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Abstract Tissue engineering has demonstrated its efficacy in promoting tissue regeneration, and extensive research has explored its application in rotator cuff (RC) tears. However, there remains a paucity of research translating from bench to clinic. A key challenge in RC repair is the healing of tendon–bone interface (TBI), for which bioactive materials suitable for interface repair are still lacking. The umbilical cord (UC), which serves as a vital repository of bioactive components in nature, is emerging as an important source of tissue engineering materials. A minimally manipulated approach is used to fabricate UC scaffolds that retain a wealth of bioactive components and cytokines. The scaffold demonstrates the ability to modulate the TBI healing microenvironment by facilitating cell proliferation, migration, suppressing inflammation, and inducing chondrogenic differentiation. This foundation sets the stage for in vivo validation and clinical translation. Following implantation of UC scaffolds in the canine model, comprehensive assessments, including MRI and histological analysis confirm their efficacy in inducing TBI reconstruction. Encouraging short‐term clinical results further suggest the ability of UC scaffolds to effectively enhance RC repair. This investigation explores the mechanisms underlying the promotion of TBI repair by UC scaffolds, providing key insights for clinical application and translational research.

Objective: Based on network pharmacology and experimental validation, this study aimed to screen the potential targets of Liuwei Dihuang decoction (LW) against mild cognitive impairment (MCI). Methods: Based on network pharmacology, this study preliminarily explored the targets and molecular mechanisms of LW in the treatment of MCI. The results showed that the mechanism of action of LW against MCI may be related to the cAMP pathway. Then, an aging cell and animal model was established to further verify its molecular mechanism. Results: A total of 23 active ingredients were identified in LW. In addition, through network pharmacological analysis, we found 22 anti-MCI active ingredients in LW, of which alisol B had the most significant effect, and predicted the potential mechanism pathway by which LW may improve MCI through the cAMP signaling pathway. Further in vivo and in vitro experiments confirmed that LW can alleviate cognitive dysfunction in aging mice and reduce D-galactose-induced senescent cells, which may be through activation of the cAMP/PKA/CREB signaling pathway. Conclusion: This study found that the traditional Chinese medicine formula LW may play a role in improving MCI by regulating the cAMP/PKA/CREB signaling pathway, which provides a reference for further clinical research on the anti-MCI effect of LW and its molecular mechanism.

Osteoporosis (OP) can result in slower bone regeneration than the normal condition due to the imbalance between osteogenesis and osteoclastogenesis, making osteoporotic bone defects healing a significant clinical challenge. Calcium phosphate cement (CPC) is a promising bone substitute material due to its good osteoinductive activity, however, the drawbacks such as fragility, slow degradation rate and incapability to control bone loss restrict its application in osteoporotic bone defects treatment. Currently, we developed the PLGA electrospun nanofiber sheets to carry alendronate (ALN) and magnesium oxide nanoparticle (nMgO) into CPC, therefore, to obtain a high-strength bone cement (C/AM-PL/C). The C/AM-PL/C bone cement had high mechanical strength, anti-washout ability, good injection performance and drug sustained release capacity. More importantly, the C/AM-PL/C cement promoted the osteogenic differentiation of bone marrow mesenchymal stem cells and neovascularization via the release of Mg2+ (from nMgO) and Ca2+ (during the degradation of CPC), and inhibited osteoclastogenesis via the release of ALN in vitro. Moreover, the injection of C/AM-PL/C cement significantly improved bone healing in an OP model with femur condyle defects in vivo. Altogether, the injectable C/AM-PL/C cement could facilitate osteoporotic bone regeneration, demonstrating its capacity as a promising candidate for treatment of osteoporotic bone defects.

Abstract Peripheral nerve injury (PNI) remains a challenging area in regenerative medicine. Nerve guide conduit (NGC) transplantation is a common treatment for PNI, but the prognosis of NGC treatment is unsatisfactory due to 1) neuromechanical unmatching and 2) the intra‐conduit inflammatory microenvironment (IME) resulting from Schwann cell pyroptosis and inflammatory‐polarized macrophages. A neuromechanically matched NGC composed of regenerated silk fibroin (RSF) loaded with poly(3,4‐ethylenedioxythiophene): poly(styrene sulfonate) (P:P) and dimethyl fumarate (DMF) are designed, which exhibits a matched elastic modulus (25.1 ± 3.5 MPa) for the peripheral nerve and the highest 80% elongation at break, better than most protein‐based conduits. Moreover, the NGC can gradually regulate the intra‐conduit IME by releasing DMF and monitoring sciatic nerve movements via piezoresistive sensing. The combination of NGC and electrical stimulation modulates the IME to support PNI regeneration by synergistically inhibiting Schwann cell pyroptosis and reducing inflammatory factor release, shifting macrophage polarization from the inflammatory M1 phenotype to the tissue regenerative M2 phenotype and resulting in functional recovery of neurons. In a rat sciatic nerve crush model, NGC promoted remyelination and functional and structural regeneration. Generally, the DMF/RSF/P:P conduit provides a new potential therapeutic approach to promote nerve repair in future clinical treatments.

Abstract Common inductor (CIM) and common capacitor (CCM) passive current‐sharing methods have the advantages of simple implementation and low cost. However, there is still a lack of detailed comparative research on the two methods, which makes researchers confused when choosing the two methods. To provide clear scheme guidance, this paper provides a detailed comparison of the performance of the two methods. Firstly, this paper reveals the difference between the current waveforms of the two methods, that is, the current waveform of the CIM method is distorted, while the CCM method is non‐distorted. Then, the mechanism of the above phenomenon is analysed in depth. Secondly, for comparing the current sharing performance of the two methods, the first harmonic approximation (FHA) equivalent circuit model considering parasitic parameters is established to obtain the system's current sharing error model, and the parameter sensitivity analysis is provided. Finally, the relationship between the current waveform, current sharing error, and load ripple of the two methods is discussed. Then, based on the two methods, a more attractive common resonate tanks (CRT) current‐sharing method is proposed. The correctness of the view in this paper has been verified by extensive simulations and experiment results.

Cyclin-dependent kinase 5 (Cdk5) activity is specifically active in neurogenesis, and Cdk5 and neocortical neurons migration related biomarker are expressed in Cos-7 cells. However, the function of Cdk5 on the transformation of immortalized Cos-7 cells into neuronal-like cells is not clear.

Abstract Background Cancer cells may develop resistance to cisplatin by various mechanisms. Yet, the exact mechanism of cisplatin in ovarian cancer remains unclear. Recent studies have shown that 3’-phospoadenosine 5’-phosphosulfate synthase 1 (PAPSS1) inhibition combined with low-dose cisplatin increases DNA damage. The aim of this study was to determine the value of targeting PAPSS1 as a cisplatin modulator in epithelial ovarian cancer (EOC). Results Increased expression of PAPSS1 was observed in both EOC cells and tissues. Also, its higher nuclear expression was distinctly associated with FIGO (The International Federation of Gynecology and Obstetrics) stage, histological subtype, metastasis, and recurrence. Down-regulation of the PAPSS1 gene increased the cisplatin sensitivity of EOC in vitro and in vivo. Expression of PAPSS1 was negatively correlated with estrogen receptor α (ERα) in EOC. Also, low nuclear PAPSS1 and high nuclear ERα expression in EOC were associated with longer overall survival and progression-free survival in all ovarian cancer and ovarian cancer patients who received platinum-based chemotherapy. PAPSS1 silencing increased the activity of ERα-signaling in EOC cells, thus sensitizing tumors to cisplatin. Conclusions These findings characterize a novel interplay between PAPSS1-mediated sulfation and ERα-signaling in EOC cisplatin resistance. PAPSS1 may be exploited as a cisplatin-sensitizing therapeutic target.

