20(S)-Protopanaxadiol Exerts Antidepressive Effects in Chronic Corticosterone-Induced Rodent Animal Models as an Activator of Brain-Type Creatine Kinase.

20(S)-Protopanaxadiol (PPD) is one of the bioactive ingredients in ginseng and possesses neuroprotective properties. Brain-type creatine kinase (CK-BB) is an enzyme involved in brain energy homeostasis via the phosphocreatine-creatine kinase system. We previously identified PPD as directly bound to CK-BB and activated its activity in vitro. In this study, we explored the antidepressive effects of PPD that target CK-BB. First, we conducted time course studies on brain CK-BB, behaviors, and hippocampal structural plasticity responses to corticosterone (CORT) administration. Five weeks of CORT injection reduced CK-BB activity and protein levels and induced depression-like behaviors and hippocampal structural plasticity impairment. Next, a CK inhibitor and an adeno-associated virus-targeting CKB were used to diminish CK-BB activity or its expression in the brain. The loss of CK-BB in the brain led to depressive behaviors and morphological damage to spines in the hippocampus. Then, a polyclonal antibody against PPD was used to determine the distribution of PPD in the brain tissues. PPD was detected in the hippocampus and cortex and observed in astrocytes, neurons, and vascular endotheliocytes. Finally, different PPD doses were used in the chronic CORT-induced depression model. Treatment with a high dose of PPD significantly increased the activity and expression of CK-BB after long-term CORT injection. In addition, PPD alleviated the damage to depressive-like behaviors and structural plasticity induced by repeated CORT injection. Overall, our study revealed the critical role of CK-BB in mediating structural plasticity in CORT-induced depression and identified CK-BB as a therapeutic target for PPD, allowing us to treat stress-related mood disorders.

Arthroscopic Lateral Meniscus Root Repair With Reverse Suture Anchor Technique.

The stability of the knee joint is crucially dependent on the integrity of the lateral meniscus posterior root, which is often accompanied by anterior cruciate ligament injury. Anchor suture repair for lateral meniscus posterior root injury not only achieves better biomechanical effects but also ensures favorable prognosis. However, the placement of anchors often requires the establishment of a posterior approach, and the insertion of an anchor is a technical challenge. In light of this, we have applied the technique of reverse anchor fixation for repairing the lateral meniscus posterior root, which not only simplifies the procedure but also effectively reduces the "bungee effect."

Generative Artificial Intelligence to Transform Inpatient Discharge Summaries to Patient-Friendly Language and Format.

Importance: By law, patients have immediate access to discharge notes in their medical records. Technical language and abbreviations make notes difficult to read and understand for a typical patient. Large language models (LLMs [eg, GPT-4]) have the potential to transform these notes into patient-friendly language and format. Objective: To determine whether an LLM can transform discharge summaries into a format that is more readable and understandable. Design, Setting, and Participants: This cross-sectional study evaluated a sample of the discharge summaries of adult patients discharged from the General Internal Medicine service at NYU (New York University) Langone Health from June 1 to 30, 2023. Patients discharged as deceased were excluded. All discharge summaries were processed by the LLM between July 26 and August 5, 2023. Interventions: A secure Health Insurance Portability and Accountability Act-compliant platform, Microsoft Azure OpenAI, was used to transform these discharge summaries into a patient-friendly format between July 26 and August 5, 2023. Main Outcomes and Measures: Outcomes included readability as measured by Flesch-Kincaid Grade Level and understandability using Patient Education Materials Assessment Tool (PEMAT) scores. Readability and understandability of the original discharge summaries were compared with the transformed, patient-friendly discharge summaries created through the LLM. As balancing metrics, accuracy and completeness of the patient-friendly version were measured. Results: Discharge summaries of 50 patients (31 female [62.0%] and 19 male [38.0%]) were included. The median patient age was 65.5 (IQR, 59.0-77.5) years. Mean (SD) Flesch-Kincaid Grade Level was significantly lower in the patient-friendly discharge summaries (6.2 [0.5] vs 11.0 [1.5]; P < .001). PEMAT understandability scores were significantly higher for patient-friendly discharge summaries (81% vs 13%; P < .001). Two physicians reviewed each patient-friendly discharge summary for accuracy on a 6-point scale, with 54 of 100 reviews (54.0%) giving the best possible rating of 6. Summaries were rated entirely complete in 56 reviews (56.0%). Eighteen reviews noted safety concerns, mostly involving omissions, but also several inaccurate statements (termed hallucinations). Conclusions and Relevance: The findings of this cross-sectional study of 50 discharge summaries suggest that LLMs can be used to translate discharge summaries into patient-friendly language and formats that are significantly more readable and understandable than discharge summaries as they appear in electronic health records. However, implementation will require improvements in accuracy, completeness, and safety. Given the safety concerns, initial implementation will require physician review.

