4% vs 2.4%, 6.9% vs 2.1% respectively). AF was an independent risk factor for all in-hospital outcomes (ORs: 2.5, 2.7 and 2.0 for bleeding, stroke, and mortality, respectively) as well as post-discharge mortality ( HRs: 1.3 95% CI: 1.2-1.5). CONCLUSION: AF is present in 25% of ACS patients and increases risk of in-hospital and post discharge adverse outcomes. Additional data is required to direct optimal management.

Association Between Outdoor Light at Night Exposure and Executive Function in Chinese Children.

BACKGROUND: Recent evidences highlight the potential impact of outdoor Light at Night (LAN) on executive function. However, few studies have investigated the association between outdoor LAN exposure and executive function. METHODS: We employed data from 48,502 Chinese children aged 5-12 years in a cross-sectional study conducted in Guangdong province during 2020-2021, to examine the association between outdoor LAN and executive function assessed using the validated parent-completed Behavior Rating Inventory of Executive Function. We assessed children's outdoor LAN exposure using the night-time satellite images based on the residential addresses. We used generalized linear mixed models to estimate the association between outdoor LAN exposure and executive function scores and executive dysfunction. RESULTS: After adjusting for potential covariates, higher quintiles of outdoor LAN exposure were associated with poorer executive function. Compared to the lowest quintile (Q1), all higher quintiles of exposure showed a significant increased global executive composite (GEC) score with ß (95% confidence intervals, CI) of 0.58 (0.28, 0.88) in Q2, 0.59 (0.28, 0.9) in Q3, 0.85 (0.54, 1.16) in Q4, and 0.76 (0.43, 1.09) in Q5. Higher quintiles of exposure were also associated with higher risks for GEC dysfunction with odd ratios (ORs) (95% CI) of 1.34 (1.18, 1.52) in Q2, 1.40 (1.24, 1.59) in Q3, 1.40 (1.23, 1.59) in Q4, and 1.39 (1.22, 1.58) in Q5. And stronger associations were observed in children aged 10-12 years. CONCLUSIONS: Our study suggested that high outdoor LAN exposure was associated with poor executive function in children. These findings suggested that future studies should determine whether interventions to reduce outdoor LAN exposure can have a positive effect on executive function.

The transcription factor WRKY22 modulates ethylene biosynthesis and root development through transactivating the transcription of ACS5 and ACO5 in Arabidopsis.

The WRKY transcription factor (TF) genes form a large family in higher plants, with 72 members in Arabidopsis (Arabidopsis thaliana). The gaseous phytohormone ethylene (ET) regulates multiple physiological processes in plants. It is known that 1-aminocyclopropane-1-carboxylic acid (ACC) synthases (ACSs, EC 4.4.1.14) limit the enzymatic reaction rate of ethylene synthesis. However, whether WRKY TFs regulate the expression of ACSs and/or ACC oxidases (ACOs, EC 1.14.17.4) remains largely elusive. Here, we demonstrated that Arabidopsis WRKY22 positively regulated the expression of a few ACS and ACO genes, thus promoting ethylene production. Inducible overexpression of WRKY22 caused shorter hypocotyls without ACC treatment. A qRT-PCR screening demonstrated that overexpression of WRKY22 activates the expression of several ACS and ACO genes. The promoter regions of ACS5, ACS11, and ACO5 were also activated by WRKY22, which was revealed by a dual luciferase reporter assay. A follow-up chromatin immunoprecipitation coupled with quantitative PCR (ChIP-qPCR) and electrophoretic mobility shift assay (EMSA) showed that the promoter regions of ACS5 and ACO5 could be bound by WRKY22 directly. Moreover, wrky22 mutants had longer primary roots and more lateral roots than wild type, while WRKY22-overexpressing lines showed the opposite phenotype. In conclusion, this study revealed that WRKY22 acts as a novel TF activating, at least, the expression of ACS5 and ACO5 to increase ethylene synthesis and modulate root development.

Low Driving Voltage Electroluminescence Device for Integrated Visual Strain Sensing.

