Dual-targeting of tumor cells and subcellular endoplasmic reticulum via AgPPIX-based Janus nanoparticles for photodynamic/immunotherapy against TNBC.

Triple-negative breast cancer (TNBC) is known for its strong invasiveness, high recurrence rates, and poor prognosis. Heme oxygenase-1 (HO-1) is closely related to tumor invasion, metastasis, recurrence and formation of tumor immunosuppression. The expression of HO-1 is high in TNBC and low in normal tissues. In this study, AgPPIX was synthesized as a heme oxygenase-1 (HO-1) inhibitor and a photosensitizer for TNBC therapy. PDA nanoparticles were synthesized and modified with anti-CD24 and p-toluenesulfonamide (PTSC) on their both sides to obtain PTSC@AgPPIX/PDA@anti-CD24 Janus nanoparticles (PAPC) for AgPPIX-targeted delivery. Anti-CD24 is targeted to CD24 on tumor cells and the PTSC moiety is targeted to endoplasmic reticulum (ER), where HO-1 is located. The results indicated that PAPC Janus nanoparticles exhibited higher cytotoxicity in 4T1 cells than that of the mono-modified nanoparticles. PAPC not only inhibited the expression of HO-1 and VEGF but also reduced TrxR activity significantly. Furthermore, PAPC not only promoted intracellular ROS production under laser irradiation for tumor photodynamic therapy (PDT) but also polarized TAMs from M2-type to M1 for tumor immunotherapy. In vivo experiments confirmed that PAPC could remodel the tumor immune microenvironment and almost completely inhibit the tumor growth in mouse models. Therefore, PAPC Janus nanoparticles are a promising nanoplatform with a dual-targeting capacity for TNBC immune/PDT synergistic therapy.

Finite-time prescribed performance tracking control of seeker stabilized platform in the discrete-time domain.

Current prescribed performance control (PPC) focuses on continuous-time systems, while this article proposes a novel discrete-time version of PPC for finite-time tracking of seeker stabilized platform in the discrete-time domain. Firstly, the newly developed performance functions are employed to impose finite-time prescribed performance on tracking errors. After that, a type of stabilization functions with respect to transformed errors are constructed for back-stepping controllers designing. On this basis, transformed errors are indirectly stabilized, and thus the pursued prescribed transient and steady-state behaviors are ensured for tracking errors via Lyapunov synthesis. Different from existing sliding-mode-control based discrete-time PPC, the addressed approach eliminates the sliding-mode structure and hence avoids high frequency chattering caused by such framework. Finally, compared simulations validate the superiority over existing methods.

Odontogenic infections in the antibiotic era: approach to diagnosis, management, and prevention.

PURPOSE: The prevalence of odontogenic infections remains one of the highest in the world. If untreated, odontogenic infections can break through the limitation, disseminate to other organs or spaces, and cause high mortality rates. However, it is still difficult to rapidly target limited or disseminated infections in clinical practice. The type of disseminated odontogenic infections and the responsible bacteria have not been described in detail. METHODS: Search databases (e.g., PubMed, MEDLINE, Web of Science, Embase) for reports published from 2018.1 to 2022.9. Use search strategies: ("odontogenic infections" OR "pulpitis" OR "periapical lesions" OR "periodontal diseases") AND ("disseminated infections" OR "complication"). RESULTS: Fourteen different types of disseminated odontogenic infections, most of which are polymicrobial infections, can spread through the body either direct or through hematogenous diffusion. Multiple microbial infections can be more invasive in the transmission of infection. Secondary infections are commonly associated with bacteria like Fusobacterium spp., Streptococcus spp., Peptostreptococcus spp., Prevotella spp., and Staphylococcus spp. Antibiotics with broad-spectrum activity are fundamental as first-line antimicrobial agents based on the microorganisms isolated from disseminated infections. CONCLUSION: This review elaborates on the epidemiology, microorganisms, risk factors, and dissemination routes, and provides evidence-based opinions on the diagnosis, multidisciplinary management, and prevention of odontogenic infections for dentists and clinicians.

Quantitative comparison of the renal pelvic urine and bladder urine to examine modifications of the urine proteome by the lower urinary tract.

