Artificial intelligence-assisted quantification and assessment of whole slide images for pediatric kidney disease diagnosis.

MOTIVATION: Pediatric kidney disease is a widespread, progressive condition that severely impacts growth and development of children. Chronic kidney disease is often more insidious in children than in adults, usually requiring a renal biopsy for diagnosis. Biopsy evaluation requires copious examination by trained pathologists, which can be tedious and prone to human error. In this study, we propose an artificial intelligence (AI) method to assist pathologists in accurate segmentation and classification of pediatric kidney structures, named as AI-based Pediatric Kidney Diagnosis (APKD). RESULTS: We collected 2935 pediatric patients diagnosed with kidney disease for the development of APKD. The dataset comprised 93 932 histological structures annotated manually by three skilled nephropathologists. APKD scored an average accuracy of 94% for each kidney structure category, including 99% in the glomerulus. We found strong correlation between the model and manual detection in detected glomeruli (Spearman correlation coefficient r = 0.98, P < .001; intraclass correlation coefficient ICC = 0.98, 95% CI = 0.96-0.98). Compared to manual detection, APKD was approximately 5.5 times faster in segmenting glomeruli. Finally, we show how the pathological features extracted by APKD can identify focal abnormalities of the glomerular capillary wall to aid in the early diagnosis of pediatric kidney disease. AVAILABILITY AND IMPLEMENTATION: https://github.com/ChunyueFeng/Kidney-DataSet.

Enzyme-catalysed [6+4] cycloadditions in the biosynthesis of natural products.

Pericyclic reactions are powerful transformations for the construction of carbon-carbon and carbon-heteroatom bonds in organic synthesis. Their role in biosynthesis is increasingly apparent, and mechanisms by which pericyclases can catalyse reactions are of major interest1. [4+2] cycloadditions (Diels-Alder reactions) have been widely used in organic synthesis2 for the formation of six-membered rings and are now well-established in biosynthesis3-6. [6+4] and other 'higher-order' cycloadditions were predicted7 in 1965, and are now increasingly common in the laboratory despite challenges arising from the generation of a highly strained ten-membered ring system8,9. However, although enzyme-catalysed [6+4] cycloadditions have been proposed10-12, they have not been proven to occur. Here we demonstrate a group of enzymes that catalyse a pericyclic [6+4] cycloaddition, which is a crucial step in the biosynthesis of streptoseomycin-type natural products. This type of pericyclase catalyses [6+4] and [4+2] cycloadditions through a single ambimodal transition state, which is consistent with previous proposals11,12. The [6+4] product is transformed to a less stable [4+2] adduct via a facile Cope rearrangement, and the [4+2] adduct is converted into the natural product enzymatically. Crystal structures of three pericyclases, computational simulations of potential energies and molecular dynamics, and site-directed mutagenesis establish the mechanism of this transformation. This work shows how enzymes are able to catalyse concerted pericyclic reactions involving ambimodal transition states.

Electrolyte Chemistry toward Ultrawide-Temperature (-25 to 75 °C) Sodium-Ion Batteries Achieved by Phosphorus/Silicon-Synergistic Interphase Manipulation.

All-weather operation is considered an ultimate pursuit of the practical development of sodium-ion batteries (SIBs), however, blocked by a lack of suitable electrolytes at present. Herein, by introducing synergistic manipulation mechanisms driven by phosphorus/silicon involvement, the compact electrode/electrolyte interphases are endowed with improved interfacial Na-ion transport kinetics and desirable structural/thermal stability. Therefore, the modified carbonate-based electrolyte successfully enables all-weather adaptability for long-term operation over a wide temperature range. As a verification, the half-cells using the designed electrolyte operate stably over a temperature range of -25 to 75 °C, accompanied by a capacity retention rate exceeding 70% even after 1700 cycles at 60 °C. More importantly, the full cells assembled with Na3V2(PO4)2O2F cathode and hard carbon anode also have excellent cycling stability, exceeding 500 and 1000 cycles at -25 to 50 °C and superb temperature adaptability during all-weather dynamic testing with continuous temperature change. In short, this work proposes an advanced interfacial regulation strategy targeted at the all-climate SIB operation, which is of good practicability and reference significance.