Abrin and ricin, both type II ribosome-inactivating proteins, are toxins of significant concern and are under international restriction by the Chemical Weapons Convention and the Biological and Toxin Weapons Convention. The development of a rapid and sensitive detection method for these toxins is of the utmost importance for the first emergency response. Emerging rapid detection techniques, such as surface-enhanced Raman spectroscopy (SERS) and lateral flow assay (LFA), have garnered attention due to their high sensitivity, good selectivity, ease of operation, low cost, and disposability. In this work, we generated stable and high-affinity nanotags, via an efficient freezing method, to serve as the capture module for SERS-LFA. We then constructed a sandwich-style lateral flow test strip using a pair of glycoproteins, asialofetuin and concanavalin A, as the core affinity recognition molecules, capable of trace measurement for both abrin and ricin. The limit of detection for abrin and ricin was 0.1 and 0.3 ng/mL, respectively. This method was applied to analyze eight spiked white powder samples, one juice sample, and three actual botanic samples, aligning well with cytotoxicity assay outcomes. It demonstrated good inter-batch and intra-batch reproducibility among the test strips, and the detection could be completed within 15 min, indicating the suitability of this SERS-LFA method for the on-site rapid detection of abrin and ricin toxins.

As a key effector of the Hippo pathway, yes‐associated protein (YAP) is a major regulator of cell proliferation and apoptosis. In this study, 23 hYAP isoforms were identified in HEK293 cells, with 14 isoforms being reported for the first time. These isoforms were classified into hYAP‐a and hYAP‐b isoforms based on the variation in exon 1. The two groups of isoforms showed distinctly different subcellular localizations. hYAP‐a isoforms could activate TEAD‐ or P73‐mediated transcription, affect the proliferation rate, and enhance the cellular chemosensitivity of HEK293 cells. Moreover, different activation abilities and pro‐cytotoxic effects were observed among hYAP‐a isoforms. However, hYAP‐b isoforms were not found to exert any significant biological effects. Our findings add to the knowledge of YAP gene structure and protein‐coding capacity and will help in the elucidation of the function and related molecular mechanisms of the Hippo‐YAP signaling pathway.

Abstract Background The potential treatment effects of heat shock protein 90 (Hsp90) inhibitors in ovarian cancer (OC) are controversial. This research aims to investigate the relationship between the level of Hsp90 in peripheral blood and the prognosis of OC patients, as well as the clinicopathological indicators. Materials and methods We retrospectively collected the clinicopathological indicators of OC patients who were admitted to the Department of Obstetrics and Gynecology of the First Affiliated Hospital of Anhui Medical University from 2017 to 2022. Hsp90 level in patient blood was detected by enzyme-linked immunosorbent assay, and the correlation between Hsp90 level and OC prognosis was systematically investigated. Kaplan–Meier method was used to draw the survival curve, and the average survival time and survival rate were calculated. The log-rank test and Cox model were used for univariate survival analysis, and the Cox proportional hazards model was applied for multivariate survival analysis. Based on the TCGA dataset of OC obtained by cBioPortal, Pearson’s correlation coefficients between Hsp90 level values and other mRNA expression values were calculated to further conduct bioinformatics analysis. GSEA and GSVA analysis were also conducted for gene functional enrichment. The expression of Hsp90 in OC tissues were evaluated and compared by Immunohistochemical staining. Results According to the established screening criteria, 106 patients were selected. The enzyme-linked immunosorbent assay results showed that 50.94% OC patients with abnormal Hsp90 level. According to the outcome of Kaplan–Meier curves, the results revealed that the abnormal level of Hsp90 was suggested to poor prognosis (P = 0.001) of OC patients. Furthermore, the result of multivariate Cox proportional hazards regression model analysis also predicted that abnormal Hsp90 level (HR = 2.838, 95%CI = 1.139–7.069, P = 0.025) was linked to poor prognosis, which could be an independent prognostic factor for the prognosis of OC patients. Moreover, top 100 genes screened by Pearson’s value associated with Hsp90, indicating that Hsp90 participated in the regulation of ATF5 target genes, PRAGC1A target genes and BANP target genes and also enriched in the metabolic processes of cell response to DNA damage stimulus, response to heat and protein folding. Conclusion Hsp90 level is positively associated with OC mortality and is a potential prognostic indicator of OC.

Abstract Objective To investigate the GSDMD, CASP1, CASP4 and CASP5 expression in peripheral blood mononuclear cells of non-small cell lung cancer patients and analyze their clinical significance. Methods 71 non-small cell lung cancer patients were selected as the study group and 50 healthy individuals as the control group. The GSDMD, CASP1, CASP4 and CASP5 expression in peripheral blood mononuclear cells of the two groups were detected by real-time fluorescence quantitative PCR. The GSDMD, CASP1, CASP4, CASP5 expression and their relationship with the clinical characteristics of the patients were analyzed. Results Compared with the control group, the GSDMD, CASP4 and CASP5 expression in PBMCs of lung cancer patients was significantly higher(P 0.05), 0.701(P

Abstract Consumer-based voice assistants have the ability to deliver evidence-based treatment, but their therapeutic potential is largely unknown. In a pilot trial of a virtual voice-based coach, Lumen, delivering problem-solving treatment, adults with mild-to-moderate depression and/or anxiety were randomized to the Lumen intervention (n = 42) or waitlist control (n = 21). The main outcomes included changes in neural measures of emotional reactivity and cognitive control, and Hospital Anxiety and Depression Scale [HADS] symptom scores over 16 weeks. Participants were 37.8 years (SD = 12.4), 68% women, 25% Black, 24% Latino, and 11% Asian. Activation of the right dlPFC (neural region of interest in cognitive control) decreased in the intervention group but increased in the control group, with an effect size meeting the prespecified threshold for a meaningful effect (Cohen’s d = 0.3). Between-group differences in the change in activation of the left dlPFC and bilateral amygdala were observed, but were of smaller magnitude (d = 0.2). Change in right dlPFC activation was also meaningfully associated (r ≥ 0.4) with changes in self-reported problem-solving ability and avoidance in the intervention. Lumen intervention also led to decreased HADS depression, anxiety, and overall psychological distress scores, with medium effect sizes (Cohen’s d = 0.49, 0.51, and 0.55, respectively), compared with the waitlist control group. This pilot trial showed promising effects of a novel digital mental health intervention on cognitive control using neuroimaging and depression and anxiety symptoms, providing foundational evidence for a future confirmatory study.

Injectable materials show their special merits in regeneration of damaged/degenerated bones in minimally-invasive approach. Injectable calcium phosphate bone cement (CPC) has attracted broad attention for its bioactivity, as compared to non-degradable polymethyl methacrylate cement. However, its brittleness, poor anti-washout property and uncontrollable biodegradability are the main challenges to limit its further clinical application mainly because of its stone-like dense structure and fragile inorganic-salt weakness. Herein, we developed a kind of injectable CPC bone cement with porous structure and improved robustness by incorporating poly(lactide-co-glycolic acid) (PLGA) nanofiber into CPC, with carboxymethyl cellulose (CMC) to offer good injectability as well as anti-wash-out capacity. Furthermore, the introduction of PLGA and CMC also enabled a formation of initial porous structure in the cements, where PLGA nanofiber endowed the cement with a dynamically controllable biodegradability which provided room for cell movement and bone ingrowth. Interestingly, the reinforced biodegradable cement afforded a sustainable provision of Ca2+ bioactive components, together with its porous structure, to improve synergistically new bone formation and osteo-integration in vivo by using a rat model of femur condyle defect. Further study on regenerative mechanisms indicated that the good minimally-invasive bone regeneration may come from the synergistic enhanced osteogenic effect of calcium ion enrichment and the improved revascularization capacity contributed from the porosity as well as the lactic acid released from PLGA nanofiber. These results indicate the injectable bone cement with high strength, anti-washout property and controllable biodegradability is a promising candidate for bone regeneration in a minimally-invasive approach.