Discovery and validation of COX2 as a target of flavonoids in Apocyni Veneti Folium: Implications for the treatment of liver injury.

ETHNOPHARMACOLOGICAL RELEVANCE: Apocyni Veneti Folium (AVF), a popular traditional Chinese medicine (TCM), is known for its effects in soothing the liver and nerves and eliminating heat and water. It is relevant from an ethnopharmacological perspective. Pharmacological research has confirmed its benefits on antihypertension, antihyperlipidemia, antidepression, liver protection, immune system boosting, antiaging, and diabetic vascular lesions. Previous studies have shown that flavonoids, the active ingredients, have a hepatoprotective effect. However, the exact mechanism has not been clarified. AIM OF THE STUDY: This study aimed to identify the active flavonoids in AVF and their corresponding targets for liver injury. Multiple methods were introduced to confirm the targets. MATERIAL AND METHODS: AVF compounds were analyzed using liquid chromatography-mass spectrometry (LC-MS). Then, network pharmacology was utilized to screen potential hepatoprotection targets of the compounds. An enzyme activity assay was performed to determine the effect of the compounds on the targets. Biolayer interferometry (BLI) was applied to confirm the direct interaction between the compounds and the targets. RESULTS: A total of 71 compounds were identified by LC-MS and 19 compounds and 112 shared targets were screened using network pharmacology. These common targets were primarily involved in the TNF signaling pathway, cancer pathways, hepatitis B, drug responses, and negative regulation of the apoptotic process. Flavonoids were the primary pharmacological substance basis of AVF. The cyclooxygenase 2 (COX2) protein was one of the direct targets of flavonoids in AVF. The enzyme activity assay and BLI-based intermolecular interactions demonstrated that the compounds astragalin, isoquercitrin, and hyperoside exhibited stronger inhibition of enzyme activity and a higher affinity with COX2 compared to epigallocatechin, quercetin, and catechin. CONCLUSIONS: COX2 was preliminarily identified as a target of flavonoids, and the mechanism of the hepatoprotective effect of AVF might be linked to flavonoids inhibiting the activity of COX2. The findings can establish the foundation for future research on the traditional hepatoprotective effect of AVF on the liver and for clinical studies on liver disorders.

Discovery and validation of PURA as a transcription target of 20(S)-protopanaxadiol: Implications for the treatment of cognitive dysfunction.

Background: 20(S)-protopanaxadiol (PPD), a ginsenoside metabolite, has prominent benefits for the central nervous system, especially in improving learning and memory. However, its transcriptional targets in brain tissue remain unknown. Methods: In this study, we first used mass spectrometry-based drug affinity responsive target stability (DARTS) to identify the potential proteins of ginsenosides and intersected them with the transcription factor library. Second, the transcription factor PURA was confirmed as a target of PPD by biolayer interferometry (BLI) and molecular docking. Next, the effect of PPD on the transcriptional levels of target genes of PURA in brain tissues was determined by qRT-PCR. Finally, bioinformatics analysis was used to analyze the potential biological features of these target proteins. Results: The results showed three overlapping transcription factors between the proteomics of DARTS and transcription factor library. BLI analysis further showed that PPD had a higher direct interaction with PURA than parent ginsenosides. Subsequently, BLI kinetic analysis, molecular docking, and mutations in key amino acids of PURA indicated that PPD specifically bound to PURA. The results of qRT-PCR showed that PPD could increase the transcription levels of PURA target genes in brain. Finally, bioinformatics analysis showed that these target proteins were involved in learning and memory function. Conclusion: The above-mentioned findings indicate that PURA is a transcription target of PPD in brain, and PPD upregulate the transcription levels of target genes related to cognitive dysfunction by binding PURA, which could provide a chemical and biological basis for the study of treating cognitive impairment by targeting PURA.

