Artificial intelligence-powered pharmacovigilance: A review of machine and deep learning in clinical text-based adverse drug event detection for benchmark datasets.

OBJECTIVE: The primary objective of this review is to investigate the effectiveness of machine learning and deep learning methodologies in the context of extracting adverse drug events (ADEs) from clinical benchmark datasets. We conduct an in-depth analysis, aiming to compare the merits and drawbacks of both machine learning and deep learning techniques, particularly within the framework of named-entity recognition (NER) and relation classification (RC) tasks related to ADE extraction. Additionally, our focus extends to the examination of specific features and their impact on the overall performance of these methodologies. In a broader perspective, our research extends to ADE extraction from various sources, including biomedical literature, social media data, and drug labels, removing the limitation to exclusively machine learning or deep learning methods. METHODS: We conducted an extensive literature review on PubMed using the query "(((machine learning [Medical Subject Headings (MeSH) Terms]) OR (deep learning [MeSH Terms])) AND (adverse drug event [MeSH Terms])) AND (extraction)", and supplemented this with a snowballing approach to review 275 references sourced from retrieved articles. RESULTS: In our analysis, we included twelve articles for review. For the NER task, deep learning models outperformed machine learning models. In the RC task, gradient Boosting, multilayer perceptron and random forest models excelled. The Bidirectional Encoder Representations from Transformers (BERT) model consistently achieved the best performance in the end-to-end task. Future efforts in the end-to-end task should prioritize improving NER accuracy, especially for 'ADE' and 'Reason'. CONCLUSION: These findings hold significant implications for advancing the field of ADE extraction and pharmacovigilance, ultimately contributing to improved drug safety monitoring and healthcare outcomes.

Association between sleep quality, depressive symptoms, and suicidal ideation in college students.

Suicide among college students is a challenging problem globally. Yet, the association between sleep quality, depressive symptoms, and suicidal ideation remains unclear. This study aims to understand if depressive symptoms mediate the relationship between sleep quality and suicide ideation and whether the interaction between depressive symptoms and sleep quality on suicidal ideation is additive. A total of 1182 college students were recruited, and sleep quality, depressive symptoms, and suicidal ideation were assessed using questionnaires. Univariate analysis, logistic regression analysis, linear regression models, and the Sobel test were performed. The results showed that, among college students, poor sleep quality was positively associated with suicidal ideation, and the association was mediated through depressive symptoms. Moreover, there was a significant additive interaction between poor sleep quality and depressive symptoms on suicidal ideation. These findings suggest that, in the process of preventing and treating suicidal ideation in college students with sleep disorders, we should focus on the evaluation and intervention of depressive symptoms and adopt multidisciplinary team interventions for college students with sleep disorders and depression.

Effect of aspirin on blood pressure in hypertensive patients: a systematic review and meta-analysis.

INTRODUCTION: Aspirin is widely used for secondary prevention in patients with hypertension. However, previous studies mainly focused on the preventive effects of aspirin, and there has been a lack of reliable evidence on whether taking aspirin affects blood pressure This study aimed to investigate whether aspirin would affect the blood pressure in patients with hypertension. METHODS: PubMed, Cochrane database, Embase, Scopus and Medline databases were searched until September 2023. For continuous variables (e.g., blood pressure reduction), the mean difference (MD) was selected as the effect magnitude indices. We used the Cochrane Collaboration's Risk of Bias tool to assess the risk of bias. RESULT: A total of five studies were included, comprising 20,312 patients. We found that aspirin did not affect SBP (MD = -0.78, 95% CI: - 2.41, 0.84). A similar result was found for DBP (MD = -0.86, 95% CI: - 2.14, 0.42). CONCLUSION: This study showed no significant difference in blood pressure between the aspirin and control groups, suggesting that aspirin does not affect blood pressure.

Circ-ZNF236 mediates stem cells from apical papilla differentiation by regulating LGR4-induced autophagy.