PURPOSE: Urine proteome is a valuable reservoir of biomarkers for disease diagnosis and monitoring. Following formation as the plasma filtrate in the kidney, urine is progressively modified by the active reabsorption and secretion of the urinary tract. However, little is known about how the urine proteome changes as it passes along the urinary tract. EXPERIMENTAL DESIGN: To investigate this, we compared the proteome composition of the renal pelvis urine (RPU) and individually self-voided bladder urine (BU) collected from seven unilateral urinary tract obstruction male patients by LC-MS/MS screening. To our knowledge, this is the first proteomic comparison of RPU and BU samples from the same individual. RESULTS: Overall, RPU and BU proteomes did not exhibit proteins that were exclusively present in all samples of one urine type while in none of the other type. Nonetheless, BU had more overrepresented proteins that were observed at a higher frequency than RPU. Label-free quantitative analyses revealed BU-RPU differential proteins that are enriched in exosomes and extracellular proteins. However, the differences were not significant after corrections for multiple testing. Interestingly, we observed a significant increase of collagen peptides with hydroxyproline modifications in the BU samples, suggesting differences in protein modifications. CONCLUSIONS AND CLINICAL RELEVANCE: Our study revealed no substantial differences at the protein level between the BU and RPU samples. Future investigations with expanded cohorts would provide more insights about the urothelial-urinary interactions.

Shh-Gli2-Runx2 inhibits vascular calcification.

BACKGROUND: In patients with chronic kidney disease (CKD), vascular calcification (VC) is common and is associated with a higher risk of all-cause mortality. Shh, one ligand for Hedgehog (Hh) signaling, participates in osteogenesis and several cardiovascular diseases. However, it remains unclear whether Shh is implicated in the development of VC. METHODS: Inorganic phosphorus 2.6 mM was used to induce vascular smooth muscle cells (VSMCs) calcification. Mice were fed with adenine diet supplement with 1.2% phosphorus to induce VC. RESULTS: Shh was decreased in VSMCs exposed to inorganic phosphorus, calcified arteries in mice fed with an adenine diet, as well as radial arteries from patients with CKD presenting VC. Overexpression of Shh inhibited VSMCs ostosteoblastic differentiation and calcification, whereas its silencing accelerated these processes. Likewise, mice treated with smoothened agonist (SAG; Hh signaling agonist) showed alleviated VC, and mice treated with cyclopamine (CPN; Hh signaling antagonist) exhibited severe VC. Additionally, overexpression of Gli2 significantly reversed the pro-calcification effect of Shh silencing on VSMCs, suggesting that Shh inhibited VC via Gli2. Mechanistically, Gli2 interacted with Runx2 and promoted its ubiquitin proteasomal degradation, therefore protecting against VC. Of interest, the pro-degradation effect of Gli2 on Runx2 was independent of Smurf1 and Cullin4B. CONCLUSIONS: Our study provided deeper insight to the pathogenesis of VC, and Shh might be a novel potential target for VC treatment.

Characterizing the Influence of a Heterotrophic Bicosoecid Flagellate Pseudobodo sp. on the Dinoflagellate Gambierdiscus balechii.

Microbial interactions including competition, mutualism, commensalism, parasitism, and predation, which can be triggered by nutrient acquisition and chemical communication, are universal phenomena in the marine ecosystem. The interactions may influence the microbial population density, metabolism, and even their environmental functions. Herein, we investigated the interaction between a heterotrophic bicosoecid flagellate, Pseudobodo sp. (Bicoecea), and a dinoflagellate, Gambierdiscus balechii (Dinophyceae), which is a well-known ciguatera food poisoning (CFP) culprit. The presence of Pseudobodo sp. inhibited the algal proliferation and decreased the cardiotoxicity of zebrafish in the algal extract exposure experiment. Moreover, a significant difference in microbiome abundance was observed in algal cultures with and without Pseudobodo sp. Chemical analysis targeting toxins was performed by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) combined with molecular networking (MN), showing a significant alteration in the cellular production of gambierone analogs and some super-carbon chain compounds. Taken together, our results demonstrated the impact of heterotrophic flagellate on the photosynthetic dinoflagellates, revealing the complex dynamics of algal toxin production and the ecological relationships related to dinoflagellates in the marine environment.