Plant-derived nanovesicles: Further exploration of biomedical function and application potential.

Extracellular vesicles (EVs) are phospholipid bilayer vesicles actively secreted by cells, that contain a variety of functional nucleic acids, proteins, and lipids, and are important mediums of intercellular communication. Based on their natural properties, EVs can not only retain the pharmacological effects of their source cells but also serve as natural delivery carriers. Among them, plant-derived nanovesicles (PNVs) are characterized as natural disease therapeutics with many advantages such as simplicity, safety, eco-friendliness, low cost, and low toxicity due to their abundant resources, large yield, and low risk of immunogenicity in vivo. This review systematically introduces the biogenesis, isolation methods, physical characterization, and components of PNVs, and describes their administration and cellular uptake as therapeutic agents. We highlight the therapeutic potential of PNVs as therapeutic agents and drug delivery carriers, including anti-inflammatory, anticancer, wound healing, regeneration, and antiaging properties as well as their potential use in the treatment of liver disease and COVID-19. Finally, the toxicity and immunogenicity, the current clinical application, and the possible challenges in the future development of PNVs were analyzed. We expect the functions of PNVs to be further explored to promote clinical translation, thereby facilitating the development of a new framework for the treatment of human diseases.

Leveraging Electronic Health Record Technology and Team Care to Address Medication Adherence: Protocol for a Cluster Randomized Controlled Trial.

BACKGROUND: Low medication adherence is a common cause of high blood pressure but is often unrecognized in clinical practice. Electronic data linkages between electronic health records (EHRs) and pharmacies offer the opportunity to identify low medication adherence, which can be used for interventions at the point of care. We developed a multicomponent intervention that uses linked EHR and pharmacy data to automatically identify patients with elevated blood pressure and low medication adherence. The intervention then combines team-based care with EHR-based workflows to address medication nonadherence. OBJECTIVE: This study aims to describe the design of the Leveraging EHR Technology and Team Care to Address Medication Adherence (TEAMLET) trial, which tests the effectiveness of a multicomponent intervention that leverages EHR-based data and team-based care on medication adherence among patients with hypertension. METHODS: TEAMLET is a pragmatic, cluster randomized controlled trial in which 10 primary care practices will be randomized 1:1 to the multicomponent intervention or usual care. We will include all patients with hypertension and low medication adherence who are seen at enrolled practices. The primary outcome is medication adherence, as measured by the proportion of days covered, and the secondary outcome is clinic systolic blood pressure. We will also assess intervention implementation, including adoption, acceptability, fidelity, cost, and sustainability. RESULTS: As of May 2023, we have randomized 10 primary care practices into the study, with 5 practices assigned to each arm of the trial. The enrollment for the study commenced on October 5, 2022, and the trial is currently ongoing. We anticipate patient recruitment to go through the fall of 2023 and the primary outcomes to be assessed in the fall of 2024. CONCLUSIONS: The TEAMLET trial will evaluate the effectiveness of a multicomponent intervention that leverages EHR-based data and team-based care on medication adherence. If successful, the intervention could offer a scalable approach to address inadequate blood pressure control among millions of patients with hypertension. TRIAL REGISTRATION: ClinicalTrials.gov NCT05349422; https://clinicaltrials.gov/ct2/show/NCT05349422. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/47930.

Evaluating Whether an Inpatient Initiative to Time Lab Draws in the Evening Reduces Anemia.