Janus Binder Chemistry for Synchronous Enhancement of Iodine Species Adsorption and Redox Kinetics toward Sustainable Aqueous Zn-I2 Batteries.

Currently, the desired research focus in energy storage technique innovation has been gradually shifted to next-generation aqueous batteries holding both high performance and sustainability. However, aqueous Zn-I2 batteries have been deemed to have great sustainable potential, owing to the merits of cost-effective and eco-friendly nature. However, their commercial application is hindered by the serious shuttle effect of polyiodides during reversible operations. In this work, a Janus functional binder based on chitosan (CTS) molecules was designed and prepared; the polar terminational groups impart excellent mechanical robustness to hybrid binders; meanwhile, it can also deliver isochronous enhancement on physical adsorption and redox kinetics toward I2 species. By feat of highly effective remission to shuttle effect, the CTS cell exhibits superb electrochemical storage capacities with long-term robustness, specifically, 144.1 mAh g-1, at a current density of 0.2 mA g-1 after 1500 cycles. Simultaneously, the undesired self-discharging issue could be also well-addressed; the Coulombic efficiency could remain at 98.8 % after resting for 24 h. More importantly, CTS molecules endow good biodegradability and reusable properties; after iodine species were reloaded, the recycled devices could also deliver specific capacities of 73.3 mAh g-1, over 1000 cycles. This Janus binder provides a potential synchronous solution to realize high comprehensive performance with high iodine utilization and further make it possible for sustainable Zn-I2 batteries.

Interfacial-Confined Isochronous Conversion to Biphasic Selenide Heterostructure with Enhanced Adsorption Behaviors for Robust High-Rate Na-Ion Storage.

Sodium-ion batteries (SIBs) have gradually become one of the most promising energy storage techniques in the current era of post-lithium-ion batteries. For anodes, transitional metal selenides (TMSe) based materials are welcomed choices , owing to relatively higher specific capacities and enriched redox active sites. Nevertheless, current bottlenecks are blamed for their poor intrinsic electronic conductivities, and uncontrollable volume expansion during redox reactions. Given that, an interfacial-confined isochronous conversion strategy is proposed, to prepare orthorhombic/cubic biphasic TMSe heterostructure, namely CuSe/Cu3 VSe4 , through using MXene as the precursor, followed by Cu/Se dual anchorage. As-designed biphasic TMSe heterostructure endows unique hierarchical structure, which contains adequate insertion sites and diffusion spacing for Na ions, besides, the surficial pseudocapacitive storage behaviors can be also proceeded like 2D MXene. By further investigation on electronic structure, the theoretical calculations indicate that biphasic CuSe/Cu3 VSe4 anode exhibits well-enhanced properties, with smaller bandgap and thus greatly improves intrinsic poor conductivities. In addition, the dual redox centers can enhance the electrochemical Na ions storage abilities. As a result, the as-designed biphasic TMSe anode can deliver a reversible specific capacity of 576.8 mAh g-1 at 0.1 A g-1 , favorable Na affinity, and reduced diffusion barriers. This work discloses a synchronous solution toward demerits in conductivities and lifespan, which is inspiring for TMSe-based anode development in SIBs systems.

Ancient bayberry increased stress resistance by enriching tissue-specific microbiome and metabolites.