Promotion framing effects on the purchase of hedonic-utilitarian bundles: ERPs evidence of the moderating role of income source.

Prior studies suggest that people are susceptible to the promotion framing effect. Yet it's still unknown if income source moderates the effect of promotion frame on consumer decision-making and the underlying neural responses. The current study applied the event-related potentials (ERPs) approach to exploring the moderating role of income source (hard-earned income and windfall income) on the promotion framing effect in a cross-category bundling context. Two promotion frames were created with identical total prices for a cross-category bundle that included both hedonic and utilitarian products. The behavioral results showed that income source moderated the effect of promotion frame on neural responses and purchase decision-making. When participants obtained a hard-earned income, they showed an attenuated N2, an enlarged LPP amplitude, and a higher purchase rate in the hedonic (vs. utilitarian) freebie condition; but when they obtained a windfall income, the effect of promotion frame disappeared. Overall, the conclusions have important ramifications for both theory and practice.

Wnt3a signaling with serum supply induces replication stress in cultured cells.

Wnt signaling plays a central role in tissue development and homeostasis, and its deregulation is implicated in many human diseases, including cancer. As an essential posttranslational modification, protein phosphorylation is critical in Wnt signaling and has been a focus of investigation using systematic approaches, including proteomics. Typically, studies were conducted by applying purified Wnt ligands to cells in a "starvation" condition to minimize the background noise. Despite leading to many important discoveries, such an approach may omit pivotal integrative effects of Wnt signaling in a complex physiological environment. In this study, we investigated the temporal dynamics of the phosphoproteome following treatments of Wnt3a conditioned medium (CM) with serum supply. This revealed three clusters of phosphoproteome changes with distinct temporal profiles with implications in gene expressions and chromatin organizations. Among these, we observed enhanced phosphorylation at the Thr543 residue of 53BP1, which is a key event in the cellular response to DNA damage. Functionally, it triggered the replication stress response pathway mediated by γH2AX accumulation and Chk1 activation, leading to a significant reduction of cells in the S phase of the cell cycle. Intriguingly, Wnt3a treatment in the serum-free condition did not activate 53BP1-Chk1 and replication stress response. Our study indicates the importance of noting the presence or absence of serum supply when studying the signaling pathways.

Constructing multiple active sites in iron oxide catalysts for improving carbonylation reactions.

Surface engineering is a promising strategy to improve the catalytic activities of heterogeneous catalysts. Nevertheless, few studies have been devoted to investigate the catalytic behavior differences of the multiple metal active sites triggered by the surface imperfections on catalysis. Herein, oxygen vacancies induced Fe2O3 catalyst are demonstrated with different Fe sites around one oxygen vacancy and exhibited significant catalytic performance for the carbonylation of various aryl halides and amines/alcohols with CO. The developed catalytic system displays excellent activity, selectivity, and reusability for the synthesis of carbonylated chemicals, including drugs and chiral molecules, via aminocarbonylation and alkoxycarbonylation. Combined characterizations disclose the formation of oxygen vacancies. Control experiments and density functional theory calculations demonstrate the selective combination of the three Fe sites is vital to improve the catalytic performance by catalyzing the elemental steps of PhI activation, CO insertion and C-N/C-O coupling respectively, endowing combinatorial sites catalyst for multistep reactions.

4D Printing of Personalized-Tunable Biomimetic Periosteum with Anisotropic Microstructure for Accelerated Vascularization and Bone Healing.