BackgroundThe quality of user interaction with therapeutic tools has been positively associated with treatment response; however, no studies have investigated these relationships for voice-based digital tools. ObjectiveThis study evaluated the relationships between objective and subjective user interaction measures as well as treatment response on Lumen, a novel voice-based coach, delivering problem-solving treatment to patients with mild to moderate depression or anxiety or both. MethodsIn a pilot trial, 42 adults with clinically significant depression (Patient Health Questionnaire-9 [PHQ-9]) or anxiety (7-item Generalized Anxiety Disorder Scale [GAD-7]) symptoms or both received Lumen, a voice-based coach delivering 8 problem-solving treatment sessions. Objective (number of conversational breakdowns, ie, instances where a participant’s voice input could not be interpreted by Lumen) and subjective user interaction measures (task-related workload, user experience, and treatment alliance) were obtained for each session. Changes in PHQ-9 and GAD-7 scores at each ensuing session after session 1 measured the treatment response. ResultsParticipants were 38.9 (SD 12.9) years old, 28 (67%) were women, 8 (19%) were Black, 12 (29%) were Latino, 5 (12%) were Asian, and 28 (67%) had a high school or college education. Mean (SD) across sessions showed breakdowns (mean 6.5, SD 4.4 to mean 2.3, SD 1.8) decreasing over sessions, favorable task-related workload (mean 14.5, SD 5.6 to mean 17.6, SD 5.6) decreasing over sessions, neutral-to-positive user experience (mean 0.5, SD 1.4 to mean 1.1, SD 1.3), and high treatment alliance (mean 5.0, SD 1.4 to mean 5.3, SD 0.9). PHQ-9 (Ptrend=.001) and GAD-7 scores (Ptrend=.01) improved significantly over sessions. Treatment alliance correlated with improvements in PHQ-9 (Pearson r=–0.02 to –0.46) and GAD-7 (r=0.03 to –0.57) scores across sessions, whereas breakdowns and task-related workload did not. Mixed models showed that participants with higher individual mean treatment alliance had greater improvements in PHQ-9 (β=–1.13, 95% CI –2.16 to –0.10) and GAD-7 (β=–1.17, 95% CI –2.13 to –0.20) scores. ConclusionsThe participants had fewer conversational breakdowns and largely favorable user interactions with Lumen across sessions. Conversational breakdowns were not associated with subjective user interaction measures or treatment responses, highlighting how participants adapted and effectively used Lumen. Individuals experiencing higher treatment alliance had greater improvements in depression and anxiety. Understanding treatment alliance can provide insights on improving treatment response for this new delivery modality, which provides accessibility, flexibility, comfort with disclosure, and cost-related advantages compared to conventional psychotherapy. Trial RegistrationClinicalTrials.gov NCT04524104; https://clinicaltrials.gov/study/NCT04524104

Uterine peristalsis is essential for gamete transport and embryo implantation. It shares the characteristics of spontaneity, rhythmicity, and directivity with gastrointestinal peristalsis. Telocytes, the “interstitial Cajal-like cells” outside the digestive canal, are also located in the uterus and may act as pacemakers. To investigate the possible origin and regulatory mechanism of periodic uterine peristalsis in the human menstrual cycle, telocytes in the myometrium were studied to determine the effect of estradiol on T-type calcium channel regulation. In this study, biopsies of the human myometrium were obtained for cell culture, and double-labeling immunofluorescence screening was used to identify telocytes and T-type calcium channel expression. Intracellular calcium signal measurements and patch-clamp recordings were used to investigate the role of T-type calcium channels in regulating calcium currents with or without estradiol. Our study demonstrates that telocytes exist in the human uterus and express T-type calcium channels. The intracellular Ca2+ fluorescence intensity marked by Fluo-4AM was dramatically decreased by NNC 55-0396, a highly selective T-type calcium channel blocker, but enhanced by estradiol. T-type calcium current amplitude increased in telocytes incubated with estradiol in a dose-dependent manner compared to the control group. In conclusion, our study demonstrated that telocytes exist in the human myometrium, expressing T-type calcium channels and estradiol-enhanced T-type calcium currents, which may be a reasonable explanation for the origin of uterine peristalsis. The role of telocytes in the human uterus as pacemakers and message transfer stations in uterine peristalsis may be worth further investigation.

Previous studies have shown that fibroblast growth factor 13 is downregulated in the brain of both Alzheimer’s disease mouse models and patients, and that it plays a vital role in the learning and memory. However, the underlying mechanisms of fibroblast growth factor 13 in Alzheimer’s disease remain unclear. In this study, we established rat models of Alzheimer’s disease by stereotaxic injection of amyloid-β (Aβ1–42)-induced into bilateral hippocampus. We also injected lentivirus containing fibroblast growth factor 13 into bilateral hippocampus to overexpress fibroblast growth factor 13. The expression of fibroblast growth factor 13 was downregulated in the brain of the Alzheimer’s disease model rats. After overexpression of fibroblast growth factor 13, learning and memory abilities of the Alzheimer’s disease model rats were remarkably improved. Fibroblast growth factor 13 overexpression increased brain expression levels of oxidative stress-related markers glutathione, superoxide dismutase, phosphatidylinositol-3-kinase, AKT and glycogen synthase kinase 3β, and anti-apoptotic factor BCL. Furthermore, fibroblast growth factor 13 overexpression decreased the number of apoptotic cells, expression of pro-apoptotic factor BAX, cleaved-caspase 3 and amyloid-β expression, and levels of tau phosphorylation, malondialdehyde, reactive oxygen species and acetylcholinesterase in the brain of Alzheimer’s disease model rats. The changes were reversed by the phosphatidylinositol-3-kinase inhibitor LY294002. These findings suggest that overexpression of fibroblast growth factor 13 improved neuronal damage in a rat model of Alzheimer’s disease through activation of the phosphatidylinositol-3-kinase/AKT/glycogen synthase kinase 3β signaling pathway.

Nanoparticles can promote the accumulation of drugs in tumors. However, they find limited clinical applications because they cannot easily penetrate the stroma of cancer tissues, and it is difficult to control drug release. We developed a multiresponse multistage drug-delivery nanogel with improved tumor permeability and responsiveness to the tumor microenvironment for the controlled delivery of anticancer agents. For this purpose, ∼100 nm multistage drug delivery nanogels with pH, redox, near-infrared stimulation, and enzyme responsiveness were grown in situ using 20 nm gold nanoparticles (AuNPs) via an emulsion-aiding crosslinking technique with cysteine crosslinker. An alginate cysteine AuNP (ACA) nanocarrier can efficiently load the cationic drug doxorubicin (DOX) to produce a multistage drug delivery nanocarrier (DOX@ACA). DOX@ACA can maintain the slow release of DOX and reduce its toxicity. In cancer tissues, the high pH and reductase microenvironment combined with the in vitro delivery of alginate and near-infrared light drove drug release. The developed nanoparticles effectively inhibited cancer cells, and in vivo evaluations showed that they effectively enhanced antitumor activity while having negligible in vivo toxicity to major organs.

Underwater bottom-sitting shell structures face threats from underwater explosion shock waves. To investigate the damage characteristics and dynamic response of bottom-sitting shell structures under underwater explosion shock waves, three-dimensional numerical models of semi-spherical and semi-cylindrical bottom-sitting reinforced concrete (RC) shells under underwater shock waves were established based on the Arbitrary Lagrangian–Eulerian (ALE) algorithm using LS-DYNA software. The influences of the shock wave transmission medium, explosive equivalent, explosive distance, hydrostatic pressure, and reinforcement on the damage characteristics and dynamic response of semi-spherical and semi-cylindrical bottom-sitting RC shell structures were studied. The results indicated that the damage and center vertical deformation of RC shells under underwater shock waves are significantly greater than those under air shock waves. With an increase in explosive equivalent or decrease in explosive distance, the damage and center vertical deformation of RC shells are increased. The damage to the inner surface of RC shells is more severe than the outer surface. The damage and center vertical deformation of RC shells can be reduced by bottom reinforcement and an increase in the diameter of the steel bar. The ‘hoop effect’ caused by hydrostatic pressure restrains the horizontal convex deformation and slightly decreases the macroscopic damage and vertical center deformation of the semi-spherical RC shell with an increase in hydrostatic pressure within the range of 0–2.0092 MPa. The hydrostatic pressure restrains the horizontal convex deformation of the semi-cylindrical RC shell. However, inward concave deformation of the shell center is increased by hydrostatic pressure, inducing an increase in the damage to and center vertical deformation of the semi-cylindrical RC shell. These findings may offer a reference for the construction and design of protective measures for underwater bottom-sitting shell structures.