The ancient bayberry demonstrates superior resistance to both biotic and abiotic stresses compared to cultivated bayberry, yet the underlying mechanisms remain largely unexplored. This study investigates whether long-term bayberry cultivation enhances stress resistance through modulation of tissue-specific microbes and metabolites. Employing microbiome amplicon sequencing alongside untargeted mass spectrometry analysis, we scrutinize the role of endosphere and rhizosphere microbial communities and metabolites in shaping the differential resistance observed between ancient and cultivated bayberry trees. Our findings highlight the presence of core microbiome and metabolites across various bayberry tissues, suggesting that the heightened resistance of ancient bayberry may stem from alterations in rhizosphere and endosphere microbial communities and secondary metabolites. Specifically, enrichment of Bacillus in roots and stems, Pseudomonas in leaves, and Mortierella in rhizosphere soil of ancient bayberry was noted. Furthermore, correlation analysis underscores the significance of enriched microbial species in enhancing ancient bayberry's resistance to stresses, with elevated levels of resistance-associated metabolites such as beta-myrcene, benzothiazole, L-glutamic acid, and gamma-aminobutyric acid identified through GC-MS metabolomics analysis. The beneficial role of these resistance-associated metabolites was further elucidated through assessment of their promotive and allelopathic effects, as well as their phytostatic and antioxidant functions in lettuce plants. Ultimately, our study delves into the intrinsic reasons behind the greater resistance of ancient bayberry to biotic and abiotic stresses by evaluating the impact of long-term planting on the microbial community and metabolites in the bayberry endosphere and rhizosphere, shedding light on the complex dynamics of host-microbial interactions.

Arbuscular Mycorrhizal Fungus Alleviates Charged Nanoplastic Stress in Host Plants via Enhanced Defense-Related Gene Expressions and Hyphal Capture.

Contamination of small-sized plastics is recognized as a factor of global change. Nanoplastics (NPs) can readily enter organisms and pose significant ecological risks. Arbuscular mycorrhizal (AM) fungi are the most ubiquitous and impactful plant symbiotic fungi, regulating essential ecological functions. Here, we first found that an AM fungus, Rhizophagus irregularis, increased lettuce shoot biomass by 25-100% when exposed to positively and negatively charged NPs vs control, although it did not increase that grown without NPs. The stress alleviation was attributed to the upregulation of gene expressions involving phytohormone signaling, cell wall metabolism, and oxidant scavenging. Using a root organ-fungus axenic growth system treated with fluorescence-labeled NPs, we subsequently revealed that the hyphae captured NPs and further delivered them to roots. NPs were observed at the hyphal cell walls, membranes, and spore walls. NPs mediated by the hyphae were localized at the root epidermis, cortex, and stele. Hyphal exudates aggregated positively charged NPs, thereby reducing their uptake due to NP aggregate formation (up to 5000 nm). This work demonstrates the critical roles of AM fungus in regulating NP behaviors and provides a potential strategy for NP risk mitigation in terrestrial ecosystems. Consequent NP-induced ecological impacts due to the affected AM fungi require further attention.

Correlation between bone density, bone metabolism markers with lipid metabolism markers and body mass index.

PURPOSE: We aimed to explore the relationship between bone mineral density (BMD), bone metabolism markers, and blood lipid-related indicators, body mass index (BMI) in elderly individuals. METHODS: A retrospective analysis was conducted on 710 patients. Patients' gender, age, height, weight, bone density values, T-scores, bone metabolism markers (including serum N-terminal propeptide of type I collagen (s-PINP), serum C-terminal telopeptide of type I collagen (s-CTX) and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and lipid-related indicators (including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG) and Castelli index 1 (TC/HDL-C index) and Castelli index 2 (LDL-C/HDL-C index) were recorded. Correlations between variables were analyzed, and patients were grouped according to gender and T-score for intergroup comparisons. RESULTS: HDL-C negatively correlates with BMD and s-CTX. TG, Castelli index, and BMI positively correlate with BMD. BMI negatively correlates with s-PINP. 1,25(OH)2D3 negatively correlates with TC, LDL-C, and Castelli index. LDL-C positively correlates with BMD in males, and TC negatively correlates with s-PINP. In females, HDL-C negatively correlates with BMD, and s-CTX positively correlates with Castelli index. 1,25(OH)2D3 negatively correlates with TC, LDL-C, and Castelli index. TG and Castelli index were higher in normal bone mass group, while HDL-C is higher in the osteoporosis group. TG and BMI positively predicted bone mass density, while HDL-C negatively predicted bone mass density. CONCLUSIONS: HDL-C may have a predictive role in osteoporosis, particularly in women. The likelihood of osteoporosis is lower in individuals with high BMI or hyperlipidemia. Some lipid metabolism markers can be used to predict osteoporosis, and further research is needed.