AIM: Human stem cells from the apical papilla (SCAPs) are an appealing stem cell source for tissue regeneration engineering. Circular RNAs (circRNAs) are known to exert pivotal regulatory functions in various cell differentiation processes, including osteogenesis of mesenchymal stem cells. However, few studies have shown the potential mechanism of circRNAs in the odonto/osteogenic differentiation of SCAPs. Herein, we identified a novel circRNA, circ-ZNF236 (hsa_circ_0000857) and found that it was remarkably upregulated during the SCAPs committed differentiation. Thus, in this study, we showed the significance of circ-ZNF236 in the odonto/osteogenic differentiation of SCAPs and its underlying regulatory mechanisms. METHODOLOGY: The circular structure of circ-ZNF236 was identified via Sanger sequencing, amplification of convergent and divergent primers. The proliferation of SCAPs was detected by CCK-8, flow cytometry analysis and EdU incorporation assay. Western blotting, qRT-PCR, Alkaline phosphatase (ALP) and Alizarin red staining (ARS) were performed to explore the regulatory effect of circ-ZNF236/miR-218-5p/LGR4 axis in the odonto/osteogenic differentiation of SCAPs in vitro. Fluorescence in situ hybridization, as well as dual-luciferase reporting assays, revealed that circ-ZNF236 binds to miR-218-5p. Transmission electron microscopy (TEM) and mRFP-GFP-LC3 lentivirus were performed to detect the activation of autophagy. RESULTS: Circ-ZNF236 was identified as a highly stable circRNA with a covalent closed loop structure. Circ-ZNF236 had no detectable influence on cell proliferation but positively regulated SCAPs odonto/osteogenic differentiation. Furthermore, circ-ZNF236 was confirmed as a sponge of miR-218-5p in SCAPs, while miR-218-5p targets LGR4 mRNA at its 3'-UTR. Subsequent rescue experiments revealed that circ-ZNF236 regulates odonto/osteogenic differentiation by miR-218-5p/LGR4 in SCAPs. Importantly, circ-ZNF236 activated autophagy, and the activation of autophagy strengthened the committed differentiation capability of SCAPs. Subsequently, in vivo experiments showed that SCAPs overexpressing circ-ZNF236 promoted bone formation in a rat skull defect model. CONCLUSIONS: Circ-ZNF236 could activate autophagy through increasing LGR4 expression, thus positively regulating SCAPs odonto/osteogenic differentiation. Our findings suggested that circ-ZNF236 might represent a novel therapeutic target to prompt the odonto/osteogenic differentiation of SCAPs.

Improving large language models for clinical named entity recognition via prompt engineering.

IMPORTANCE: The study highlights the potential of large language models, specifically GPT-3.5 and GPT-4, in processing complex clinical data and extracting meaningful information with minimal training data. By developing and refining prompt-based strategies, we can significantly enhance the models' performance, making them viable tools for clinical NER tasks and possibly reducing the reliance on extensive annotated datasets. OBJECTIVES: This study quantifies the capabilities of GPT-3.5 and GPT-4 for clinical named entity recognition (NER) tasks and proposes task-specific prompts to improve their performance. MATERIALS AND METHODS: We evaluated these models on 2 clinical NER tasks: (1) to extract medical problems, treatments, and tests from clinical notes in the MTSamples corpus, following the 2010 i2b2 concept extraction shared task, and (2) to identify nervous system disorder-related adverse events from safety reports in the vaccine adverse event reporting system (VAERS). To improve the GPT models' performance, we developed a clinical task-specific prompt framework that includes (1) baseline prompts with task description and format specification, (2) annotation guideline-based prompts, (3) error analysis-based instructions, and (4) annotated samples for few-shot learning. We assessed each prompt's effectiveness and compared the models to BioClinicalBERT. RESULTS: Using baseline prompts, GPT-3.5 and GPT-4 achieved relaxed F1 scores of 0.634, 0.804 for MTSamples and 0.301, 0.593 for VAERS. Additional prompt components consistently improved model performance. When all 4 components were used, GPT-3.5 and GPT-4 achieved relaxed F1 socres of 0.794, 0.861 for MTSamples and 0.676, 0.736 for VAERS, demonstrating the effectiveness of our prompt framework. Although these results trail BioClinicalBERT (F1 of 0.901 for the MTSamples dataset and 0.802 for the VAERS), it is very promising considering few training samples are needed. DISCUSSION: The study's findings suggest a promising direction in leveraging LLMs for clinical NER tasks. However, while the performance of GPT models improved with task-specific prompts, there's a need for further development and refinement. LLMs like GPT-4 show potential in achieving close performance to state-of-the-art models like BioClinicalBERT, but they still require careful prompt engineering and understanding of task-specific knowledge. The study also underscores the importance of evaluation schemas that accurately reflect the capabilities and performance of LLMs in clinical settings. CONCLUSION: While direct application of GPT models to clinical NER tasks falls short of optimal performance, our task-specific prompt framework, incorporating medical knowledge and training samples, significantly enhances GPT models' feasibility for potential clinical applications.