BACKGROUND: Hospital acquired anemia is common during admission and can result in increased transfusion and length of stay. Recumbent posture is known to lead to lower hemoglobin measurements. We tested to see if an initiative promoting evening lab draws would lead to higher hemoglobin measurements due to more time in upright posture during the day and evening. METHODS: We included patients hospitalized on 2 medical units, beginning March 26, 2020 and discharged prior to January 25, 2021. On one of the units, we implemented an initiative to have routine laboratory draws in the evening rather than the morning starting on August 26, 2020. There were 1217 patients on the control unit and 1265 on the intervention unit during the entire study period. First we used a linear mixed-effects model to see if timing of blood draw was associated with hemoglobin level in the pre-intervention period. We then compared levels of hemoglobin before and after the intervention using a difference-in-difference analysis. RESULTS: In the pre-intervention period, evening blood draws were associated with higher hemoglobin compared to morning (0.28; 95% CI, 0.22-0.35). Evening blood draws increased with the intervention (10.3% vs 47.9%, P > 0.001). However, the intervention floor was not associated with hemoglobin levels in difference-in-difference analysis (coefficient of -0.15; 95% CI, -0.51-0.21). CONCLUSIONS: While evening blood draws were associated with higher hemoglobin levels, an intervention that successfully changed timing of routine labs to the evening did not lead to an increase in hemoglobin levels.

Self-reported adherence and reasons for nonadherence among patients with low proportion of days covered for antihypertension medications.

BACKGROUND: Incorporation of pharmacy fill data into the electronic health record has enabled calculations of medication adherence, as measured by proportion of days covered (PDC), to be displayed to clinicians. Although PDC values help identify patients who may be nonadherent to their medications, it does not provide information on the reasons for medication-taking behaviors. OBJECTIVE: To characterize self-reported adherence status to antihypertensive medications among patients with low refill medication adherence. Our secondary objective was to identify the most common reasons for nonadherence and examine the patient sociodemographic characteristics associated with these barriers. METHODS: Participants were adult patients seen in primary care clinics of a large, urban health system and on antihypertensive therapy with a PDC of less than 80% based on 6-month linked electronic health record-pharmacy fill data. We administered a validated medication adherence screener and a survey assessing reasons for antihypertensive medication nonadherence. We used descriptive statistics to characterize these data and logistic and Poisson regression models to assess the relationship between sociodemographic characteristics and adherence barriers. RESULTS: The survey was completed by 242 patients (57% female; 61.2% White; 79.8% not Latino/a or Hispanic). Of these patients, 45% reported missing doses of their medications in the last 7 days. In addition, 48% endorsed having at least 1 barrier to adherence and 38.4% endorsed 2 or more barriers. The most common barriers were being busy and having difficulty remembering to take medications. Compared with White participants, Black participants (incident rate ratio = 2.49; 95% CI = 1.93-3.22) and participants of other races (incident rate ratio = 2.16; 95% CI = 1.62-2.89) experienced a greater number of barriers. CONCLUSIONS: Nearly half of patients with low PDC reported nonadherence in the prior week, suggesting PDC can be used as a screening tool. Augmenting PDC with brief self-report tools can provide insights into the reasons for nonadherence. DISCLOSURES: Dr Kharmats, Ms Martinez, Dr Belli, Ms Zhao, Dr Mann, Dr Schoenthaler, and Dr Blecker received grants from the National Institute of Health/National Heart, Lung, Blood Institute. Dr Voils holds a license by Duke University for the DOSE-Nonadherence measure and is a consultant for New York University Grossman School of Medicine. This research was supported by the NIH (R01HL156355). Dr Kharmats received a postdoctoral training grant from the National Institutes of Health (5T32HL129953-04). Dr Voils was supported by a Research Career Scientist award from the Health Services Research & Development Service of the Department of Veterans Affairs (RCS 14-443). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the United States Government.

Protective Effect of 20(S)-Protopanaxadiol on D-Gal-Induced Cognitively Impaired Mice Based on Its Target Protein Brain-type Creatine Kinase.