Clinical efficacy and influencing factors of percutaneous kyphoplasty for osteoporotic vertebral compression fractures: a 10-year follow-up study.

BACKGROUND: To date, few reports have evaluated the long-term outcome of percutaneous kyphoplasty (PKP) for osteoporotic vertebral compression fractures (OVCFs) and the factors influencing the long-term outcome of this procedure are uncertain. METHODS: A total of 91 patients underwent PKP for thoracolumbar OVCFs from June 2012 to December 2012. Pain Visual Analogue Scores (VAS) and Oswestry Disability Index (ODI) were recorded preoperatively and after 10-year follow-up. Factors that may affect surgical outcome, such as gender, age, height, weight, hypertension, diabetes, cause of injury, fracture segment, length of hospitalization, history of previous spinal surgery, preoperative bone mineral density (BMD), preoperative VAS and ODI scores, length of surgery, bone cement dosage, postoperative standardized anti-osteoporosis treatment, and other new vertebral fractures, were analyzed by multiple linear regression with VAS and ODI scores at the last follow-up. The correlation factors affecting the efficacy were analyzed. RESULTS: The preoperative and final follow-up pain VAS was 7.9 ± 1.1 and 2.2 ± 1.1. ODI scores were 30.4 ± 4.2 and 10.7 ± 2.6. The difference was statistically significant (P < 0.05). Most of the patients were females aged 65-75 years who suffered low-energy injuries, with most of the fracture segments in the thoracolumbar region (T11-L2). At the final follow-up visit, 12 cases (13.19%) developed other new vertebral fractures, and 33 cases (36.26%) continued to adhere to anti-osteoporosis treatment after discharge. Multiple linear regression analysis showed that there was a statistical difference between gender and VAS score at the last follow-up (P < 0.05), and between age, cause of injury and postoperative standardized anti-osteoporosis treatment and ODI at the last follow-up (P < 0.05). There were no statistically significant differences between the other factors and the final follow-up VAS and ODI scores (P > 0.05). CONCLUSION: The long-term outcome after PKP is satisfactory. Age, gender, cause of injury, and standardized postoperative anti-osteoporosis treatment may be factors affecting the long-term outcome.

[Yeast extract improves the inflammatory response of HepG2 cells induced by ethyl alcohol and lipopolysaccharide].

OBJECTIVE: To explore the ameliorative effect of yeast extract(YE) on the inflammatory response of human hepatoma cells(HepG2) induced by ethyl alcohol(EtOH) and lipopolysaccharide(LPS), and further explore the potential molecular mechanism based on Toll-like receptor 4(TLR4)/nuclear factor kappa B(NF-κB) signaling pathway. METHODS: HepG2 cells were induced by 50 mmol/L EtOH and 1 µg/mL LPS combined with YE intervention. The expression level of inflammatory cytokines was detected by ELISA. The expression level of TLR4 and the nuclear translocation of NF-κB were detected by immunofluorescence staining. The expression levels of TLR4, NF-κB, phospho-NF-κB-P65(P-NF-κB-p65), nucleus-phospho-NF-κB-p65(N-P-NF-κB-p65), tumor necrosis factor-α(TNF-α), interleukin-6(IL-6), and interleukin-1ß(IL-1ß) were detected by Western blot. RESULTS: Compared with the control group, the cells in EtOH+LPS group produced a large number of inflammatory factors and had a significant inflammatory response. YE intervention significantly alleviated EtOH+LPS induced hepatocyte inflammatory response. Further molecular mechanism studies showed that YE significantly reduced TLR4 expression level and inhibited NF-κB nuclear translocation in hepatocytes. CONCLUSION: YE can effectively inhibit the inflammatory response of HepG2 cells induced by EtOH and LPS, and its molecular mechanism may be related to the down-regulation of TLR4/NF-κB pathway.