The application of gelatin hydrogels is hampered by their poor mechanical properties, which are unfavorable for debridement and diabetic wound healing. Herein, bovine serum albumin (BSA)-bridged gelatin hydrogels biopotentiated by bone marrow mesenchymal stem cell (BMSC)-derived nanovesicles (NV), named NV@BSA-GEL, were fabricated by reinforcement of gelatin hydrogels with genipin and BSA in a one-pot, low-cost green approach based on amide bonding-guided crosslinking. Genipin introduction endowed the crosslinking of gelatin hydrogels with weak mechanical properties that were reinforced by BSA bridging to realize suitable mechanical properties for wound dressing, including excellent flexibility and appropriate rigidity. The bioactivity of NV released by the hydrogels resulted in efficient ROS scavenging and favorable immunomodulatory activity as well as promoted cell proliferation and migration of fibroblasts and vascular endothelial cells. Proteomic analysis confirmed that NV harbors a variety of growth factors that can promote wound healing. In vivo, the NV@BSA-GEL hydrogel had superior wound healing effects compared to BSA-GEL, including faster wound healing, stimulation of angiogenesis, contributing to an anti-inflammatory extracellular matrix, and promoting skin maturation, with no systemic toxicity. Thus, the combined merits of NV@BSA-GEL suggest that it has high potential as a new hydrogel dressing for the safe and efficient treatment of diabetic wounds.

AbstractThe human intestinal epithelium has an impressive ability to respond to insults and its homeostasis is maintained by well-regulated mechanisms under various pathophysiological conditions. Nonetheless, acute injury and inhibited regeneration of the intestinal epithelium occur commonly in critically ill surgical patients, leading to the translocation of luminal toxic substances and bacteria to the bloodstream. Effective therapies for the preservation of intestinal epithelial integrity and for the prevention of mucosal hemorrhage and gut barrier dysfunction are limited, primarily because of a poor understanding of the mechanisms underlying mucosal disruption. Noncoding RNAs (ncRNAs), which include microRNAs (miRNAs), long ncRNAs (lncRNAs), circular RNAs (circRNAs), and small vault RNAs (vtRNAs), modulate a wide array of biological functions and have been identified as orchestrators of intestinal epithelial homeostasis. Here, we feature the roles of many important ncRNAs in controlling intestinal mucosal growth, barrier function, and repair after injury—particularly in the context of postoperative recovery from bowel surgery. We review recent literature surrounding the relationships between lncRNAs, microRNAs, and RNA-binding proteins and how their interactions impact cell survival, proliferation, migration, and cell-to-cell interactions in the intestinal epithelium. With advancing knowledge of ncRNA biology and growing recognition of the importance of ncRNAs in maintaining the intestinal epithelial integrity, ncRNAs provide novel therapeutic targets for treatments to preserve the gut epithelium in individuals suffering from critical surgical disorders.

Abstract Background Tumor characteristics can be prognostically relevant in patients with high‐grade serous ovarian carcinoma (HGSOC). This study aimed to determine whether different subtypes of HGSOC, especially the mesenchymal subtype, are associated with overall survival (OS) or progression‐free survival (PFS) in patients with HGSOC. Methods PubMed, Embase, and the Cochrane Library were searched for studies published up to September 2020. The eligibility criteria were (1) population: patients with HGSOG with molecular subtyping of their tumor, (2) exposure: mesenchymal subtype, (3) non‐exposure: differentiated, immunoreactive, proliferative, and other non‐mesenchymal subtypes, (4) outcome: survival, with hazard ratios (HRs), and (5) English language. Results The mesenchymal subtype showed no statistically significant difference in OS compared with the immunoreactive subtype (HR = 1.47, 95% CI: 0.78–2.78, p = 0.238; I2 = 81.2%, pheterogeneity = 0.005) or all non‐mesenchymal subtypes (HR = 1.65, 95% CI: 0.97–2.80, p = 0.063; I2 = 79.4%, pheterogeneity = 0.008). The mesenchymal subtype showed no statistically significant difference in PFS compared with the immunoreactive subtype (HR = 1.19, 95% CI: 0.71–2.00, p = 0.514; I2 = 71.6%, pheterogeneity = 0.030) but a significant differences was observed when using all non‐mesenchymal subtypes as reference (HR = 1.51, 95% CI: 1.00–2.28, p = 0.049). The results were robust according to the sensitivity analyses. Conclusions There are no statistically significant differences in OS between the mesenchymal subtype of HGSOC and other subtypes of HGSOC. Because of statistical power, this meta‐analysis cannot conclude about non‐inferiority, and the relationship between the molecular subtypes and HGSOC prognosis remains controversial. Based on one study, the mesenchymal subtype could have a poorer PFS than the non‐mesenchymal subtypes of HGSOC, but this conclusion requires further evidence.

Abstract Background It is well-known that both macrophages and osteocytes are critical regulators of osteogenesis and osteoclastogenesis, yet there is limited understanding of the macrophage-osteocyte interaction, and how their crosstalk could affect bone homeostasis and mineralization. This research therefore aims to investigate the effects of macrophage polarization on osteocyte maturation and mineralization process. Methods A macrophage-derived conditioned medium based osteocyte culture was set up to investigate the impact of macrophages on osteocyte maturation and terminal mineralization. Surgically induced osteoarthritis (OA) rat model was used to further investigate the macrophage-osteocyte interaction in inflammatory bone remodeling, as well as the involvement of the Notch signaling pathway in the mineralization process. Results Our results identified that osteocytes were confined in an immature stage after the M1 macrophage stimulation, showing a more rounded morphology, higher expression of early osteocyte marker E11, and significantly lower expression of mature osteocyte marker DMP1. Immature osteocytes were also found in inflammatory bone remodeling areas, showing altered morphology and mineralized structures similar to those observed under the stimulation of M1 macrophages in vitro, suggesting that M1 macrophages negatively affect osteocyte maturation, leading to abnormal mineralization. The Notch signaling pathway was found to be down regulated in M1 macrophage-stimulated osteocytes as well as osteocytes in inflammatory bone. Overexpression of the Notch signaling pathway in osteocytes showed a significant circumvention on the negative effects from M1 macrophage. Conclusion Taken together, our findings provide valuable insights into the mechanisms involved in abnormal bone mineralization under inflammatory conditions.

Abstract Polylactic acid (PLA) is a versatile and biodegradable scaffold widely used in biomedical fields to repair tissue defects. Exosomes derived from mesenchymal stem cells (MSCs) are nano-sized extracellular vesicles, which play an important role in tissue engineering in recent years. The primary focus of this study was to develop a bioactive 3D PLA scaffold using exosome-based strategy to improve its osteogenic and immunoregulatory potential. We firstly successfully isolated MSC-derived exosomes (MSC-Exo). Morphological analysis revealed that MSC-Exo exhibits a typical cup-shaped morphology with high expression of exosomal marker CD63. MSC-Exo internalization into recipient cells were also investigated using flow cytometry and confocal laser scanning microscopy. Porous 3D PLA scaffold coated MSC-Exo were used for immunoregulatory and osteogenic testing. Exosomes released from 3D PLA scaffold were validated in RAW264.7 and hBMSCs. The cell proliferation and live/dead assay indicated high biocompatibility for PLA-Exo scaffold. Additionally, PLA-Exo scaffold could reduce the pro-inflammatory marker expression and reactive oxygen species (ROS) production, indicating potential immunoregulatory potential. It is also confirmed that PLA-Exo scaffold could potentiate osteogenic differentiation in the osteogenesis assay. In conclusion, our results demonstrate this bioactive 3D-printed PLA scaffolds with MSC-Exo modification holds immunoregulatory potential and favor osteogenic differentiation, thus having potential applications in bone tissue regeneration.