As a pivotal component in human-machine interactions, display devices have undergone rapid development in modern life. Displays such as alternative current electroluminescence|alternative current electroluminescent (ACEL) devices with high flexibility and long operational lifetimes are essential for wearable electronics. However, ACEL devices are constrained by their inherent high driving voltage and complex fabrication processes. Our work presents an easy blade-coating method for fabricating flexible ACEL display devices based on an all-solution process. By dispersing BaTiO3 and ZnS/Cu powder into waterborne polyurethane, we successfully combined dielectric and fluorescence functionalities within a single layer, significantly reducing the device's driving voltage. Additionally, the ionic conducting hydrogel was chosen as a transparent electrode to achieve good electrical contact and strong interfacial adhesion through in situ polymerization. Owing to the unique method, our ACEL device exhibits high flexibility, low driving voltage (20-100 V), high brightness (300+ cd/m2 at 60 V), and environmental friendliness. Furthermore, by repurposing the hydrogel electrode, we integrated strain visualization capabilities within a single device, highlighting its potential for applications such as wearable healthcare monitoring.

Long-term exposure to ambient fine particulate matter (PM2.5) and attributable pulmonary tuberculosis notifications in Ningxia Hui Autonomous Region, China: a health impact assessment.

INTRODUCTION: Long-term exposure to fine particulate matter (≤2.5 µm (PM2.5)) has been associated with pulmonary tuberculosis (TB) notifications or incidence in recent publications. Studies quantifying the relative contribution of long-term PM2.5 on TB notifications have not been documented. We sought to perform a health impact assessment to estimate the PM2.5- attributable TB notifications during 2007-2017 in Ningxia Hui Autonomous Region (NHAR), China. METHODS: PM2.5 attributable TB notifications were estimated at township level (n=358), stratified by age group and summed across NHAR. PM2.5-associated TB-notifications were estimated for total and anthropogenic PM2.5 mass and expressed as population attributable fractions (PAFs). The main analysis used effect and uncertainty estimates from our previous study in NHAR, defining a counterfactual of the lowest annual PM2.5 (30 µg/m3) level, above which we assumed excess TB notifications. Sensitivity analyses included counterfactuals based on the 5th (31 µg/m3) and 25th percentiles (38 µg/m3), and substituting effect estimates from a recent meta-analysis. We estimated the influence of PM2.5 concentrations, population growth and baseline TB-notification rates on PM2.5 attributable TB notifications. RESULTS: Over 2007-2017, annual PM2.5 had an estimated average PAF of 31.2% (95% CI 22.4% to 38.7%) of TB notifications while the anthropogenic PAF was 12.2% (95% CI 9.2% to 14.5%). With 31 and 38 µg/m3 as counterfactuals, the PAFs were 29.2% (95% CI 20.9% to 36.3%) and 15.4% (95% CI 10.9% to 19.6%), respectively. PAF estimates under other assumptions ranged between 6.5% (95% CI 2.9% to 9.6%) and 13.7% (95% CI 6.2% to 19.9%) for total PM2.5, and 2.6% (95% CI 1.2% to 3.8%) to 5.8% (95% CI 2.7% to 8.2%) for anthropogenic PM2.5. Relative to 2007, overall changes in PM2.5 attributable TB notifications were due to reduced TB-notification rates (-23.8%), followed by decreasing PM2.5 (-6.2%), and population growth (+4.9%). CONCLUSION: We have demonstrated how the potential impact of historical or hypothetical air pollution reduction scenarios on TB notifications can be estimated, using public domain, PM2.5 and population data. The method may be transferrable to other settings where comparable TB-notification data are available.

How does carbon biased technological progress promote carbon haze collaborative Governance？Evidence from Chinese cities.

Carbon dioxide (CO2) emissions and haze pollution are often thought to have the same origin, the burning of fossil fuels. However, their relationship is not always synergistic and may even exhibit mutual constraints. Carbon-biased technological progress has emerged as a promising approach for simultaneously achieving three goals - to reduce CO2 emissions, alleviate the haze pressure, and keep economic growth. This study empirically investigates the impact and mechanisms of carbon-biased technological progress on carbon haze collaborative governance using data from 286 Chinese cities during 2006-2021. The results indicate that: (1) Carbon biased technological progress positively influences carbon haze collaborative governance. (2) This progress achieves coordination by enhancing element allocation efficiency, carbon efficiency, and responding to public environmental demands. (3) The facilitating role of carbon biased technological progress to carbon haze collaborative governance will work better if external conditions are met. Moreover, the effectiveness of carbon-biased technological progress in promoting coordination is contingent upon high levels of marketization, government intervention, environmental regulation, and technical advancements. Local and regional governments should foster conducive conditions for carbon dioxide and haze pollution coordination, optimize the allocation and flow of carbon resources, ensure harmonization between environmental regulation policies and other sectors, and bolster international cooperation and technical knowledge exchange to collectively address global environmental challenges.