An ideal biomimetic periosteum is expected to wrap various bone surfaces to orchestrate an optimal microenvironment for bone regeneration, including facilitating local vascularization, recruiting osteoblasts, and mineralizing the extracellular matrix (ECM). To mimic the role of the natural periosteum in promoting bone repair, a 4D printing technique to inlay aligned cell sheets on shape-shifting hydrogel is used, containing biophysical signals and spatially adjustable physical properties, for the first time. The outer hydrogel layer endows the biomimetic periosteum with the ability to digitally coordinate its 3D geometry to match the specific macroscopic bone shape to maintain a bone healing microenvironment. The inner aligned human mesenchymal stem cells (hMSCs) layer not only promotes the migration and angiogenesis of co-cultured cells but also exhibits excellent osteogenic differentiation properties. In vivo experiments show that apart from morphing preset shapes as physical barriers, the aligned biomimetic periosteum can actively facilitate local angiogenesis and early-stage osteogenesis. Altogether, this present work provides a novel route to construct a personalized biomimetic periosteum with anisotropic microstructure by introducing a tunable shape to maintain the bone reconstruction microenvironment and this strategy can be extended to repair sophisticated bone defects.

Hedgehog signaling is a potential therapeutic target for vascular calcification.

BACKGROUND: Patients with chronic kidney disease (CKD) suffered from vascular calcification (VC), one major contributor for their increased mortality rate. Hedgehog (Hh) signaling plays a crucial role in physiological bone mineralization and is associated with several cardiovascular diseases. However, the molecular changes underlying VC is ill defined and it remains unclear whether Hh signaling intervention affects VC. METHODS: We constructed human primary vascular smooth muscle cell (VSMC) calcification model and performed RNA sequencing. Alizarin red staining and calcium content assay were conducted to identify the occurrence of VC. Three different R packages were applied to determine differentially expressed genes (DEGs). Enrichment analysis and protein-protein interaction (PPI) network analysis were carried out to explore the biological roles of DEGs. qRT-PCR assay was then applied to validate the expression of key genes. By using Connectivity Map (CMAP) analysis, several small molecular drugs targeting these key genes were obtained, including SAG (Hedgehog signaling activator) and cyclopamine (CPN) (Hedgehog signaling inhibitor), which were subsequently used to treat VSMC. RESULTS: Obvious Alizarin red staining and increased calcium content identified the occurrence of VC. By integrating results from three R packages, we totally obtained 166 DEGs (86 up-regulated and 80 down-regulated), which were significantly enriched in ossification, osteoblast differentiation, and Hh signaling. PPI network analysis identified 10 key genes and CMAP analysis predicted several small molecular drugs targeting these key genes including chlorphenamine, isoeugenol, CPN and phenazopyridine. Notably, our in vitro experiment showed that SAG markedly alleviated VSMC calcification, whereas CPN significantly exacerbated VC. CONCLUSIONS: Our research provided deeper insight to the pathogenesis of VC and indicated that targeting Hh signaling pathway may represent a potential and effective therapy for VC.

Ultraviolet Light-Based Micropattern Printing on Titanium Surfaces to Promote Early Osseointegration.

Patterned interfaces are widely used for surface modification of biomaterials because of a morphological unit similar to that of native tissue. However, engineering fast and cost-effective high-resolution micropatterns directly onto titanium surfaces remains a grand challenge. Herein, a simply designed ultraviolet (UV) light-based micropattern printing to obtain geometrical patterns on implant interfaces is fabricated by utilizing customized photomasks and titanium dioxide (TiO2 ) nanorods as a photo-responsive platform. The technique manipulates the cytoskeleton of micropatterning cells on the surface of TiO2 nanorods. The linear pattern surface shows the elongated morphology and parallel linear arrangements of human mesenchymal stem cells (hMSCs), significantly enhancing their osteogenic differentiation. In addition to the upregulated expression of key osteo-specific function genes in vitro, the accelerated osseointegration between the implant and the host bone is obtained in vivo. Further investigation indicates that the developed linear pattern surface has an outstanding effect on the cytoskeletal system, and finally activates Yes-Associated Protein (YAP)-mediated mechanotransduction pathways, initiating hMSCs osteogenic differentiation. This study not only offers a microfabrication method that can be extended to fabricate various shape- and size-controlled micropatterns on titanium surfaces, but also provides insight into the surface structure design for enhanced bone regeneration.

Exogenous L-lactate administration in rat hippocampus increases expression of key regulators of mitochondrial biogenesis and antioxidant defense.