SHED-derived exosomes attenuate trigeminal neuralgia after CCI of the infraorbital nerve in mice via the miR-24-3p/IL-1R1/p-p38 MAPK pathway.

BACKGROUND: Microglial activation in the spinal trigeminal nucleus (STN) plays a crucial role in the development of trigeminal neuralgia (TN). The involvement of adenosine monophosphate-activated protein kinase (AMPK) and N-methyl-D-aspartate receptor 1 (NMDAR1, NR1) in TN has been established. Initial evidence suggests that stem cells from human exfoliated deciduous teeth (SHED) have a potential therapeutic effect in attenuating TN. In this study, we propose that SHED-derived exosomes (SHED-Exos) may alleviate TN by inhibiting microglial activation. This study sought to assess the curative effect of SHED-Exos administrated through the tail vein on a unilateral infraorbital nerve chronic constriction injury (CCI-ION) model in mice to reveal the role of SHED-Exos in TN and further clarify the potential mechanism. RESULTS: Animals subjected to CCI-ION were administered SHED-Exos extracted by differential ultracentrifugation. SHED-Exos significantly alleviated TN in CCI mice (increasing the mechanical threshold and reducing p-NR1) and suppressed microglial activation (indicated by the levels of TNF-α, IL-1ß and IBA-1, as well as p-AMPK) in vivo and in vitro. Notably, SHED-Exos worked in a concentration dependent manner. Mechanistically, miR-24-3p-upregulated SHED-Exos exerted a more significant effect, while miR-24-3p-inhibited SHED-Exos had a weakened effect. Bioinformatics analysis and luciferase reporter assays were utilized for target gene prediction and verification between miR-24-3p and IL1R1. Moreover, miR-24-3p targeted the IL1R1/p-p38 MAPK pathway in microglia was increased in CCI mice, and participated in microglial activation in the STN. CONCLUSIONS: miR-24-3p-encapsulated SHED-Exos attenuated TN by suppressing microglial activation in the STN of CCI mice. Mechanistically, miR-24-3p blocked p-p38 MAPK signaling by targeting IL1R1. Theoretically, targeted delivery of miR-24-3p may offer a potential strategy for TN.

Hsa-miR-27b-5p suppresses the osteogenic and odontogenic differentiation of stem cells from human exfoliated deciduous teeth via targeting BMPR1A: An ex vivo study.

AIM: Recently, miR-27b-5p was shown to be abundantly expressed in extracellular vehicles (EVs) from the inflammatory microenvironment. This study determined the role of miR-27b-5p in regulating osteogenic and odontogenic differentiation of stem cells from human exfoliated deciduous teeth (SHEDs) and further examined the regulatory mechanism of bone morphogenetic protein receptor type-1A (BMPR1A). METHODOLOGY: Characteristics of SHEDs and SHEDs-EVs derived from SHEDs were evaluated respectively. The expression of miR-27b-5p in SHEDs and EVs was detected during osteo-induction. Mechanically, SHEDs were treated with miR-27b-5p mimics or an inhibitor, and the osteogenic/odontogenic differentiation and proliferation were assessed. Bioinformatic analysis and luciferase reporter were utilized for target gene prediction and verification. Finally, BMPR1A-overexpressed plasmids were transfected into SHEDs to investigate the participation of the BMPR1A/SMAD4 pathway. Data were analysed using Student's t-test, one-way analysis of variance and Chi-square test. RESULTS: MiR-27b-5p was expressed in both SHEDs and EVs and was significantly increased at the initial stage of differentiation and then decreased in a time-dependent manner (p < .01). Upregulation of miR-27b-5p significantly suppressed osteogenic/odontogenic differentiation of SHEDs and inhibited proliferation (p < .05), whereas inhibition of miR-27b-5p enhanced the differentiation (p < .05). Dual-luciferase reporter assay and pull-down assay confirmed the binding site between miR-27b-5p and BMPR1A (p < .05). The overexpression of BMPR1A rescued the effect of miR-27b-5p, while contributed to the decrease of pluripotency (p < .05). Additionally, miR-27b-5p maintained pluripotency in BMPR1A-overexpressed SHEDs (p < .05). CONCLUSIONS: MiR-27b-5p in SHEDs/EVs was inversely associated with differentiation and suppressed the osteogenic and odontogenic differentiation of SHEDs and maintained the pluripotency of SHEDs partly by shuttering BMPR1A-targeting BMP signalling. Theoretically, inhibition of miR-27b-5p represents a potential strategy to promote osteanagenesis and dentinogenesis. However, miR-27b-5p capsuled EVs might maintain cell pluripotency and self-renewal for non-cell-targeted therapy.