Unsupervised 3D Object Segmentation of Point Clouds by Geometry Consistency.

In this paper, we study the problem of 3D object segmentation from raw point clouds. Unlike existing methods which usually require a large amount of human annotations for full supervision, we propose the first unsupervised method, called OGC, to simultaneously identify multiple 3D objects in a single forward pass, without needing any type of human annotations. The key to our approach is to fully leverage the dynamic motion patterns over sequential point clouds as supervision signals to automatically discover rigid objects. Our method consists of three major components, 1) the object segmentation network to directly estimate multi-object masks from a single point cloud frame,2)the auxiliary self-supervised scene flow estimator,and 3)our core object geometry consistency component. By carefully designing a series of loss functions, we effectively take into account the multi-object rigid consistency and the object shape invariance in both temporal and spatial scales. This allows our method to truly discover the object geometry even in the absence of annotations. We extensively evaluate our method on five datasets, demonstrating the superior performance for object part instance segmentation and general object segmentation in both indoor and the challenging outdoor scenarios. Our code and data are available at https://github.com/vLAR-group/OGC.

Semi-automatic computed tomography angiography quantification assessment is an alternative method to digital subtraction angiography in intracranial stenosis: a multicenter study.

Background: The recent randomized controlled trials studying intracranial atherosclerotic stenosis (ICAS) have used digital subtraction angiography (DSA) to quantify stenosis and enroll patients. However, some disadvantages of DSA such as invasive features, contrast agent overuse, and X-ray radiation overexposure, were not considered in these studies. This study aimed to explore whether computed tomography angiography (CTA) with semi-automatic analysis could be an alternative method to DSA in quantifying the absolute stenotic degree in clinical trials. Methods: Patients with 50-99% ICAS were consecutively screened, prospectively enrolled, and underwent CTA and DSA between March 2021 and December 2021 at 6 centers. This study was registered at www.chictr.org.cn (ChiCTR2100052925). The absolute stenotic degree of ICAS on CTA with semi-automatic analysis was calculated by several protocols using minimal/maximum/mean diameters of stenosis and reference site from a semi-automatic analysis software. Intraclass correlation coefficient (ICC) was used to evaluate the reliabilities of quantifying stenotic degree on CTA. The optimal protocol for quantifying ICAS on CTA was explored. The agreements of quantifying ICAS in calcified or non-calcified lesions and 50-69% or 70-99% stenosis on CTA and DSA were assessed. Results: A total of 191 participants (58.8±10.7 years; 148 men) with 202 lesions were enrolled. The optimal protocol for quantifying ICAS on CTA was calculated as (1 - the minimal diameter of stenosis/the mean diameter of reference) × 100% for its highest agreement with DSA [ICC, 0.955, 95% confidence interval (CI): 0.944-0.966, P<0.001]. Among the 202 lesions, 80.2% (162/202) exhibited severe stenosis on DSA. The accuracy of CTA in detecting severe ICAS was excellent (sensitivity =95.1%, positive predictive value =98.1%). The agreements between DSA and CTA in non-calcified lesions (ICC, 0.960 vs. 0.849) and severe stenosis (ICC, 0.918 vs. 0.841) were higher than those in calcified lesions and moderate stenosis. Conclusions: CTA with semi-automatic analysis demonstrated an excellent agreement with DSA in quantifying ICAS, making it promising to replace DSA for the measurement of absolute stenotic degree in clinical trials.

Rare codon recoding for efficient noncanonical amino acid incorporation in mammalian cells.