Ginseng is an important medicinal herb consumed as dietary supplements. Ginsenosides and their metabolites have been reported to enhance cognitive performance, but their underlying mechanisms remain unclear. Brain-type creatine kinase (CK-BB) was previously screened out as one of the potential targets in brain tissues. In vitro, the strongest direct interaction between 20(S)-protopanaxadiol (PPD), a ginsenoside metabolite, and CK-BB was detected using biolayer interferometry (BLI). Drug affinity responsive target stability, cellular thermal shift assay, BLI, and isothermal titration calorimetry were subsequently used, and the binding of PPD to CK-BB was verified. The binding sites of the CK-BB/PPD complex were clarified by molecular docking and site-directed mutagenesis. Enzyme activity assay showed that the binding of PPD to CK-BB in vitro enhanced its activity. In vivo, PPD increased CK-BB activity in D-gal-induced mice. PPD also improved the D-gal-induced cognitive deficits and ameliorated alterations in oxidative stress and hippocampal synaptic plasticity. Therefore, the integration of PPD with its target protein CK-BB may promote CK-BB activity, thereby ameliorating hippocampal synaptic plasticity and cognitive deficits in D-gal-treated mice.

Metabolism, pharmacokinetics, and bioavailability of yuanhuacine in rat using LC-MS.

Yuanhuacine is a Daphne-type diterpene ortho-ester and is one of the main active ingredients of genkwa flos. Anticancer activity of yuanhuacine has been well investigated in various tumor cells and animal models, but information on metabolism and pharmacokinetics is limited. The aims of the present study were to investigate the metabolic and pharmacokinetic profiles of yuanhuacine in rat. The metabolic profile of yuanhuacine was obtained from rat plasma, urine, and feces using ultra-high-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry. A total of seven metabolites were detected, and the proposed metabolic pathways involved oxidation and glucuronidation. A simple and sensitive ultra-high-performance liquid chromatography-tandem mass spectrometry method was developed for the determination of yuanhuacine in rat plasma. The linear range of yuanhuacine was 1-1000 ng/ml (R2  = 0.998). The intra- and inter-precision (coefficient of variation %) of the assay was 3.86-6.18% and 2.65-5.75%, respectively, and the intra- and inter-accuracy (relative error %) was -3.83-4.77% and -3.03-5.11%, respectively. The extraction recovery, matrix effect, stability, and incurred sample reanalysis of yuanhuacine were within acceptable levels. The established method was validated and successfully applied to the preclinical pharmacokinetic study of yuanhuacine. The absolute oral bioavailability of yuanhuacine was calculated as 1.14%, and it reached the maximum plasma concentration of 28.21 ± 2.79 ng/ml in rat plasma at 2 h in the oral dosing group. The apparent volume of distribution of intravenous and intragastric administrations was 26.07 ± 6.45 and 21.83 ± 3.54 L/kg, respectively. The half-life of elimination of yuanhuacine was 9.64 ± 1.53 h in the intravenous dosing group.

ccTCM: A quantitative component and compound platform for promoting the research of traditional Chinese medicine.

Traditional Chinese medicine (TCM) databases play a vital role in bridging the gap between TCM and modern medicine, as well as in promoting the popularity of TCM. Elucidating the bioactive ingredients of Chinese medicinal materials is key to TCM modernization and new drug discovery. However, one drawback of current TCM databases is the lack of quantitative data on the constituents of Chinese medicinal materials. Herein, we present ccTCM, a web-based platform designed to provide a component and compound-content-based resource on TCM and analysis services for medical experts. In terms of design features, ccTCM combines resource distribution, similarity analysis, and molecular-mechanism analysis to accelerate the discovery of bioactive ingredients in TCM. ccTCM contains 273 Chinese medicinal materials commonly used in clinical settings, covering 29 functional classifications. By searching and comparing, we finally adopted 2043 studies, from which we collected the compounds contained in each TCM with content greater than 0.001 %, and a total of 1449 were extracted. Subsequently, we collected 40,767 compound-target pairs by integrating multiple databases. Taken together, ccTCM is a versatile platform that can be used by TCM scientists to perform scientific and clinical TCM studies based on quantified ingredients of Chinese medicinal materials. ccTCM is freely accessible at http://www.cctcm.org.cn.