Microbubble Biointerfacing by Regulation of the Platelet Membrane Surfactant Activity at the Gas-Liquid Interface for Acute Thrombosis Targeting.

Biointerfacing nanomaterials with cell membranes has been successful in the functionalization of nanoparticles or nanovesicles, but microbubble functionalization remains challenging due to the unique conformation of the lipid monolayer structure at the gas-liquid interface that provides insufficient surfactant activity. Here, we describe a strategy to rationally regulate the surfactant activity of platelet membrane vesicles by adjusting the ratio of proteins to lipids through fusion with synthetic phospholipids (i.e., liposomes). A "platesome" with the optimized protein-to-lipid ratio can be assembled at the gas-liquid interface in the same manner as pulmonary surfactants to stabilize a microsized gas bubble. Platesome microbubbles (PMBs) inherited 61.4 % of the platelet membrane vesicle proteins and maintained the active conformation of integrin αIIbß3 without the talin 1 for fibrin binding. We demonstrated that the PMBs had good stability, long circulation, and superior functionality both in vitro and in vivo. Moreover, by molecular ultrasound imaging, the PMBs provide up to 11.8 dB of ultrasound signal-to-noise ratio enhancement for discriminating between acute and chronic thrombi. This surface tension regulating strategy may provide a paradigm for biointerfacing microbubbles with cell membranes, offering a potential new approach for the construction of molecular ultrasound contrast agents for the diagnosis of different diseases.

Modulation of Mechanical Properties of Short Bioinspired Peptide Materials by Single Amino-Acid Mutations.

The occurrence of modular peptide repeats in load-bearing (structural) proteins is common in nature, with distinctive peptide sequences that often remain conserved across different phylogenetic lineages. These highly conserved peptide sequences endow specific mechanical properties to the material, such as toughness or elasticity. Here, using bioinformatic tools and phylogenetic analysis, we have identified the GX8 peptide with the sequence GLYGGYGX (where X can be any residue) in a wide range of organisms. By simple mutation of the X residue, we demonstrate that GX8 can be self-assembled into various supramolecular structures, exhibiting vastly different physicochemical and viscoelastic properties, from liquid-like coacervate microdroplets to hydrogels to stiff solid materials. A combination of spectroscopic, electron microscopy, mechanical, and molecular dynamics studies is employed to obtain insights into molecular scale interactions driving self-assembly of GX8 peptides, underscoring that π-π stacking and hydrophobic interactions are the drivers of peptide self-assembly, whereas the X residue determines the extent of hydrogen bonding that regulates the macroscopic mechanical response. This study highlights the ability of single amino-acid polymorphism to tune the supramolecular assembly and bulk material properties of GX8 peptides, enabling us to cover a broad range of potential biomedical applications such as hydrogels for tissue engineering or coacervates for drug delivery.

Deep neural network for modeling soliton dynamics in the mode-locked laser.

Integrating the information of the first cycle of an optical pulse in a cavity into the input of a neural network, a bidirectional long short-term memory (Bi_LSTM) recurrent neural network (RNN) with an attention mechanism is proposed to predict the dynamics of a soliton from the detuning steady state to the stable mode-locked state. The training and testing are based on two typical nonlinear dynamics: the conventional soliton evolution from various saturation energies and soliton molecule evolution under different group velocity dispersion coefficients of optical fibers. In both cases, the root mean square error (RMSE) for 80% of the test samples is below 15%. In addition, the width of the conventional soliton pulse and the pulse interval of the soliton molecule predicted by the neural network are consistent with the experimental results. These results provide a new insight into the nonlinear dynamics modeling of the ultrafast fiber laser.

Schiff Base Complex Cocatalyst with Coordinatively Unsaturated Cobalt Sites for Photoelectrochemical Water Oxidation.