The ability to genetically encode noncanonical amino acids (ncAAs) has empowered proteins with improved or previously unknown properties. However, existing strategies in mammalian cells rely on the introduction of a blank codon to incorporate ncAAs, which is inefficient and limits their widespread applications. In this study, we developed a rare codon recoding strategy that takes advantage of the relative rarity of the TCG codon to achieve highly selective and efficient ncAA incorporation through systematic engineering and big data-model predictions. We highlight the broad utility of this strategy for the incorporation of dozens of ncAAs into various functional proteins at the wild-type protein expression levels, as well as the synthesis of proteins with up to six-site ncAAs or four distinct ncAAs in mammalian cells for downstream applications.

Comparison of the short-term outcomes between Y-incision aortic annular enlargement and traditional aortic annular enlargement techniques.

Background: The short-term efficacy and safety of the Y-incision technique of aortic annular enlargement (AAE) has been established. We aimed to determine how the short-term outcomes of the Y-incision technique compared to traditional AAE techniques. Methods: From February 2011 to June 2022, 380 patients at the University of Michigan Hospital underwent aortic valve replacement (AVR) with AAE using either traditional annular enlargement techniques (Traditional group, n=270), including Nicks [63% (171/270)], Manouguian [34% (91/270)], and others [3% (8/270)], or the Y-incision technique (Y-incision group, n=110). Propensity score matching was performed by controlling for age, sex, body surface area (BSA), hypertension, diabetes, dialysis, chronic lung disease, stroke, prior cardiac surgery, primary indication, operative status, concomitant procedures, and prosthesis type, to generate a balanced cohort of 103 pairs. Results: There were no differences in demographics, comorbidities, primary indications of the operations, or concomitant procedures between the matched groups. The median native aortic annulus diameter, measured in the operating room, was 21 mm for both groups. Median prosthesis size was 23 in the Traditional group, and 27 in the Y-incision group (P<0.001). There were no differences in perioperative complications/outcomes between the matched groups, including operative mortality, which was 3.9% (8/206) overall. Short-term survival was similar between the groups on Kaplan-Meier analysis; one-year survival was 95% in the Traditional group, and 97% in the Y-incision group (P=0.54). The Y-incision group had significantly lower mean aortic valve gradients (7 vs. 10 mmHg, P<0.001), larger aortic valve areas (2.2 vs. 1.8 cm2, P=0.007), and less moderate/severe patient-prosthesis mismatch (PPM) (5.5% vs. 23%, P=0.039) on one-year follow-up echocardiography. Conclusions: The Y-incision technique was as safe and more effective in enlarging the aortic annulus and upsizing the prosthetic valve than the traditional techniques of AAE in AVR for small aortic annuli.

Aortic annular enlargement with Y-incision/rectangular patch.

The Y-incision/rectangular patch aortic annular enlargement (Y-incision AAE) is our go-to technique for aortic annular/root enlargement at the University of Michigan for its simplicity and effectiveness. A complete aortotomy is used for first-time surgical aortic valve replacements (SAVRs), and a partial aortotomy is frequently used in reoperative SAVR. The Y-incision is made through the left-non commissure, underneath the aortic annulus to the left and right fibrous trigones. A rectangular patch is sewn to the aorto-mitral curtain from the left fibrous trigone to the right fibrous trigone and transitioned to the aortic annulus on both sides. The enlarged aortic annulus/root is sized with the valve-shape end of the sizer, and the largest size that can touch all three nadirs of the aortic annulus with one strut facing the left-right commissure is chosen. The non-pledgetted valve sutures are placed in a non-everting suture fashion on the aortic annulus, and inside-outside-inside on the patch. The sutures at the nadir of the non-coronary sinus and left coronary sinus are tied first. The proximal ascending aorta is enlarged with a posterior longitudinal aortotomy, and the distal end of the patch is trimmed to a triangular shape to facilitate the closure of the aortotomy with the "Roof" technique. In the 142 consecutives cases, the median size of prosthetic valve used was 29 and upsizing was 3-4 valve sizes. Outcomes included one death, one stroke, two pacemaker implantations for complete heart block including one case of aortic valve endocarditis with Gerbode fistula, and no reoperation for post-operative bleeding. The median aortic valve mean gradient was 7 mmHg and aortic valve area was 2.4 cm2 two years after SAVR. The median left ventricular mass index regression was 41% in 12-24 months in patients with moderate/severe aortic stenosis.