Abstract Background Due to insufficient basic medical knowledge and inappropriate learning strategies, students of 8-year medical programme encountered many obstacles in the initial stage of basic medicine learning. This study was to determine whether a prerequisite course can improve basic medicine learning performance and adjust learning strategies to adapt to basic medicine learning. Methods A prerequisite course of histology was constructed by a two-round modified Delphi study. Seventy-four students of 8-year medical programme were subjected to two groups: the prerequisite course group (PC group) and non-prerequisite course group (NPC group). The PC group take part in the prerequisite course by student-centred blended learning approach but NPC group not. The PC and NPC group underwent requisite histology teaching activities after prerequisite course. Examination of the prerequisite course and requisite histology course were carried out. Effect of the prerequisite course was evaluated by an empirical method using a questionnaire-based approach. Results The results of examinations showed students' scores of the PC group were significantly higher than those of students of NPC group in both prerequisite course and requisite histology examinations (P

Over the last decade, the superior properties of graphene have contributed to intensive studies on the fabrication and applications of graphene nanocomposites. Ex-situ homologous recombination and recombination techniques were listed. Because of their remarkable features, including thermal conductivity and high-specific area, graphene and its derivatives have a significant prospective for medical and biological applications, including drug delivery and bio-imaging. The usage of graphene-based nanomaterials is a hot topic in medicinal research. Many research studies have been performed on graphene-based composites, but only a few reviews have been published regarding their applications in the biomedical field and potential risk factors associated with human well-being and the environment. Hence, this review paper aims to provide in-depth information on ongoing knowledge and results about the properties of graphene-based composites. The discovery, developmental methods, structural properties, and synthesis of graphene nanomaterials have been discussed. After a brief description of the most common methods used for fabricating or extracting graphene derivatives, the main steps of graphene-based composite preparation are introduced. Applications of graphene-based composites in drug delivery, medical, and biomedical fields have been addressed. Finally, the future perspectives and challenges associated with the applications of graphene-based composites have been summarized.Highlights Compositions and characteristics of nanocomposite materials reinforced with graphene, graphene oxide, reduced graphene oxide, and modified graphene.The synthesis method of graphene and the manufacturing of graphene-based composites.Latest developments in graphene-based composites for biomedical applications.Consequences of the large-scale production of graphene-based composites.

Tumor-associated macrophages (TAMs), one of the dominating constituents of tumor microenvironment, are important contributors to cancer progression and treatment resistance. Therefore, regulation of TAMs polarization from M2 phenotype towards M1 phenotype has emerged as a new strategy for tumor immunotherapy. Herein, we successfully initiated antitumor immunotherapy by inhibiting TAMs M2 polarization via autophagy intervention with polyethylene glycol-conjugated gold nanoparticles (PEG-AuNPs). PEG-AuNPs suppressed TAMs M2 polarization in both in vitro and in vivo models, elicited antitumor immunotherapy and inhibited subcutaneous tumor growth in mice. As demonstrated by the mRFP-GFP-LC3 assay and analyzing the autophagy-related proteins (LC3, beclin1 and P62), PEG-AuNPs induced autophagic flux inhibition in TAMs, which is attributed to the PEG-AuNPs induced lysosome alkalization and membrane permeabilization. Besides, TAMs were prone to polarize towards M2 phenotype following autophagy activation, whereas inhibition of autophagic flux could reduce the M2 polarization of TAMs. Our results revealed a mechanism underlying PEG-AuNPs induced antitumor immunotherapy, where PEG-AuNPs reduce TAMs M2 polarization via induction of lysosome dysfunction and autophagic flux inhibition. This study elucidated the biological effects of nanomaterials on TAMs polarization and provided insight into harnessing the intrinsic immunomodulation capacity of nanomaterials for effective cancer treatment.

The mammalian intestinal epithelium is a rapidly self-renewing tissue in the body and its homeostasis is tightly controlled by numerous factors at multiple levels. The RNA-binding protein HuR (human antigen R) is intimately involved in many aspects of gut mucosal pathobiology and plays an important role in maintaining integrity of the intestinal epithelium by regulating stability and translation of target mRNAs. Nonetheless, deregulation of HuR expression and altered binding affinity of HuR for target transcripts occur commonly in various gut mucosal disorders. In this review, we highlight the essential role of HuR in the intestinal epithelium homeostasis and discuss recent results that interactions between HuR and noncoding RNAs (ncRNAs), including circular RNAs, long ncRNAs, small vault RNAs, and microRNAs, influence gut mucosal regeneration and regulate barrier function in various pathophysiological conditions. These exciting discoveries advance our knowledge of HuR biological function in the gut mucosa and also create a fundamental basis for developing novel therapies to protect intestinal epithelial integrity in critically ill patients.

Engineering light-controlled K+ pumps from Na+-pumping rhodopsins (NaR) greatly expands the scope of optogenetic applications. However, the limited knowledge regarding the kinetic and selective mechanism of K+ uptake has significantly impeded the modification and design of light-controlled K+ pumps, as well as their practical applications in various fields, including neuroscience. In this study, we presented K+-dependent photocycle kinetics and photocurrent of a light-driven Na+ pump called Nonlabens dokdonensis rhodopsin 2 (NdR2). As the concentration of K+ increased, we observed the accelerated decay of M intermediate in the wild type (WT) through flash photolysis. In 100 mM KCl, the lifetime of the M decay was approximately 1.0 s, which shortened to around 0.6 s in 1 M KCl. Additionally, the K+-dependent M decay kinetics were also observed in the G263W/N61P mutant, which transports K+. In 100 mM KCl, the lifetime of the M decay was approximately 2.5 s, which shortened to around 0.2 s in 1 M KCl. According to the competitive model, in high KCl, K+ may be taken up from the cytoplasmic surface, competing with Na+ or H+ during M decay. This was further confirmed by the K+-dependent photocurrent of WT liposome. As the concentration of K+ increased to 500 mM, the amplitude of peak current significantly dropped to approximately ~60%. Titration experiments revealed that the ratio of the rate constant of H+ uptake (kH) to that of K+ uptake (kK) is >108. Compared to the WT, the G263W/N61P mutant exhibited a decrease of approximately 40-fold in kH/kK. Previous studies focused on transforming NaR into K+ pumps have primarily targeted the intracellular ion uptake region of Krokinobacter eikastus rhodopsin 2 (KR2) to enhance K+ uptake. However, our results demonstrate that the naturally occurring WT NdR2 is capable of intracellular K+ uptake without requiring structural modifications on the intracellular region. This discovery provides diverse options for future K+ pump designs. Furthermore, we propose a novel photocurrent-based approach to evaluate K+ uptake, which can serve as a reference for similar studies on other ion pumps. In conclusion, our research not only provides new insights into the mechanism of K+ uptake but also offers a valuable point of reference for the development of optogenetic tools and other applications in this field.

Background: In this study, we analyzed intestinal flora in an experimental mouse model of chronic kidney disease (CKD) and investigated whether oral supplementation with probiotic Lactobacillus rhamnosus GG could slow the decline in renal function and inflammatory status of mice with CKD. Methods: We surgically induced chronic kidney disease in C57BL/6J male mice aged 8–9 weeks. We used dual-stage 5/6 nephrectomy for this, while the mock group underwent a mock procedure. The experimental (CKD mice) and mock group were administered a daily dose of 10 × 109 colony forming unit (CFU) of probiotic L. rhamnosus GG or 2 g of maltodextrin as a placebo by oral gavage, respectively, for 5 weeks. At the end of the experiment, the fecal samples of the mice were collected and prepared for intestinal microbial diversity analysis. We examined the serum chemistry and renal histology of the mice. Results: Important serum and blood biomarkers were associated with the development of CKD, including increased serum concentrations of creatine, cystatin C, blood urea nitrogen (BUN), and a protein—interleukin-6 (denoted as IL-6), whereas decreased serum albumin concentration was also observed in the mice with CKD. The intestinal flora of the mice with CKD significantly declined in terms of diversity, richness, and homogeneity. The consumption of L. rhamnosus GG probiotic via oral gavage significantly decreased the serum concentration level present in creatinine and blood urea nitrogen. However, it increased albumin in the group with CKD. After probiotic treatment, serum IL-6 levels dropped considerably, and the kidney histopathology score in mice with CKD who were given L. rhamnosus GG improved. Moreover, supplementation with the probiotic significantly improved floral richness and lineage diversity in the mice with CKD.Conclusions: In this study, we found that probiotics significantly attenuated renal failure development, reduced serum levels of proinflammatory cytokine IL-6, and increased the abundance and lineage diversity of intestinal flora in mice with chronic kidney disease.