Integrating inorganic oxygen evolution cocatalysts (OECs) with photoanodes is regarded as an available strategy to increase the photogenerated charge utilization for accelerated water oxidation kinetics. Nevertheless, most widely used transition metal (oxyhydr)oxides OECs suffer from inevitable charge recombination at photoanode/OECs interfaces and underabundant catalytic active sites. Herein, a cobalt-organic complex with microflower-like features (denoted as MF) was constructed by coordination of Schiff base ligands and Co2+ metal ions and then decorated on porous BiVO4 employed as photoanodes for photoelectrochemical (PEC) water oxidation. The as-synthesized BiVO4/MF photoanode achieves a photocurrent density of 4.38 mA cm-2 and at 1.23 VRHE in 0.5 M Na2SO4 electrolyte under simulated 1 sun illumination, over approximately 5.48 times larger than that of BiVO4 counterpart, and exhibits a 120 mV cathodic shift of onset potential with outstanding photostability. Systematic characterizations reveal that the improved PEC efficiency is mainly attributed to the well-designed coordinatively unsaturated Co2+ sites, which not only serve as powerful photohole extraction engines along reversed interfacial Co-O-Bi bonds to promote charge transfer across the BiVO4/complex interface but also act as reaction active centers by accelerating surface water oxidation kinetics. This work provides new insights for designing highly effective OECs for PEC water oxidation.

Design, synthesis, and evaluation of hydrazones as dual inhibitors of ryanodine receptors and acetylcholinesterases for Alzheimer's disease.

Alzheimer's disease (AD) implicates neuronal loss, plaque and neurofibrillary tangle formation, and disturbed neuronal Ca2+ homeostasis, which leads to severe dementia, memory loss, as well as thinking and behavioral perturbations that could ultimately lead to death. Calcium dysregulation and low acetylcholine levels are two main mechanisms implicated in Alzheimer's disease progression. Simultaneous inhibition of calcium oscillations (store overload-induced Ca2+ release [SOICR]) and acetylcholinesterase (AChE) by a single molecule may bring a new breath of hope for AD treatment. Here, we described some dantrolene derivatives as dual inhibitors of the ryanodine receptor and AChE. Two series of acylhydrazone/sulfonylhydrazone derivatives with aromaticgroup were designed and synthesized. In this study, the target compounds were evaluated for their ability to inhibit SOICR and AChE in vitro, using dantrolene and donepezil as positive controls. Compound 22a exhibited excellent and balanced inhibitory potency against SOICR (inhibition (%) = 90.1, IC50 = 0.162 µM) and AChE (inhibition (%) = 93.5, IC50 = 0.372 µM). Docking simulations showed that several preferred compounds could bind to the active sites of both the proteins, further validating the rationality of the design strategy. Potential therapeutic effects in AD were evaluated using the Barnes maze and Morris water maze tests, which demonstrated that compound 22a significantly improved memory and cognitive behavior in AD model mice. Moreover, it was also found that compound 22a could enhance synaptic strength by measuring hippocampal long-term potentiation (LTP) in brain slices. These results suggested that the introduction of a sulfonyl-hydrazone scaffold and aromatic substitution to dantrolene derivatives provided a useful template for the development of potential chemical entities against AD.

Reducing airborne transmission of SARS-CoV-2 by an upper-room ultraviolet germicidal irradiation system in a hospital isolation environment.