Changes in aortic root dimensions post aortic root enlargement with Y-incision and modified aortotomy.

Background: Lifetime management in aortic stenosis (AS) can be facilitated by aortic root enlargement (ARE) to improve anatomy for future valve-in-valve (ViV) procedures. A mitral valve-sparing ARE technique ("Y-incision") and sinotubular junction (STJ) enlargement ("roof" patch aortotomy) allow upsizing by 3-4 valve sizes, but quantitative analysis of changes in root anatomy is lacking. Methods: Among 78 patients who underwent ARE by Y-incision technique (± roof aortotomy closure) we identified 45 patients with high-quality pre- and post-operative computed tomography angiography (CTA) scans to allow analysis of change in aortic root dimensions. Detailed measurements of the annulus/basilar ring and sinuses were performed by an expert imager on both pre- and post-operative CTAs. The basal ring was defined as the functional annulus when a bioprosthetic valve was present. Results: Average age was 65±11 years, the majority were female (29, 64%), and 9 (20%) had undergone prior aortic valve replacement (AVR). Valve upsizing was ≥3 sizes in 41 (91%). Post-operative mean basal ring diameter was larger compared to the native annular diameter (26.3 vs. 25.3 mm, P<0.01) and substantially larger than prior prosthetic valve in redo AVR (25.6 vs. 19.3 mm, P<0.001). Diameters of the sinuses at pre-operative computed tomography (CT) increased by +7.7±2.8 [right sinuses of Valsalva (R SVS)], +6.7±3.0 [left sinuses of Valsalva (L SVS)], and +6.6±2.9 mm [non-coronary sinuses of Valsalva (N SVS)]. Mean diameter of the STJ increased to 38.3±3.7 post-operative (+8.1±3.2 mm). Left main (LM) and right coronary artery (RCA) heights decreased by -6.3±3.3 and -3.7±3.4 mm respectively due to the supra-annular position of the valve, however, the post-operative valve-to-coronary (VTC) artery distances were 6.6±2.3 and 4.9±2.0 mm, respectively. Conclusion: The Y-incision root enlargement technique significantly enlarges the sinus and STJ diameters by 6-7 mm while preserving VTC distances despite upsizing by 3-4 valve sizes, resulting in post-operative anatomy that is favorable for future transcatheter aortic valve-in-surgical aortic valve (TAV-in-SAV).

Bifidobacterium longum subsp. infantis regulates Th1/Th2 balance through the JAK-STAT pathway in growing mice.

Objectives: Bifidobacterium longum subsp. infantis is a dominant bacterium in infant gut, which plays a critical role in maintaining the health and development of infants. This study investigated the abilities of eight different strains of B. longum subsp. infantis to regulate the T helper (Th)1/Th2 balance. Methods: Eight B. longum subsp. infantis strains, including I2MI (FJSWXI2MIM1), I4MI [FJSWXI4MI (CCFM1270)], I4MNI (FJSWXI4MNIM1), I5TI (FJSWXI5TIM1), I6TI (FJSWXI6TIM1), I8TI [FJSWXI8TI (CCFM1271)], I10TI [FJSWXI10TI (CCFM1272)], and B6MNI [BJSWXB6MNIM1 (CCFM1269)], were gavaged to BALB/C pups in both female (n = 8) and male (n = 8) mice starting from 1 to 3 weeks old (1 × 109 CFU/day/mice). Selected immune cells were assessed by immunofluorescence and flow cytometry. Cytokines and immunoglobulins were determined by ELISA. Bacterial and bifidobacterial communities were determined by 16S rRNA gene sequencing and bifidobacterial groEL sequencing. Results: B. longum subsp. infantis I4MI and I8TI were shown to increase the ration of colonic IgG2a/IgE in male mice (P < 0.05). B6MNI was demonstrated to significantly increase the levels of colonic IFN-γ and IgG2a, as well as the ratio of IgG2a/IgE in female mice (P < 0.05). It was also shown to significantly increase the ratio of colonic IgG2a/IgE (P < 0.05) and reduce the level of colonic IL-4 in male mice (P < 0.05). Furthermore, B6MNI was demonstrated to regulate colonic JAK/STAT pathway in both male and female mice. I4MI, I5TI, and B6MNI were shown to increase the relative abundance of Bifidobacterium and B. longum subsp. infantis in both male and female mice, whereas I8TI was only shown to increase the relative abundance of Bifidobacterium and B. longum subsp. infantis in male mice (P < 0.05). Conclusion: These results indicated supplementation with B. longum subsp. infantis in early infancy may regulate the Th1/Th2 immune balance, which may prevent the development of related diseases.