There are always installation errors in linear Fresnel concentrating photovoltaic (CPV) system that make the system unable to work under the designed conditions. Based on the optical, thermal, electrical, and structural coupling principle, the influences of vertical position (including distance and direction) e of concentrator deviation from the focal length on the thermal (heat flux and temperature distributions), electrical (average electrical efficiency) and structural (stress and deflection) characteristics of PV panel under natural convection conditions were investigated numerically by MCRT-FVM-FEM coupling method. The results reveal that, the thermal, electrical and structural characteristics change slightly with the tilt angle α of PV panel from 15° to 60°, while these characteristics experience a relatively greater change for α increasing to 75°. The concentrator position has little effect on the flow and temperature fields near the PV panel. Compared with the situation at α = 30°, changing the concentrator position at α = 75° has a more obvious effect on the thermal and structural characteristics of PV panel. When the concentrator moves from the designed position (e = 0 mm) to the deviated position (e = −45mm) at α = 75°, the maximum thermal stress and maximum deflection of cells are dropped by 30.12% and 13.72%, respectively. Even if the concentrator moves the same distance, different directions (upward and downward) of movement can lead to differences in the thermal and structural characteristics. The change trend and magnitude of average electrical efficiency with the position of concentrator when α = 30° are both opposite to those when α = 75°. The average electrical efficiency at α = 30° decreases from 7.76% at the designed position (e = 0 mm) to 7.62% at the deviated position (e = −45mm), while the average electrical efficiency at α = 75° increases from 9.26% to 10.54%.

Islands are not only important strategic space for China’s social and economic development, but also important barrier for ecological security. Evaluating the ecological status of islands is the basis for rational utilization, protection and management. In this paper, 77 islands were selected and the ecological status of each island in 2019 was evaluated according to the evaluation method of Island Ecological Index. The results showed that the majority of evaluated islands were of good ecological status, the ecological status of township-level islands with residents and non-resident islands was significantly better than that of village-level islands with residents, the distribution of Island Ecological Index in the Bohai Sea, the Yellow Sea and the East China Sea was similar, and the proportion of islands of good ecological status was higher than that of islands in the South China Sea. Vegetation coverage, natural shoreline retention rate and sewage treatment rate were the main factors affecting the ecological status of islands in 2019. Effective measures should be taken to help improve the ecological status of islands and promote the realization of sustainable development of islands, such as strengthening the investment in ecological protection and construction of village-level islands with residents, rationalizing the use of island resources, optimizing the pattern of protection and development, retaining natural shorelines, improving the sewage treatment capacity and so on.

The highly toxic plant toxin ricin is one of the most known threatening toxins. Accurate and sensitive biosensing methods for the first emergency response and intoxication treatment, are always pursued in the biodefense field. Screening affinity molecules is the fundamental mainstream approach for developing biosensing methods. Compared with common affinity molecules such as antibodies and oligonucleotide aptamers, peptides have great potential as biosensing modules with more accessible chemical synthesis capability and better batch-to-batch stability than antibodies, more abundant interaction sites, and robust sensing performance towards complex environments. However, anti-ricin peptides are so scant to be screened and discovered, and an advanced screening strategy is the utmost to tackle this issue. Here, we present a new in silico-in vitro iteration-assisted affinity maturation strategy of anti-ricin peptides. We first obtained affinity peptides targeting ricin through phage display with five panning rounds of “coating-elution-amplification-enrichment” procedures. The binding affinity and kinetic parameters characterized by surface plasmon resonance (SPR) showed that we had obtained four peptides owning dissociation constants (KD) around 2~35 μM, in which peptide PD-2-R5 has the lower KD of 4.7 μM and higher stable posture to interact with ricin. We then constructed a new strategy for affinity maturity, composing two rounds of in silico-in vitro iterations. Firstly, towards the single-site alanine scanning mutation peptide library, the molecular docking predictions match the SPR evaluation results well, laying a solid foundation for designing a full saturation mutated peptide library. Secondly, plenty of in silico saturation mutation prediction results guided the discovery of peptides PD2-R5-T3 and PD-2-R5-T4 with higher affinity from only a limited number of SPR evaluation experiments. Both evolved peptides had increased affinity by about 5~20 times, i.e., KD of 230 nM and 900 nM. A primary cellular toxicity assay indicated that both peptides could protect cells against ricin damage. We further established an SPR assay based on PD-2-R5-T3 and PD-2-R5-T4 elongated with an antifouling peptide linkage and achieved good linearity with a sensitivity of 1 nM and 0.5 nM, respectively. We hope this new affinity-mature strategy will find its favorable position in relevant peptide evolution, biosensing, and medical countermeasures for biotoxins to protect society’s security and human life better.

Intestinal epithelial integrity is commonly disrupted in patients with critical disorders, but the exact underlying mechanisms are unclear. Long noncoding RNAs transcribed from ultraconserved regions (T-UCRs) control different cell functions and are involved in pathologies. Here, we investigated the role of T-UCRs in intestinal epithelial homeostasis and identified T-UCR uc.230 as a major regulator of epithelial renewal, apoptosis, and barrier function. Compared with controls, intestinal mucosal tissues from patients with ulcerative colitis and from mice with colitis or fasted for 48 hours had increased levels of uc.230. Silencing uc.230 inhibited the growth of intestinal epithelial cells (IECs) and organoids and caused epithelial barrier dysfunction. Silencing uc.230 also increased IEC vulnerability to apoptosis, whereas increasing uc.230 levels protected IECs against cell death. In mice with colitis, reduced uc.230 levels enhanced mucosal inflammatory injury and delayed recovery. Mechanistic studies revealed that uc.230 increased CUG-binding protein 1 (CUGBP1) by acting as a natural decoy RNA for miR-503, which interacts with Cugbp1 mRNA and represses its translation. These findings indicate that uc.230 sustains intestinal mucosal homeostasis by promoting epithelial renewal and barrier function and that it protects IECs against apoptosis by serving as a natural sponge for miR-503, thereby preserving CUGBP1 expression.

Summary: The identification, uptake, and clearance of nanoparticles (NPs) by phagocytes are critical in NP-based therapeutics. The cell membrane coating technique has recently emerged as an ideal surface modification approach to help NP bypass phagocytosis. CD47, a regulatory protein for phagocytosis, is a cell surface glycoprotein expressed on all cell types, including platelets. Herein, we enclosed bioactive glass (BG) with a platelet membrane to bestow BG with unique cell surface functions for immune evasion and immunomodulation. Compared with the uncoated particles, platelet membrane-coated BG shows reduced cellular uptake and can generate an immune environment favorable for osteogenesis. This is evidenced by the triggering of robust osteogenic differentiation in bone mesenchymal stromal cells, suggesting the synergistic effect of platelet membrane and BG in bone regeneration. These collectively indicate that cell membrane coating is a promising approach to enhance the therapeutic efficacy of biomaterials and thus provide new insight into biomaterial-mediated bone regeneration.