Prognostic significance of ING3 expression in patients with cancer: A systematic review and meta-analysis.

Background: It has been reported that ING3 inhibits the progression of various cancers. However, some studies have shown that it promotes the development of prostate cancer. The purpose of this study was to investigate whether ING3 expression is associated with the prognosis of patients with cancer. Materials and methods: PubMed, Cochrane Database, Embase, Medline, ScienceDirect, Scopus and Web of Science were searched until September 2022. The hazard ratio (HR)/odds ratio (OR) and 95% confidence interval (95% CI) were calculated using Stata 17 software. We used the Newcastle-Ottawa Scale (NOS) to assess the risk of bias. Result: Seven studies involving 2371 patients with five types of cancer were included. The results showed that high expression of ING3 was negatively associated with a more advanced TNM stage (III-IV vs. I-II) (OR=0.61, 95% CI: 0.43-0.86), lymph node metastasis (OR=0.67, 95% CI: 0.49-0.90) and disease-free survival (HR=0.63, 95% CI: 0.37-0.88). However, ING3 expression was not associated with overall survival (HR=0.77, 95% CI: 0.41-1.12), tumor size (OR=0.67, 95% CI: 0.33-1.37), tumor differentiation (OR=0.86, 95% CI: 0.36-2.09) and gender (OR=1.14, 95% CI: 0.78-1.66). Conclusion: This study showed that the expression of ING3 was associated with better prognosis, suggesting that ING3 may be a potential biomarker for cancer prognosis. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier (CRD42022306354).

PD-1 Suppresses the Osteogenic and Odontogenic Differentiation of Stem Cells from Dental Apical Papilla via Targeting SHP2/NF-κB Axis.

Stem cells from the apical papilla (SCAPs) are important for tooth root development and regeneration of root dentin. Here, we examined the expression of programmed cell death protein-1 (PD-1) in SCAPs and investigated the effects of PD-1 on odontogenic and osteogenic differentiation, as well as the relationship between PD-1 and SHP2/NF-κB signals. SCAPs were obtained and cultured in the related medium. The proliferation ability was evaluated by the cell counting kit 8 (CCK-8) and the 5-ethynyl-20-deoxyuridine (EdU) assay. Alkaline phosphatase (ALP) activity assay, ALP staining, Western blot, real-time quantitative reverse-transcription polymerase chain reaction (RT-qPCR), Alizarin Red S (ARS) staining, and immunofluorescence (IF) staining were performed to explore the osteo/odontogenic potential and the involvement of SHP2/NF-κB pathways. Besides, we transplanted SCAPs components into mouse calvaria defects to evaluate osteogenesis in vivo. We found that human SCAPs expressed PD-1 for the first time. PD-1 knockdown enhanced the osteo/odontogenic differentiation of SCAPs by suppressing the SHP2 pathway and activating the NF-κB pathway. Overexpression of PD-1 inhibited the osteogenesis and odontogenesis of SCAPs via activation of SHP2 signal and inhibition of the NF-κB pathway. PD-1 activated SHP2 signal to block NF-κB signal and then played a vital role in osteo/odontogenic differentiation of SCAPs.

Mendelian randomization rules out the causal relationship between serum lipids and cholecystitis.