L-lactate plays a critical role in learning and memory. Studies in rats showed that administration of exogenous L-lactate into the anterior cingulate cortex and hippocampus (HPC) improved decision-making and enhanced long-term memory formation, respectively. Although the molecular mechanisms by which L-lactate confers its beneficial effect are an active area of investigations, one recent study found that L-lactate supplementation results in a mild reactive oxygen species burst and induction of pro-survival pathways. To further investigate the molecular changes induced by L-lactate, we injected rats with either L-lactate or artificial CSF bilaterally into the dorsal HPC and collected the HPC after 60 minutes for mass spectrometry. We identified increased levels of several proteins that include SIRT3, KIF5B, OXR1, PYGM, and ATG7 in the HPC of the L-lactate treated rats. SIRT3 (Sirtuin 3) is a key regulator of mitochondrial functions and homeostasis and protects cells against oxidative stress. Further experiments identified increased expression of the key regulator of mitochondrial biogenesis (PGC-1α) and mitochondrial proteins (ATPB, Cyt-c) as well as increased mitochondrial DNA (mtDNA) copy number in the HPC of L-lactate treated rats. OXR1 (Oxidation resistance protein 1) is known to maintain mitochondrial stability. It mitigates the deleterious effects of oxidative damage in neurons by inducing a resistance response against oxidative stress. Together, our study suggests that L-lactate can induce expression of key regulators of mitochondrial biogenesis and antioxidant defense. These findings create new research avenues to explore their contribution to the L-lactate's beneficial effect in cognitive functions as these cellular responses might enable neurons to generate more ATP to meet energy demand of neuronal activity and synaptic plasticity as well as attenuate the associated oxidative stress.

Efficacy of Continuous Renal Replacement Therapy and Intermittent Hemodialysis in Patients with Renal Failure in Intensive Care Unit: A Systemic Review and Meta-analysis.

Objective: This study aimed to compare the clinical efficacy of continuous renal replacement therapy (CRRT) and intermittent hemodialysis (IHD) in patients with renal failure in intensive care unit (ICU). Methods: Relevant studies were searched in the databases including EMBASE, Cochrane Library, and MEDLINE (PubMed) from inception to January 04, 2021. The inclusion of available studies and the collection of data were independently conducted by two authors after reviewing the full text. Pooled analyses of relative risk (RR) and weighted mean difference (WMD) were performed to compare the outcomes of renal recovery, short-term mortality, length of ICU stays, and length of in-hospital stays between the two different treatment groups. Publication bias was assessed by the funnel plot. Results: A total of 11 RCT studies including 1740 patients with renal failure were eligible for final analysis. Among them, 894 patients (51.4%) underwent CRRT and 846 patients (48.6%) received IHD. Pooled analysis did not find significant differences in renal recovery and short-term mortality between the two groups. Interestingly, patients underwent CRRT showed significantly shorter length of ICU stay and in-hospital stay than those who underwent IHD (ICU stay: RR: -0.61, 95%CI: -1.10--0.11, P < 0.05; I2 = 93.6%; in-hospital stay: RR: -0.56, 95%CI: -1.41-0.28, P < 0.05; I2 = 97.7%). No significant publication biases were observed on the funnel plots. Conclusion: Compared with IHD, CRRT had similar effects on renal recovery and short-term mortality in patients with renal failure in ICU. As a promising technique in clinical practice, CRRT could significantly reduce the length of ICU stay and in-hospital stay of patients, which was of great significance for the reduction of medical costs and the long-term benefits of patients, thereby reducing the burden on society and individuals.

Selective Targeting of Class I HDAC Reduces Microglial Inflammation in the Entorhinal Cortex of Young APP/PS1 Mice.