The gut microbiota plays an important role in central nervous system (CNS) disorders. Apolipoprotein E (ApoE) can affect the composition of the gut microbiota and is closely related to the CNS. However, the mechanism by which ApoE affects cognitive dysfunction through the gut microbiota–brain axis has thus far not been investigated. In this study, we used wild-type mice and ApoE knockout (ApoE–/–) mice to replicate the aging model and examined the effects of ApoE deletion on cognitive function, hippocampal ultrastructure, synaptophysin (SYP) and postsynaptic density 95 (PSD-95) in aging mice. We also explored whether ApoE deletion affects the gut microbiota and the metabolite profile of the hippocampus in aging mice and finally examined the effect of ApoE deletion on lipids and oxidative stress in aging mice. The results showed that the deletion of ApoE aggravated cognitive dysfunction, hippocampal synaptic ultrastructural damage and dysregulation of SYP and PSD-95 expression in aging mice. Furthermore, ApoE deletion reduced gut microbial makeup in aging mice. Further studies showed that ApoE deletion altered the hippocampal metabolic profile and aggravated dyslipidemia and oxidative stress in aging mice. In brief, our findings suggest that loss of ApoE alters the composition of the gut microbiota, which in turn may affect cognitive function in aging mice through the gut microbiota–brain axis.

At present, China is in the stage of the COVID-19 epidemic where regular prevention and control measures are required to contain the spread of disease. Reports of new sporadic cases are still widespread across China and medical personnel remain at high risk of exposure to infection. This is especially the case for medical staff working within emergency departments. Most gynecological emergency cases are complex and a high proportion require emergency surgical treatment. By referring to national regulations and requirements on COVID-19 prevention and control, and by summarizing our experiences in the battle against COVID-19 within Wuhan, this consensus report provides recommendations on the triage, reception, consultation, admission and surgical management of gynecological emergency patients. We also make suggestions for the environmental layout and disinfection and the medical waste management. This consensus aims to optimize the diagnosis and treatment process of gynecological emergency patients and reduce the exposure risk of medical staff within the current context of routine COVID-19 prevention and control.

BackgroundAging is an important cause of cognitive dysfunction. Liuwei Dihuang decoction (LW), a commonly applied Chinese medicine formula, is widely used for the treatment of aging-related diseases in China. Previously, LW was confirmed to be effective in prolonging life span and reducing oxidative stress in aged mice. Unfortunately, the underlying mechanism of LW remains unclear. The aim of this study was to interpret the mechanism by which LW alleviates cognitive dysfunction related to aging from the perspective of the microbiota-gut-brain axis.MethodAll C57BL/6 mice (n = 60) were randomly divided into five groups: the control, model, vitamin E (positive control group), low-dose LW and high-dose LW groups (n = 12 in each group). Except for those in the control group, D-galactose was subcutaneously injected into mice in the other groups to induce the aging model. The antiaging effect of LW was evaluated by the water maze test, electron microscopy, 16S rRNA sequencing, combined LC–MS and GC–MS metabolomics, and ELISA.ResultsLiuwei Dihuang decoction ameliorated cognitive dysfunction and hippocampal synaptic ultrastructure damage in aging mice. Moreover, LW decreased Proteobacteria abundance and increased gut microbiota diversity in aging mice. Metabolomic analysis showed that LW treatment was associated with the significantly differential abundance of 14 metabolites, which were mainly enriched in apelin signaling, sphingolipid metabolism, glycerophospholipid and other metabolic pathways. Additionally, LW affected lipid metabolism and oxidative stress in aging mice. Finally, we also found that LW-regulated microbial species such as Proteobacteria and Fibrobacterota had potential relationships with lipid metabolism, oxidative stress and hippocampal metabolites.ConclusionIn brief, LW improved cognitive function in aging mice by regulating lipid metabolism and oxidative stress through restoration of the homeostasis of the microbiota-gut-brain axis.

Livelihood vulnerability assessment has become an important policy tool for identifying groups in need of immediate intervention. Based on survey data covering 427 households in the Hulunbuir Grasslands in northern China, an indicator-based livelihood vulnerability assessment system (LVAS) was established by combining the sustainable livelihood framework and the exposure–sensitivity–adaptation framework, which described the livelihood vulnerability of households across the household life cycle in terms of the dimensions of exposure, sensitivity, and adaptation. A multiple linear regression model was used to identify the key variables that determine livelihood vulnerability. The results show that the livelihoods of pastoral households in the Hulunbuir Grasslands are moderately vulnerable overall, with a high level of exposure, a medium level of sensitivity, and a low level of adaptive capacity. As the household life cycle progresses (from the starting period to the empty-nest period), the adaptive capacity of pastoral households gradually decreases, and their livelihood vulnerability increases. The variables that most exacerbate the vulnerability of pastoral households’ livelihoods in this region are policy–ecological risks, climate–disaster risks and socioeconomic risks, and the main ways to reduce vulnerability are to improve these households’ productive capital, diversify their sources of livelihood, and improve their access to information. The results of the study provide empirical support for similar settings in different regions worldwide that aim to achieve a “win–win” situation of ecological conservation and sustainable livelihood development.

As an important transcription factor, heat shock factor 1 (HSF1) plays an endogenous anti-inflammation role in the body and can alleviate multiple organ dysfunction caused by sepsis, which contributes to an uncontrolled inflammatory response. The NLRP3 inflammasome is a supramolecular complex that plays key roles in immune surveillance. Inflammation is accomplished by NLRP3 inflammasome activation, which leads to the proteolytic maturation of IL-1β and pyroptosis. However, whether HSF1 is involved in the activation of the NLRP3 inflammasome in septic acute lung injury (ALI) has not been reported. Here, we show that HSF1 suppresses NLRP3 inflammasome activation in transcriptional and post-translational modification levels. HSF1 can repress NLRP3 expression via inhibiting NF-κB phosphorylation. HSF1 can inhibit caspase-1 activation and IL-1β maturation via promoting NLRP3 ubiquitination. Our finding not only elucidates a novel mechanism for HSF1-mediated protection of septic ALI but also identifies new therapeutic targets for septic ALI and related diseases.

The Xe isotope comagnetometer in the nuclear magnetic resonance regime can be used as a promising high-precision inertial measurement unit because of the absolute frequency measurement and high bandwidth. The fluctuation of the electron spin polarization leads to equivalent magnetic noise in the Xe isotope comagnetometer, which is one of the main factors limiting the stability of the comagnetometer. Here, we demonstrate systematic research of equivalent magnetic noise suppression and analyze the influence of the electron spin polarization on the Xe isotope comagnetometer. Based on the spin–exchange method between Xe isotopes and alkali metal atoms through the Fermi contact hyperfine interaction, the error equation of the Xe Larmor frequency is established. The equivalent magnetic noise can be suppressed by controlling the static magnetic field. This suppression method for Xe isotope comagnetometers improved the stability while maintaining high bandwidth. The experimental results show that this method can reduce the fluctuations of the 129Xe and 131Xe frequencies by 75% and 68.6%, respectively.

Abstract Background Window of implantation (WOI) displacement is one of the endometrial origins of embryo implantation failure, especially repeated implantation failure (RIF). An accurate prediction tool for endometrial receptivity (ER) is extraordinarily needed to precisely guide successful embryo implantation. We aimed to establish an RNA-Seq-based endometrial receptivity test (rsERT) tool using transcriptomic biomarkers and to evaluate the benefit of personalized embryo transfer (pET) guided by this tool in patients with RIF. Methods This was a two-phase strategy comprising tool establishment with retrospective data and benefit evaluation with a prospective, nonrandomized controlled trial. In the first phase, rsERT was established by sequencing and analyzing the RNA of endometrial tissues from 50 IVF patients with normal WOI timing. In the second phase, 142 patients with RIF were recruited and grouped by patient self-selection (experimental group, n = 56; control group, n = 86). pET guided by rsERT was performed in the experimental group and conventional ET in the control group. Results The rsERT, comprising 175 biomarker genes, showed an average accuracy of 98.4% by using tenfold cross-validation. The intrauterine pregnancy rate (IPR) of the experimental group (50.0%) was significantly improved compared to that (23.7%) of the control group (RR, 2.107; 95% CI 1.159 to 3.830; P = 0.017) when transferring day-3 embryos. Although not significantly different, the IPR of the experimental group (63.6%) was still 20 percentage points higher than that (40.7%) of the control group (RR, 1.562; 95% CI 0.898 to 2.718; P = 0.111) when transferring blastocysts. Conclusions The rsERT was developed to accurately predict the WOI period and significantly improve the pregnancy outcomes of patients with RIF, indicating the clinical potential of rsERT-guided pET. Trial registration Chinese Clinical Trial Registry: ChiCTR-DDD-17013375. Registered 14 November 2017, http://www.chictr.org.cn/index.aspx