Comparative transcriptomics revealed neurodevelopmental impairments and ferroptosis induced by extremely small iron oxide nanoparticles.

Iron oxide nanoparticles are a type of nanomaterial composed of iron oxide (Fe3O4 or Fe2O3) and have a wide range of applications in magnetic resonance imaging. Compared to iron oxide nanoparticles, extremely small iron oxide nanoparticles (ESIONPs) (∼3 nm in diameter) can improve the imaging performance due to a smaller size. However, there are currently no reports on the potential toxic effects of ESIONPs on the human body. In this study, we applied ESIONPs to a zebrafish model and performed weighted gene co-expression network analysis (WGCNA) on differentially expressed genes (DEGs) in zebrafish embryos of 48 hpf, 72 hpf, 96 hpf, and 120 hpf using RNA-seq technology. The key hub genes related to neurotoxicity and ferroptosis were identified, and further experiments also demonstrated that ESIONPs impaired the neuronal and muscle development of zebrafish, and induced ferroptosis, leading to oxidative stress, cell apoptosis, and inflammatory response. Here, for the first time, we analyzed the potential toxic effects of ESIONPs through WGCNA. Our studies indicate that ESIONPs might have neurotoxicity and could induce ferroptosis, while abnormal accumulation of iron ions might increase the risk of early degenerative neurological diseases.

Fluorinated hydroxyapatite conditions a favorable osteo-immune microenvironment via triggering metabolic shift from glycolysis to oxidative phosphorylation.

BACKGROUND: Biological-derived hydroxyapatite is widely used as a bone substitute for addressing bone defects, but its limited osteoconductive properties necessitate further improvement. The osteo-immunomodulatory properties hold crucial promise in maintaining bone homeostasis, and precise modulation of macrophage polarization is essential in this process. Metabolism serves as a guiding force for immunity, and fluoride modification represents a promising strategy for modulating the osteoimmunological environment by regulating immunometabolism. In this context, we synthesized fluorinated porcine hydroxyapatite (FPHA), and has demonstrated its enhanced biological properties and osteogenic capacity. However, it remains unknown whether and how FPHA affects the immune microenvironment of the bone defects. METHODS: FPHA was synthesized and its composition and structural properties were confirmed. Macrophages were cultured with FPHA extract to investigate the effects of FPHA on their polarization and the related osteo-immune microenvironment. Furthermore, total RNA of these macrophages was extracted, and RNA-seq analysis was performed to explore the underlying mechanisms associated with the observed changes in macrophages. The metabolic states were evaluated with a Seahorse analyzer. Additionally, immunohistochemical staining was performed to evaluate the macrophages response after implantation of the novel bone substitutes in critical size calvarial defects in SD rats. RESULTS: The incorporation of fluoride ions in FPHA was validated. FPHA promoted macrophage proliferation and enhanced the expression of M2 markers while suppressing the expression of M1 markers. Additionally, FPHA inhibited the expression of inflammatory factors and upregulated the expression of osteogenic factors, thereby enhancing the osteogenic differentiation capacity of the rBMSCs. RNA-seq analysis suggested that the polarization-regulating function of FPHA may be related to changes in cellular metabolism. Further experiments confirmed that FPHA enhanced mitochondrial function and promoted the metabolic shift of macrophages from glycolysis to oxidative phosphorylation. Moreover, in vivo experiments validated the above results in the calvarial defect model in SD rats. CONCLUSION: In summary, our study reveals that FPHA induces a metabolic shift in macrophages from glycolysis to oxidative phosphorylation. This shift leads to an increased tendency toward M2 polarization in macrophages, consequently creating a favorable osteo-immune microenvironment. These findings provide valuable insights into the impact of incorporating an appropriate concentration of fluoride on immunometabolism and macrophage mitochondrial function, which have important implications for the development of fluoride-modified immunometabolism-based bone regenerative biomaterials and the clinical application of FPHA or other fluoride-containing materials.