Upper-room ultraviolet germicidal irradiation (UVGI) technology can potentially inhibit the transmission of airborne disease pathogens. There is a lack of quantitative evaluation of the performance of the upper-room UVGI for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) airborne transmission under the combined effects of ventilation and UV irradiation. Therefore, this study aimed to explore the performance of the upper-room UVGI system for reducing SARS-CoV-2 virus transmission in a hospital isolation environment. Computational fluid dynamics and virological data on SARS-CoV-2 were integrated to obtain virus aerosol exposure in the hospital isolation environment containing buffer rooms, wards and bathrooms. The UV inactivation model was applied to investigate the effects of ventilation rate, irradiation flux and irradiation height on the upper-room UVGI performance. The results showed that increasing ventilation rate from 8 to 16 air changes per hour (ACH) without UVGI obtained 54.32% and 45.63% virus reduction in the wards and bathrooms, respectively. However, the upper-room UVGI could achieve 90.43% and 99.09% virus disinfection, respectively, with the ventilation rate of 8 ACH and the irradiation flux of 10 µW cm-2. Higher percentage of virus could be inactivated by the upper-room UVGI at a lower ventilation rate; the rate of improvement of UVGI elimination effect slowed down with the increase of irradiation flux. Increase irradiation height at lower ventilation rate was more effective in improving the UVGI performance than the increase in irradiation flux at smaller irradiation height. These results could provide theoretical support for the practical application of UVGI in hospital isolation environments.

Exercise improves cognitive dysfunction and neuroinflammation in mice through Histone H3 lactylation in microglia.

BACKGROUND: Exercise is postulated to be a promising non-pharmacological intervention for the improvement of neurodegenerative disease pathology. However, the mechanism of beneficial effects of exercise on the brain remains to be further explored. In this study, we investigated the effect of an exercise-induced metabolite, lactate, on the microglia phenotype and its association with learning and memory. RESULTS: Microglia were hyperactivated in the brains of AlCl3/D-gal-treated mice, which was associated with cognitive decline. Running exercise ameliorated the hyperactivation and increased the anti-inflammatory/reparative phenotype of microglia and improved cognition. Mice were injected intraperitoneally with sodium lactate (NaLA) had similar beneficial effects as that of exercise training. Exogenous NaLA addition to cultured BV2 cells promoted their transition from a pro-inflammatory to a reparative phenotype. CONCLUSION: The elevated lactate acted as an "accelerator" of the endogenous "lactate timer" in microglia promoting this transition of microglia polarization balance through lactylation. These findings demonstrate that exercise-induced lactate accelerates the phenotypic transition of microglia, which plays a key role in reducing neuroinflammation and improving cognitive function.

Prediction of outcomes for symptomatic spinal cavernous malformation surgery: a multicenter prospective clinical study.

PURPOSE: Clinical outcome of spinal cavernous malformation (SCM) varies because of its unclear natural history, and reliable prognostic prediction model for SCM patients is limited. The aim of the present study was to investigate potential factors that predict one-year neurological status in postoperative patients with SCM. METHODS: This was a multicenter prospective observational study in consecutive patients with SCMs. SCMs treated microsurgically between January 2015 and January 2021 were included. Outcome was defined as the American Spinal Injury Association Impairment Scale (AIS) grade at one year after operation. Multivariable analyses were used to construct the best predictive model for patient outcomes. RESULTS: We identified 268 eligible SCM patients. Neurological outcome had worsened from preoperative baseline in 51 patients (19.0%) at one year. In the multivariable logistic regression, the best predictive model for unfavorable outcome included symptom duration ≥ 26 months (95% CI 2.80-16.96, P < 0.001), size ≤ 5 mm (95% CI 1.43-13.50, P = 0.010), complete intramedullary (95% CI 1.69-8.14, P = 0.001), subarachnoid hemorrhage (95% CI 2.92-12.57, P < 0.001), AIS B (95% CI 1.91-40.93, P = 0.005) and AIS C (95% CI 1.12-14.54, P = 0.033). CONCLUSIONS: Admission size of the lesion, morphology, symptom duration, AIS grade and the presence of subarachnoid hemorrhage were strong outcome predictors regarding prognostication of neurological outcome in postoperative patients with SCMs. A decision to surgically remove a symptomatic SCM should be justified by systematic analysis of all factors potentially affecting outcome.

The bioceramic sealer iRoot SP promotes osteogenic differentiation of human stem cells from apical papilla via miR-141-3p/SPAG9/MAPK signalling pathway.