Depression is a major psychiatric disease affecting all ages and is often co-morbid with neurodegeneration in the elderly. Depression and neurodegeneration are associated with decreased neurotrophic factors. In this mini-review the functions and potential therapeutic use of a newly discovered trophic factor, Neurotrophic factor-α1 (NF-α1), also known as Carboxypeptidase E (CPE), in depression and neuroprotection are discussed. NF-α1/CPE expression is enriched in CA3 neurons of the hippocampus. Families carrying null and homozygous non-sense mutations of the NF-α1/CPE gene share common clinical features including childhood onset obesity, type 2 diabetes, impaired intellectual abilities and hypogonadotrophic hypogonadism. Studies in animal models such as CPE knockout (KO) mice and CPEfat/fat mutant mice exhibit similar phenotypes. Analysis of CPE-KO mouse brain revealed that hippocampal CA3 was completely degenerated after weaning stress, along with deficits in hippocampal long-term potentiation. Carbamazepine effectively blocked weaning stress-induced hippocampal CA3 degeneration, suggesting the stress induced epileptic-like neuronal firing led to the degeneration. Analysis of possible mechanisms underlying NF-α1/CPE -mediated neuroprotection revealed that it interacts with the serotonin receptor, 5-HTR1E, and via β arrestin activation, subsequently upregulates ERK1/2 signaling and pro-survival protein, BCL2, levels. Furthermore, the NF-α1/CPE promoter contains a peroxisome proliferator-activated receptor (PPARγ) binding site which can be activated by rosiglitazone, a PPARγ agonist, to up-regulate expression of NF-α1/CPE and neurogenesis, resulting in anti-depression in animal models. Rosiglitazone, an anti-diabetic drug administered to diabetic patients resulted in decline of depression. Thus, NF-α1/CPE is a potential therapeutic agent or drug target for treating depression and neurodegenerative disorders.

Bone regeneration in large segmental defects depends on the action of osteoblasts and the ingrowth of new blood vessels. Therefore, it is important to promote the release of osteogenic/angiogenic growth factors. Since the discovery of heparin, its anticoagulant, anti-inflammatory, and anticancer functions have been extensively studied for over a century. Although the application of heparin is widely used in the orthopedic field, its auxiliary effect on bone regeneration is yet to be unveiled. Specifically, approximately one-third of the transforming growth factor (TGF) superfamily is bound to heparin and heparan sulfate, among which TGF-β1, TGF-β2, and bone morphogenetic protein (BMP) are the most common growth factors used. In addition, heparin can also improve the delivery and retention of BMP-2 in vivo promoting the healing of large bone defects at hyper physiological doses. In blood vessel formation, heparin still plays an integral part of fracture healing by cooperating with the platelet-derived growth factor (PDGF). Importantly, since heparin binds to growth factors and release components in nanomaterials, it can significantly facilitate the controlled release and retention of growth factors [such as fibroblast growth factor (FGF), BMP, and PDGF] in vivo. Consequently, the knowledge of scaffolds or delivery systems composed of heparin and different biomaterials (including organic, inorganic, metal, and natural polymers) is vital for material-guided bone regeneration research. This study systematically reviews the structural properties and auxiliary functions of heparin, with an emphasis on bone regeneration and its application in biomaterials under physiological conditions.

Abstract Control over soft‐to‐hard tissue interfaces is attracting intensive worldwide research efforts. Herein, a bioactive film‐guided soft–hard interface design (SHID) for multi‐tissue integrative regeneration is shown. Briefly, a soft bioactive film with good elasticity matchable to native ligament tissue, is incorporated with bone‐mimic components (calcium phosphate cement, CPC) to partially endow the soft‐film with hard‐tissue mimicking feature. The hybrid film is elegantly compounded with a clinical artificial ligament to act as a buffer zone to bridge the soft (ligament) and hard tissues (bone). Moreover, the bioactive film‐decorated ligament can be rolled into a 3D bio‐instructive implant with spatial‐controllable distribution of CPC bioactive motifs. CPC then promotes the recruitment and differentiation of endogenous cells in to the implant inside part, which enables a vascularized bone growth into the implant, and forms a structure mimicking the biological ligament–bone interface, thereby significantly improving osteointegration and biomechanical property. Thus, this special design provides an effective SHID‐guided implant‐bioactivation strategy unreached by the traditional manufacturing methods, enlightening a promising technology to develop an ideal SHID for translational use in the future.

It is presently difficult to achieve dental pulp vitality maintenance and regeneration in adult teeth. Dentin destruction results in the exposure of the dental pulp tissue to infectious oral environments, thereby triggering continuous severe pulp inflammation that impedes the self-regenerative capacity of the pulp. For these reasons, the regeneration of dentin bridges to block pulp tissue from the oral environment is an indispensable step. Nevertheless, this goal is difficult to achieve using present strategies, because the importance of immunoregulation in the pulp inflammatory microenvironment has been ignored. In our previous study, we found that the nanomaterial dihydrolipoic acid-functionalized gold nanoclusters (DHLA-AuNCs) efficiently regulated inflammatory responses in microglia (resident macrophages in the central nervous system), suggesting that DHLA-AuNCs may induce dentin bridge regeneration by regulating dental pulp macrophage responses. In the present study, we found that DHLA-AuNCs inhibited the M1 phenotype while promoting the M2 phenotype in macrophages in inflammatory conditions in vitro. This regulation of the inflammatory environment in dental pulp enhanced the differentiation of human dental pulp stromal cells (hDPC) toward odontoblasts, a beneficial effect on dentin regeneration. DHLA-AuNCs also had a direct role in the differentiation and mineralization of hDPC. These findings suggest that DHLA-AuNCs facilitate dentin regeneration through both efficient immunomodulation and direct induction of stromal cell differentiation/mineralization, providing a potential therapeutic nanomaterial for dentin bridge regeneration, effects that would be beneficial for dental pulp regeneration.

Schizophrenia is a complex neuropsychiatric disorder affected by both genetic and epigenetic factors. Except for neuronal dysfunction, oligodendroglial abnormalities also contribute to the disease pathogenesis, characterized by a robust dysregulation of oligodendrocyte and myelin related genes. Accumulating evidence shows that histone modifications play important roles in transcriptional regulation of the genes crucial for oligodendrocyte differentiation and myelination. Specifically, the histone acetylation and methylation were two well-recognized histone modification abnormalities in the schizophrenic brains. In this mini-review, we will describe the dynamic changes of histone acetylation and methylation in schizophrenia, which may coordinate and induce deleterious epigenetic memory in oligodendroglial cells, and further lead to oligodendrocyte and myelin deficits. Precise modulation of histone modification status in oligodendroglial cells needs to secure the balance of epigenetic marks, which may revise the therapeutic strategy for the white matter etiology of neuropsychiatric disorders.

Abstract The fourth‐order generalised integrator is very suitable for single‐phase phase‐locked loop because it can provide orthogonal signal conveniently and block harmonic voltages effectively. In the conventional fourth‐order generalised integrator based phase‐locked loop, the resonance frequency of fourth‐order generalised integrator needs to be adjusted according to the grid frequency. To improve the phase‐locked loop performance, a non‐adaptive fourth‐order generalised integrator is suggested for single‐phase system, and this paper presents a correction method. According to the estimated grid frequency, the amplitude imbalance and phase error caused by non‐adaptive fourth‐order generalised integrator can be calculated, and two adaptive units are added to deal with the problems. Moreover, the small‐signal model of the proposed phase‐locked loop is carried out, and the control parameters are tuned. Compared to conventional fourth‐order generalised integrator based phase‐locked loop, the proposed phase‐locked loop shows a better performance, which is verified through simulation and experimental results.