BACKGROUND: The relationship between serum lipids and cholecystitis is still under investigation. To examine the causal effect of serum lipids on cholecystitis using the Mendelian randomization method. METHODS: We conducted univariable Mendelian randomization (MR) analyses using summary statistics from two independent genome-wide association studies (GWAS) on serum lipids (n = 132,908) and cholecystitis (n = 361,194). Mainly, the inverse-variance weighted (IVW) method was utilized to combine each SNP's causal estimation, and the MR-Egger was adopted as a complementary method, together with the weighted median. Cochrane's Q value was employed to appraise heterogeneity. The MR-Egger intercept and MR-PRESSO were used to detect the horizontal pleiotropy. RESULTS: Our univariable results displayed a minor protective effect of serum low-density lipoprotein (LDL) cholesterol (OR [95% CI] = 0.9984483 [0.9984499, 0.9984468]; p = 0.008) on cholecystitis. No significant causal effect of total cholesterol (TC) (OR [95% CI] = 0.9994228 [0.9994222, 0.9994233]; p = 0.296), triglycerides (OR [95% CI] = 0.9990893 [0.9990882, 0.9990903]; p = 0.238) and high-density lipoprotein (HDL) cholesterol (OR [95% CI] = 0.9997020 [0.9997017, 0.9997023]; p = 0.565) was found on cholecystitis. CONCLUSION: These findings suggest that LDL cholesterolhas a slight protective effect on cholecystitis, which can be easily affected by confounding factors. TC, triglycerides and HDL cholesterol don't have causal effect on cholecystitis. The protective effect of serum lipids on cholecystitis, though possible, remain less certain.

The role of the excitation:inhibition functional balance in the mPFC in the onset of antidepressants.

Currently available antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), generally require weeks to months to produce a therapeutic response, but the mechanism of action underlying the delayed onset of antidepressant-like action remains to be elucidated. The balance between excitatory glutamatergic pyramidal neurons and inhibitory γ-aminobutyric acid (GABA) interneurons, i.e., the excitation:inhibition functional (E:I) balance, in the medial prefrontal cortex (mPFC) is critical in regulating several behaviors and might play an important mediating role in the mechanism of rapid antidepressant-like action reported by several studies. In the present study, the multichannel electrophysiological technique was used to record the firing activities of pyramidal neurons and interneurons and investigate the effects of a single dose of fluoxetine and ketamine (both 10 mg/kg, i.p.) on the E:I functional balance in the rat mPFC after 90 min or 24 h, and the forced swimming test (FST) was used to evaluate the antidepressant-like effects of fluoxetine and ketamine. The present study also explored the effects of chronic treatment with fluoxetine (10 mg/kg, i.g.) for 7 d or 21 d on the E:I functional balance in the mPFC. The present results suggested that a single dose of ketamine could both significantly increase the firing activities of pyramidal neurons and significantly decrease the firing activities of interneurons in the mPFC and exerted significant antidepressant-like action on the FST after 90 min and 24 h, but fluoxetine had no such effects under the same conditions. However, chronic treatment with fluoxetine for 21 d (but not 7 d) could significantly affect the firing activities of pyramidal neurons and interneurons in the mPFC. Taken together, the present results indicated that rapid regulation of the E:I functional balance in the mPFC might be an important common mechanism of rapid-acting antidepressants and the delayed onset of SSRIs might be partly attributed to their inability to rapidly regulate the E:I functional balance in the mPFC. The present study provided a new entry point to the development of rapid-acting antidepressants.

CTP-CM enhances osteogenic differentiation of hPDLSCs via NF-κB pathway.

OBJECTIVE: The conditioned medium of calcined tooth powder (CTP-CM) is a type of biomimetic mineralized material and well contributing to bone healing and bone formation in vivo. However, little is known about the effect of CTP-CM on human periodontal ligament stem cells (hPDLSCs) as well as the underlying mechanisms. METHODS: ALP activity assay was conducted to select the concentration with the highest ALP level, which was used for the following experiments. Cell proliferation was measured by cell counting kit-8 assay and flow cytometry analysis. Expression levels of osteogenic markers in CTP-CM-induced hPDLSCs were evaluated with real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), immunofluorescence staining, and Western blot. Mineralization of CTP-CM-induced hPDLSCs was evaluated by alizarin red staining. Furthermore, the involvement of NF-κB pathway was examined by immunofluorescence staining and Western blot. RESULTS: 20 µg/ml was selected for the further experiments. Functional studies demonstrated that CTP-CM exerted almost no influence on the proliferation of hPDLSCs and CTP-CM increased the osteogenic differentiation of hPDLSCs. Mechanistically, CTP-CM leads to activation of NF-κB signaling pathway. When treated with BMS345541, the osteogenic differentiation of CTP-CM-treated hPDLSCs was significantly attenuated. CONCLUSION: CTP-CM can promote the osteogenic differentiation of hPDLSCs via activating NF-κB pathway.

Assessing Young Adults' ENDS Use via Ecological Momentary Assessment and a Smart Bluetooth Enabled ENDS Device.