Kangaroo Care for Relieving Neonatal Pain Caused by Invasive Procedures: A Systematic Review and Meta-Analysis.

Objective: Neonates develop significant pain responses during invasive procedures, and nonpharmacological interventions are better means of pain relief. An increasing number of studies have confirmed the effectiveness of kangaroo care (KC) in relieving neonatal pain caused by invasive procedures, but conclusions are inconsistent. In this study, a literature search and meta-analysis were performed to evaluate the effect of kangaroo care on relieving neonatal pain. Methods: The works of literature related to the application of KC in neonatal invasive procedures in the databases of Pubmed, Embase, Springer Link, Ovid, CNKI, and CBM were searched, and the RCT literature from database establishment to July 2022, was selected to evaluate the risk of bias, combined with statistical pain relief outcome indicators. Results: 12 pieces of literature were finally included in this study, with a total of 1172 newborns, including 585 newborns (49.9%) using KC and 587 newborns (50.1%) using the control group method. Meta-analysis showed that an infant's heart rate during invasive procedures under KC intervention was significantly lower than that of other interventions (MD = -6.77, 95% CI (-13.03, -0.50), Z = -2.12, P=0.03), but compared to other nonpharmacological interventions, there was no clear advantage in the overall evaluation of pain reduction in infants (MD = -0.36, 95% CI (-0.80, 0.08), Z = -1.60, P=0.11). Conclusion: The heart rate of KC intervention during invasive procedures in infants is significantly lower than that of other interventions, and it can significantly relieve pain in infants, but the effect is not more than that of oral sucrose (or glucose) or standard care. KC combined with oral sucrose may achieve a better pain relief effect in infants, but more studies are still needed to verify it.

Natural cell based biomimetic cellular transformers for targeted therapy of digestive system cancer.

Digestive system cancer is the most common cause of cancer death in the world. Although cancer treatment options are increasingly diversified, the mortality rate of malignant cancer of the digestive system remains high. Therefore, it is necessary to explore effective cancer treatment methods. Recently, biomimetic nanoparticle delivery systems based on natural cells that organically integrate the low immunogenicity, high biocompatibility, cancer targeting, and controllable, versatile functionality of smart nanocarrier design with natural cells have been expected to break through the bottleneck of tumor targeted therapy. In this review, we focus on the dynamic changes and complex cellular communications that occur in vivo in natural cells based vehicles. Recent studies on the development of advanced targeted drug delivery systems using the dynamic behaviors such as specific surface protein affinity, morphological changes, and phenotypic polarization of natural cells are summarized. In addition to drug delivery mediated by dynamic behavior, functional "delivery" based on the natural cell themselves is also involved. Aiming to make the best use of the functions of cells, providing clues for the development of advanced drug delivery platforms.

Target engagement of ginsenosides in mild cognitive impairment using mass spectrometry-based drug affinity responsive target stability.

Background: Mild cognitive impairment (MCI) is a transitional condition between normality and dementia. Ginseng is known to have effects on attenuating cognitive deficits in neurogenerative diseases. Ginsenosides are the main bioactive component of ginseng, and their protein targets have not been fully understood. Furthermore, no thorough analysis is reported in ginsenoside-related protein targets in MCI. Methods: The candidate protein targets of ginsenosides in brain tissues were identified by drug affinity responsive target stability (DARTS) coupled with label-free liquid chromatography-mass spectrometry (LC-MS) analysis. Network pharmacology approach was used to collect the therapeutic targets for MCI. Based on the above-mentioned overlapping targets, we built up a protein-protein interaction (PPI) network in STRING database and conducted gene ontology (GO) enrichment analysis. Finally, we assessed the effects of ginseng total saponins (GTS) and different ginsenosides on mitochondrial function by measuring the activity of the mitochondrial respiratory chain complex and performing molecular docking. Results: We screened 2526 MCI-related protein targets by databases and 349 ginsenoside-related protein targets by DARTS. On the basis of these 81 overlapping genes, enrichment analysis showed the mitochondria played an important role in GTS-mediated MCI pharmacological process. Mitochondrial function analysis showed GTS, protopanaxatriol (PPT), and Rd increased the activities of complex I in a dose-dependent manner. Molecular docking also predicted the docking pockets between PPT or Rd and mitochondrial respiratory chain complex I. Conclusion: This study indicated that ginsenosides might alleviate MCI by targeting respiratory chain complex I and regulating mitochondrial function, supporting ginseng's therapeutic application in cognitive deficits.