AIM: The premixed bioceramic sealer iRoot SP that is widely used clinically has been reported to kill bacterial biofilms and promote osteogenic differentiation of human stem cells from the apical papilla (hSCAPs). Although miR-141-3p has been substantiated to be involved in the osteogenic process, the underlying mechanisms remain unclear. The aim of this study was to investigate the role of miR-141-3p in osteogenic differentiation and underlying mechanisms of iRoot SP-treated hSCAPs. METHODOLOGY: hSCAPs were extracted from tissue blocks with enzyme digestion and identified by using immunofluorescence, flow cytometry and alizarin red staining. The mRNA expression level of miR-141-3p in hSCPAs after culture with iRoot SP was examined by quantitative real-time PCR (qRT-PCR) assay. SPAG9 was identified as a downstream target gene of miR-141-3p by dual-luciferase report assay. Alkaline phosphatase (ALP) staining and activity detection, alizarin red staining, calcium concentration assay, qRT-PCR and western blot were used to estimate osteogenic differentiation ability and involved protein expression levels of the osteogenic makers and signalling pathway-related factors in iRoot SP-treated hSCAPs. Data were analysed by one-way anova and post hoc Tukey's test to determine any statistical differences between the experimental groups and the control group. p < .05 was considered statistically significant. RESULTS: Expression of miR-141-3p was reduced in iRoot SP-treated hSCAPs with the increased exposure time up to 7 days, and the western blot and qRT-PCR results revealed that the osteogenic markers osteocalcin (OCN), osterix (OSX), runt-related transcription factor 2 (RUNX2) and dentin sialophosphoprotein (DSPP) were inversely correlated with miR-141-3p. The negative regulatory relationship between miR-141-3p and SPAG9/ mitogen-activated protein kinases (MAPK) signalling axis was validated in this in vitro experiments. CONCLUSIONS: The bioceramic sealer iRoot SP promoted osteogenic differentiation of hSCAPs by inhibiting miR-141-3p following down-regulated SPAG9 expression, and activated MAPK pathway. These findings proposed a novel therapeutic impact of bioceramic sealer iRoot SP inducing bone regeneration in refractory periapical periodontitis.

Differential expression of circular RNAs in interleukin 6-promoted osteogenic differentiation of human stem cells from apical papilla.

INTRODUCTION: Studies have shown that interleukin 6 (IL-6) can regulate stem cell osteogenic differentiation; however, the exact mechanism is not clear. Circular RNAs (circRNAs) are closed circular non-coding RNAs that are involved in the process of stem cell osteogenic differentiation. Therefore, the purpose of this present study was to investigate the effect of IL-6 treatment on osteogenic differentiation of human apical tooth papillae stem cells (hSCAPs), and to detect the difference in circRNA expression using gene microarray technology. METHODS: After extraction and identification of hSCAPs, alkaline phosphatase (ALP) activity, alizarin red staining, and calcium ion quantitative assay were used to determine the changes of ALP enzyme, mineralized nodules, and matrix calcium levels before and after IL-6 treatment of hSCAPs gene microarray technology was used to analyze the changes in circRNA expression levels before and after IL-6 induction of mineralization. The four selected circRNAs were validated by qRT-PCR. Moreover, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to predict the potential functions and biological signaling pathways of circRNAs. Finally, these data are integrated and analyzed to construct circRNA-microRNA-mRNA networks. RESULTS: Alp and Alizarin red staining confirmed that IL-6 promoted the osteogenic differentiation of hSCAPs. The gene microarray results identified 132 differentially expressed circRNAs, of which 117 were upregulated and 15 were downregulated. Bioinformatic analysis predicted that the circRNA-406620/miR-103a-3p/FAT atypical cadherin 4 (FAT4) pathway might be involved in regulating IL-6 to promote osteogenic differentiation of hSCAPs. CONCLUSION: Differentially expressed circRNAs might be closely involved in regulating IL-6 to promote osteogenic differentiation of hSCAPs.