INTRODUCTION: The assessment of electronic nicotine delivery systems (ENDS) use poses unique challenges that go beyond established assessment methods for tobacco cigarettes. Recent studies have proposed using ecological momentary assessment (EMA), a method to collect self-reported data on mobile devices, or data passively collected by "smart" Bluetooth enabled ENDS to assess use. The current study sought to compare ENDS use data using EMA and puff counts collected from a smart device. AIMS AND METHODS: We recruited 18 young adult ENDS users (age M = 23.33; 44.4% female) from the San Francisco Bay Area. For a total of 30 days, participants completed daily diaries by EMA and used a second-generation smart Bluetooth enabled ENDS that collected puff data. Repeated measures correlations, multilevel regressions, and paired t tests assessed concordance of EMA reports and ENDS data. A subset of four highly compliant participants were selected for sensitivity analyses. RESULTS: Among all 18 participants, completion of EMA daily diaries was high (77.4%). The ENDS device collected approximately twice as many puffs per day as participants reported. Compared with self-reported number of sessions and amount of e-liquid used, self-reported puff counts had the highest correlation with device-collected puff counts (rrm = 0.49; p < .001). Correlations between self-reported and device-collected puff counts improved among the subset of four highly compliant participants (rrm = 0.59; p < .001). CONCLUSIONS: Self-reports potentially underestimate use of ENDS. Puff counts appear to be the best self-reported measure to assess ENDS use compared with number of sessions or liquid volume. IMPLICATIONS: The comparison of EMA self-reports and passively collected ENDS device data can inform future efforts to assess ENDS use. Self-reported puff counts are preferable over number of sessions or amount of liquid used, but compared with objective usage data, self-reported puff counts may still underestimate actual use. ENDS use behavior is likely higher than users estimate and report. Future research on improved measures of ENDS use is needed.

Temporal variability profiling of the default mode across epilepsy subtypes.

OBJECTIVE: Epilepsies are a group of neurological disorders sharing certain core features, but also demonstrate remarkable pathogenic and symptomatic heterogeneities. Various subtypes of epilepsy have been identified with abnormal shift in the brain default mode network (DMN). This study aims to evaluate the fine details of shared and distinct alterations in the DMN among epileptic subtypes. METHODS: We collected resting-state functional magnetic resonance imaging (MRI) data from a large epilepsy sample (n = 371) at a single center, including temporal lobe epilepsy (TLE), frontal lobe epilepsy (FLE), and genetic generalized epilepsy with generalized tonic-clonic seizures (GGE-GTCS), as well as healthy controls (HC, n = 150). We analyzed temporal dynamics profiling of the DMN, including edge-wise and node-wise temporal variabilities, and recurrent dynamic states of functional connectivity, to identify abnormalities common to epilepsies as well as those specific to each subtype. RESULTS: The analyses revealed that hypervariable edges within the specific DMN subsystem were shared by all subtypes (all PNBS  < .005), and deficits in node-wise temporal variability were prominent in TLE (all t(243) ≤ 2.51, PFDR  < .05) and FLE (all t(302) ≤ -2.65, PFDR  < .05) but relatively weak in GGE-GTCS. Moreover, dynamic states were generally less stable in patients than controls (all P's < .001). SIGNIFICANCE: Collectively, these findings demonstrated general DMN abnormalities common to different epilepsies as well as distinct dysfunctions to subtypes, and provided insights into understanding the relationship of pathophysiological mechanisms and brain connectivity.

Dentin-Derived Inorganic Minerals Promote the Osteogenesis of Bone Marrow-Derived Mesenchymal Stem Cells: Potential Applications for Bone Regeneration.

BACKGROUND: Oral and maxillofacial bone loss is highly prevalent among populations, and nowadays, increased attention has been focused on dentin derivatives serving as desirable graft materials for bone regeneration. In this study, dentin-derived inorganic mineral (DIM) was fabricated with a high-temperature calcination technique and the effects of DIM on the osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMMSCs) and the bone formation were elucidated. METHODS: The effects of DIM on BMMSC proliferation and apoptosis capacity were evaluated by CCK-8, flow cytometry, and EdU assays. Alkaline phosphatase (ALP) activity detection, ALP staining, alizarin red staining, and osteogenic marker expression analysis were performed to investigate the influence of DIM on the osteogenic differentiation of BMMSCs, as well as the relevant signal mechanisms. The model of critical-sized defects in the calvarium of rats was constructed for exploring the in vivo efficiency of DIM on bone regeneration. RESULTS: Cell viability assays indicated that DIM had no cytotoxicity. BMMSCs cultured with DIM presented a higher level of osteogenic differentiation ability than those in the control group. The activation in ERK and p38 signals was detected in DIM-treated BMMSCs, and both pathways and osteogenic process were suppressed while using ERK inhibitor U0126 and p38 inhibitor SB203580, respectively. Furthermore, the animal experiments revealed that DIM could dramatically enhance new bone formation compared to the control group. CONCLUSION: DIM could promote BMMSC osteogenic differentiation via triggering the ERK and p38 MAPK signaling pathways and might be a novel predictable material for facilitating bone formation.