A possible mechanism to the antidepressant-like effects of 20 (S)-protopanaxadiol based on its target protein 14-3-3 ζ.

Background: Ginsenosides and their metabolites have antidepressant-like effects, but the underlying mechanisms remain unclear. We previously identified 14-3-3 ζ as one of the target proteins of 20 (S)-protopanaxadiol (PPD), a fully deglycosylated ginsenoside metabolite. Methods: Corticosterone (CORT) was administered repeatedly to induce the depression model, and PPD was given concurrently. The tail suspension test (TST) and the forced swimming test (FST) were used for behavioral evaluation. All mice were sacrificed. Golgi-cox staining, GSK 3ß activity assay, and Western blot analysis were performed. In vitro, the kinetic binding analysis with the Biolayer Interferometry (BLI) was used to determine the molecular interactions. Results: TST and FST both revealed that PPD reversed CORT-induced behavioral deficits. PPD also ameliorated the CORT-induced expression alterations of hippocampal Ser9 phosphorylated glycogen synthase kinase 3ß (p-Ser9 GSK 3ß), Ser133 phosphorylated cAMP response element-binding protein (p-Ser133 CREB), and brain-derived neurotrophic factor (BDNF). Moreover, PPD attenuated the CORT-induced increase in GSK 3ß activity and decrease in dendritic spine density in the hippocampus. In vitro, 14-3-3 ζ protein specifically bound to p-Ser9 GSK 3ß polypeptide. PPD promoted the binding and subsequently decreased GSK 3ß activity. Conclusion: These findings demonstrated the antidepressant-like effects of PPD on the CORT-induced mouse depression model and indicated a possible target-based mechanism. The combination of PPD with the 14-3-3 ζ protein may promote the binding of 14-3-3 ζ to p-GSK 3ß (Ser9) and enhance the inhibition of Ser9 phosphorylation on GSK 3ß kinase activity, thereby activating the plasticity-related CREB-BDNF signaling pathway.

A Spatial-Motion-Segmentation Algorithm by Fusing EDPA and Motion Compensation.

Motion segmentation is one of the fundamental steps for detection, tracking, and recognition, and it can separate moving objects from the background. In this paper, we propose a spatial-motion-segmentation algorithm by fusing the events-dimensionality-preprocessing algorithm (EDPA) and the volume of warped events (VWE). The EDPA consists of depth estimation, linear interpolation, and coordinate normalization to obtain an extra dimension (Z) of events. The VWE is conducted by accumulating the warped events (i.e., motion compensation), and the iterative-clustering algorithm is introduced to maximize the contrast (i.e., variance) in the VWE. We established our datasets by utilizing the event-camera simulator (ESIM), which can simulate high-frame-rate videos that are decomposed into frames to generate a large amount of reliable events data. Exterior and interior scenes were segmented in the first part of the experiments. We present the sparrow search algorithm-based gradient ascent (SSA-Gradient Ascent). The SSA-Gradient Ascent, gradient ascent, and particle swarm optimization (PSO) were evaluated in the second part. In Motion Flow 1, the SSA-Gradient Ascent was 0.402% higher than the basic variance value, and 52.941% faster than the basic convergence rate. In Motion Flow 2, the SSA-Gradient Ascent still performed better than the others. The experimental results validate the feasibility of the proposed algorithm.

αvß3 integrin-specific exosomes engineered with cyclopeptide for targeted delivery of triptolide against malignant melanoma.