Tumor suppressor function of RBMS3 overexpression in EOC associated with immune cell infiltration.

Objectives: Epithelial ovarian cancer (EOC) is considered to be a prevalent female malignancy with both high incidence and mortality. It is reported that RNA-binding protein 3 (RBMS3) executives a tumor suppressor function in different cancers. This investigation was designed to examine the expression of RBMS3 in epithelial ovarian cancer, the effects on EOC cells, and its connection to immune cells that infiltrate tumors in the EOC microenvironment. Methods: The expression levels of RBMS3 in EOC tissues as well as their correlations with immune cell infiltration and clinical outcome were examined using bioinformatics approaches. Western blotting as well as immunohistochemistry were carried out to determine the protein levels in EOC tissues. In addition, qRT-PCR was employed to look at the expression of the mRNA. The role of RBMS3 in EOC cells was investigated, and an RBMS3 lentiviral vector was developed. The effects of RBMS3 on subcutaneous tumor development, the proliferation protein Ki-67, the tumor angiogenesis indicator CD31, and its function in controlling the tumor immune microenvironment were evaluated by in vivo tests. Results: There was a considerable decrease in RBMS3 expression in EOC tissues, which was linked to a poor prognosis for patients and the infiltration of multiple immune cell. Given immunohistochemical studies, tissues with increased RBMS3 expression had decreased markers of myeloid-derived suppressor cells, regulatory T cells, and M2 macrophages, whereas M1 macrophage markers were elevated. RBMS3 appears to suppress the capabilities of proliferating, invading, and migrating in EOC cells according to in vitro tests, whereas tumors overexpressing RBMS3 developed more slowly in syngeneic mouse models. The overexpression of RBMS3 led to a decline in the levels of Ki-67 protein and CD31. Additionally, it showed a negatively correlation with markers of regulatory T cell, myeloid-derived suppressor cell, and M2 macrophage but a positive correlation with markers of M1 macrophage. Conclusions: The findings revealed that elevated RBMS3 expression plays a tumor suppressor role in EOC and was connected to patient survival in EOC. The studies conducted in vitro and in vivo demonstrated a link between RBMS3 expression and the infiltration of certain immune cells, indicating a function for RBMS3 in the immunosuppressive tumor microenvironment and its promising efficiency as a novel target for immunotherapy against EOC.

The effect of fecal microbiota transplantation on antibiotic-associated diarrhea and its impact on gut microbiota.

BACKGROUND: Antibiotic-associated diarrhea (AAD) refers to symptoms of diarrhea that cannot be explained by other causes after the use of antibiotics. AAD is thought to be caused by a disruption of intestinal ecology due to antibiotics. Fecal Microbiota Transplantation (FMT) is a treatment method that involves transferring microbial communities from the feces of healthy individuals into the patient's gut. METHOD: We selected 23 AAD patients who received FMT treatment in our department. Before FMT, we documented patients' bowel movement frequency, abdominal symptoms, routine blood tests, and inflammatory markers, and collected fecal samples for 16S rRNA sequencing to observe changes in the intestinal microbiota. Patients' treatment outcomes were followed up 1 month and 3 months after FMT. RESULTS: Out of the 23 AAD patients, 19 showed a clinical response to FMT with alleviation of abdominal symptoms. Among them, 82.61% (19/23) experienced relief from diarrhea, 65% (13/20) from abdominal pain, 77.78% (14/18) from abdominal distension, and 57.14% (4/7) from bloody stools within 1 month after FMT. Inflammatory markers IL-8 and CRP significantly decreased after FMT, but there were no noticeable changes in WBC, IL-6, and TNF-α before and after transplantation. After FMT, the abundance of Bacteroides and Faecalibacterium increased in patients' fecal samples, while the abundance of Escherichia-Shigella and Veillonella decreased. CONCLUSION: FMT has a certain therapeutic effect on AAD, and can alleviate abdominal symptoms and change the intestinal microbiota of patients.