Electrically compensated, tattoo-like electrodes for epidermal electrophysiology at scale.

Epidermal electrophysiology is widely carried out for disease diagnosis, performance monitoring, human-machine interaction, etc. Compared with thick, stiff, and irritating gel electrodes, emerging tattoo-like epidermal electrodes offer much better wearability and versatility. However, state-of-the-art tattoo-like electrodes are limited in size (e.g., centimeters) to perform electrophysiology at scale due to challenges including large-area fabrication, skin lamination, and electrical interference from long interconnects. Therefore, we report large-area, soft, breathable, substrate- and encapsulation-free electrodes designed into transformable filamentary serpentines that can be rapidly fabricated by cut-and-paste method. We propose a Cartan curve-inspired transfer process to minimize strain in the electrodes when laminated on nondevelopable skin surfaces. Unwanted signals picked up by the unencapsulated interconnects can be eliminated through a previously unexplored electrical compensation strategy. These tattoo-like electrodes can comfortably cover the whole chest, forearm, or neck for applications such as multichannel electrocardiography, sign language recognition, prosthetic control or mapping of neck activities.

Circular RNA SIPA1L1 promotes osteogenesis via regulating the miR-617/Smad3 axis in dental pulp stem cells.

BACKGROUND: Bone regeneration is preferred for bone loss caused by tumors, bone defects, fractures, etc. Recently, mesenchymal stem cells are considered as optimistic tools for bone defect therapy. Dental pulp stem cells (DPSCs) are a promising candidate for regenerative medicine and bone regeneration. Our previous study showed that upregulated circSIPA1L1 during osteogenesis of DPSCs is of significance. In this paper, the potential role of circSIPA1L1 in osteogenesis of DPSCs and its underlying mechanisms are explored. METHODS: The circular structure of circSIPA1L1 was identified by Sanger sequencing and PCR. Regulatory effects of circSIPA1L1 and miR-617 on mineral deposition in DPSCs were assessed by alkaline phosphatase (ALP) and alizarin red S (ARS) staining and in vivo bone formation assay were conducted to verify the biological influences of circSIPA1L1 on DPSCs. Western blot was performed to detect the protein expression of Smad3. Localization of circSIPA1L1 and miR-617 was confirmed by FISH. Dual-luciferase reporter assay and rescue experiments were conducted to investigate the role of the circSIPA1L1/miR-617/Smad3 regulatory axis in osteogenesis of DPSCs. RESULTS: Sanger sequencing and back-to-back primer experiments confirmed the closed-loop structure of circSIPA1L1. CircSIPA1L1 could promote the committed differentiation of DPSCs. MiR-617 was predicted to be the target binding circSIPA1L1 through MiRDB, miRTarBase, and TargetScan database analyses, which was further confirmed by dual-luciferase reporter assay. FISH results showed that circSIPA1L1 and miR-617 colocalize in the cytoplasm of DPSCs. MiR-617 exerted an inhibitory effect on the osteogenesis of DPSCs. Knockdown of circSIPA1L1 or upregulation of miR-617 downregulated phosphorylated Smad3. In addition, rescue experiments showed that knockdown of miR-617 reversed the inhibitory effect of circSIPA1L1 on osteogenesis of DPSCs. CONCLUSION: CircRNASIPA1L1 promotes osteogenesis of DPSCs by adsorbing miR-617 and further targeting Smad3.

Intermittent Administration of Parathyroid Hormone Enhances Odonto/Osteogenic Differentiation of Stem Cells from the Apical Papilla via JNK and P38 MAPK Pathways.