BACKGROUND: Melanoma is the most malignant skin tumor and is difficult to cure with the alternative treatments of chemotherapy, biotherapy, and immunotherapy. Our previous study showed that triptolide (TP) exhibited powerful tumoricidal activity against melanoma. However, the clinical potential of TP is plagued by its poor aqueous solubility, short half-life, and biotoxicity. Therefore, developing an ideal vehicle to efficiently load TP and achieving targeted delivery to melanoma is a prospective approach for making full use of its antitumor efficacy. RESULTS: We applied exosome (Exo) derived from human umbilical cord mesenchymal stromal cells (hUCMSCs) and engineered them exogenously with a cyclic peptide, arginine-glycine-aspartate (cRGD), to encapsulate TP to establish a bionic-targeted drug delivery system (cRGD-Exo/TP), achieving synergism and toxicity reduction. The average size of cRGD-Exo/TP was 157.34 ± 6.21 nm, with a high drug loading of 10.76 ± 1.21%. The in vitro antitumor results showed that the designed Exo delivery platform could be effectively taken up by targeted cells and performed significantly in antiproliferation, anti-invasion, and proapoptotic activities in A375 cells via the caspase cascade and mitochondrial pathways and cell cycle alteration. Furthermore, the biodistribution and pharmacokinetics results demonstrated that cRGD-Exo/TP possessed superior tumor targetability and prolonged the half-life of TP. Notably, cRGD-Exo/TP significantly inhibited tumor growth and extended survival time with negligible systemic toxicity in tumor-bearing mice. CONCLUSION: The results indicated that the functionalized Exo platform provides a promising strategy for targeted therapy of malignant melanoma.

ScaleGCN: Efficient and Effective Graph Convolution via Channel-Wise Scale Transformation.

Graph convolutional networks (GCNs) have shown success in many graph-based applications as they can combine node features and graph topology to obtain expressive embeddings. While there exist numerous GCN variants, a typical graph convolution layer uses neighborhood aggregation and fully-connected (FC) layers to extract topological and node-wise features, respectively. However, when the receptive field of GCNs becomes larger, the tight coupling between the number of neighborhood aggregation and FC layers can increase the risk of over-fitting. Also, the FC layer between two successive aggregation operations will mix and pollute features in different channels, bringing noise and making node features hard to converge at each channel. In this article, we explore graph convolution without FC layers. We propose scale graph convolution, a new graph convolution using channel-wise scale transformation to extract node features. We provide empirical evidence that our new method has lower over-fitting risk and needs fewer layers to converge. We show from both theoretical and empirical perspectives that models with scale graph convolution have lower computational and memory costs than traditional GCN models. Experimental results on various datasets show that our method can achieve state-of-the-art results, in a cost-effective fashion.

Characterization of a Novel Carbapenem-Resistant Klebsiella michiganensis Strain Coharboring the blaSIM-1, blaOXA-1, blaCTX-M-14, qnrS, and aac(6')-Ib-cr Genes.

Carbapenem-resistant Klebsiella michiganensis (CRKM) and Klebsiella oxytoca (CRKO) strains have occasionally been reported to cause severe infections. However, SIM-producing K. michiganensis strains have never been described. In this study, we phenotypically and genetically characterized 6 CRKM and CRKO strains isolated over the past 10 years at a Chinese tertiary hospital. All six strains were positive for the mCIM test, and five were positive for the MBL test. Carbapenemase-encoding genes (blaKPC, blaNDM, blaVIM, blaIMP, blaOXA-23, blaOXA-24, blaOXA-51, and blaOXA-58) and another 12 resistance genes were screened by PCR, and blaKPC, blaNDM, and blaIMP were identified in five strains. However, the CRKM strain KM41, which was resistant to IPM and MEM with minimum inhibitory concentrations (MICs) of 4 µg/ml and 16 µg/ml, respectively, had positive mCIM and MBL results but lacked the eight carbapenemase-encoding genes. Whole-genome sequencing of the KM41 strain revealed more than 20 drug resistance genes; in particular, blaSIM-1, blaOXA-1, blaCTX-M-14, qnrS, aac(6')-Ib-cr, aadA17, and aar-3 were found to be located in a single plasmid. To the best of our knowledge, this is the first description of a K. michiganensis strain coharboring blaSIM-1, blaOXA-1, blaCTX-M-14, qnrS, and aac(6')-Ib-cr in China.