OBJECTIVE: Parathyroid hormone (PTH) is considered to be essential during the tooth development. Stem cells from the apical papilla (SCAPs) are responsible for dentine formation. However, the interaction between PTH and SCAPs remains unclear. This study was aimed at investigating the effects of PTH on odonto/osteogenic differentiation capacity of SCAPs and elucidating the underlying molecular mechanisms. Materials and Methods. Here, SCAPs were isolated and identified in vitro. Effects of PTH on the proliferation of SCAPs were determined by Cell Counting Kit-8 (CCK-8), flow cytometry (FCM), and EdU. Alkaline phosphatase (ALP) activity, alizarin red staining, Western blot, and RT-PCR were carried out to detect the odonto/osteogenic differentiation of PTH-treated SCAPs as well as the participation of the MAPK signaling pathway. RESULTS: An ALP activity assay determined that 10-8 mol/L PTH was the optimal concentration for the induction of SCAPs with no significant influence on the proliferation of SCAPs as indicated by CCK-8, FCM, and EdU. The expression of odonto/osteogenic markers was significantly upregulated in mRNA levels and protein levels. Moreover, intermittent treatment of PTH also increased phosphorylation of JNK and P38, and the differentiation was suppressed following the inhibition of JNK and P38 MAPK pathways. CONCLUSION: PTH can regulate the odonto/osteogenic differentiation of SCAPs via JNK and P38 MAPK pathways.

A temporal chronnectomic framework: Cigarette smoking preserved the prefrontal dysfunction in schizophrenia.

The widespread cigarette smoking behavior in schizophrenia is generally attributed to its alleviation of patients' symptomatology by the self-medication hypothesis. The prefrontal cortex (PFC), which predominantly supports orchestrating thoughts and actions, might underlie the biological underpinnings of smoking behavior in schizophrenia. However, few studies have focused on the impact of smoking on the prefrontal function in schizophrenia. This study assumed that smoking-related alterations on the prefrontal dynamics of information integration (chronnectome) were different between healthy control (HC) and schizophrenia patient (SP). We recruited SP smokers (N = 22)/nonsmokers (N = 27) and HC smokers (N = 22)/nonsmokers (N = 21) who underwent resting-state functional magnetic resonance imaging (rsfMRI) with a total of 240 volumes (lasting for 480 s). We employed a chronnectomic density analysis on the rsfMRI signal by using a sliding-window method. We examined the interaction effect between smoking status and diagnosis utilizing two-way analysis of covariance under permutation test. Whereas disease-related reduced effects were found on the bilateral dorsolateral PFC chronnectomic density, no smoking effect was observed. As regards interaction effect, a smoking-related reduced effect was found on the right dorsolateral PFC chronnectomic density in HC, while a smoking-related increased effect was observed in SP. Nevertheless, post-hoc analysis revealed significant group difference between SP smokers and HC nonsmokers. Therefore, these results indicated a smoking-related preservation effect on disrupted prefrontal dynamics in schizophrenia that cannot restore it to normal levels. The novel findings yield a prefrontal-based chronnectome framework to elaborate upon the self-medication hypothesis in schizophrenia.

Impaired interactions among white-matter functional networks in antipsychotic-naive first-episode schizophrenia.

Schizophrenia has been conceptualized as a disorder arising from structurally pathological alterations to white-matter fibers in the brain. However, few studies have focused on white-matter functional changes in schizophrenia. Considering that converging evidence suggests that white-matter resting state functional MRI (rsfMRI) signals can effectively depict neuronal activity and psychopathological status, this study examined white-matter network-level interactions in antipsychotic-naive first-episode schizophrenia (FES) to facilitate the interpretation of the psychiatric pathological mechanisms in schizophrenia. We recruited 42 FES patients (FESs) and 38 healthy controls (HCs), all of whom underwent rsfMRI. We identified 11 white-matter functional networks, which could be further classified into deep, middle, and superficial layers of networks. We then examined network-level interactions among these 11 white-matter functional networks using coefficient Granger causality analysis. We employed group comparisons on the influences among 11 networks using network-based statistic. Excitatory influences from the middle superior corona radiate network to the superficial orbitofrontal and deep networks were disrupted in FESs compared with HCs. Additionally, an extra failure of suppression within superficial networks (including the frontoparietal network, temporofrontal network, and the orbitofrontal network) was observed in FESs. We additionally recruited an independent cohort (13 FESs and 13 HCs) from another center to examine the replicability of our findings across centers. Similar replication results further verified the white-matter functional network interaction model of schizophrenia. The novel findings of impaired interactions among white-matter functional networks in schizophrenia indicate that the pathophysiology of schizophrenia may also lie in white-matter functional abnormalities.