BG45 is a class Ⅰ histone deacetylase inhibitor (HDACI) with selectivity for HDAC3. Our previous study demonstrated that BG45 can upregulate the expression of synaptic proteins and reduce the loss of neurons in the hippocampus of APPswe/PS1dE9 (APP/PS1) transgenic mice (Tg). The entorhinal cortex is a pivotal region that, along with the hippocampus, plays a critical role in memory in the Alzheimer's disease (AD) pathology process. In this study, we focused on the inflammatory changes in the entorhinal cortex of APP/PS1 mice and further explored the therapeutic effects of BG45 on the pathologies. The APP/PS1 mice were randomly divided into the transgenic group without BG45 (Tg group) and the BG45-treated groups. The BG45-treated groups were treated with BG45 at 2 months (2 m group), at 6 months (6 m group), or twice at 2 and 6 months (2 and 6 m group). The wild-type mice group (Wt group) served as the control. All mice were killed within 24 h after the last injection at 6 months. The results showed that amyloid-ß (Aß) deposition and IBA1-positive microglia and GFAP-positive astrocytes in the entorhinal cortex of the APP/PS1 mice progressively increased over time from 3 to 8 months of age. When the APP/PS1 mice were treated with BG45, the level of H3K9K14/H3 acetylation was improved and the expression of histonedeacetylase1, histonedeacetylase2, and histonedeacetylase3 was inhibited, especially in the 2 and 6 m group. BG45 alleviated Aß deposition and reduced the phosphorylation level of tau protein. The number of IBA1-positive microglia and GFAP-positive astrocytes decreased with BG45 treatment, and the effect was more significant in the 2 and 6 m group. Meanwhile, the expression of synaptic proteins synaptophysin, postsynaptic density protein 95, and spinophilin was upregulated and the degeneration of neurons was alleviated. Moreover, BG45 reduced the gene expression of inflammatory cytokines interleukin-1ß and tumor necrosis factor-α. Closely related to the CREB/BDNF/NF-kB pathway, the expression of p-CREB/CREB, BDNF, and TrkB was increased in all BG45 administered groups compared with the Tg group. However, the levels of p-NF-kB/NF-kB in the BG45 treatment groups were reduced. Therefore, we deduced that BG45 is a potential drug for AD by alleviating inflammation and regulating the CREB/BDNF/NF-kB pathway, and the early, repeated administration of BG45 can play a more effective role.

Comparative analysis of outer membrane vesicles from uropathogenic Escherichia coli reveal the role of aromatic amino acids synthesis proteins in motility.

Uropathogenic Escherichia coli (UPEC) are causative agent that causes urinary tract infections (UTIs) and the recent emergence of multidrug resistance (MDR) of UPEC increases the burden on the community. Recent studies of bacterial outer membrane vesicles (OMV) identified various factors including proteins, nucleic acids, and small molecules which provided inter-cellular communication within the bacterial population. However, the components of UPEC-specific OMVs and their functional role remain unclear. Here, we systematically determined the proteomes of UPEC-OMVs and identified the specific components that provide functions to the recipient bacteria. Based on the functional network of OMVs' proteomes, a group of signaling peptides was found in all OMVs which provide communication among bacteria. Moreover, we demonstrated that treatment with UPEC-OMVs affected the motility and biofilm formation of the recipient bacteria, and further identified aromatic amino acid (AAA) biosynthesis proteins as the key factors to provide their movement.

A Class I HDAC Inhibitor BG45 Alleviates Cognitive Impairment through the CaMKII/ITPKA/Ca2+ Signaling Pathway.

Alzheimer's disease (AD) seriously endangers the health and life of elderly individuals worldwide. However, despite all scientific efforts, at the moment there are no effective clinical treatment options for AD. In this work, the effect of the class I histone deacetylase inhibitor (HDACI) BG45 on synapse-related proteins was investigated in primary neurons from APP/PS1 transgenic mice. The results showed that BG45 can upregulate the expression of synaptotagmin-1 (SYT-1) and neurofilament light chain (NF-L) in primary neurons. In vivo, the APPswe/PS1dE9 (APP/PS1) transgenic mice were treated with BG45 (30 mg/kg) daily for 12 days. Behavioral testing of BG45-treated APP/PS1 mice showed improvements in learning and memory. BG45 can alleviate damage to the dendritic spine and reduce the deposition of Aß. Similar to the in vitro results, synapse-related proteins in the prefrontal cortex were increased after BG45 treatment. Proteomic analysis results highlighted the differences in the biological processes of energy metabolism and calmodulin regulation in APP/PS1 mice with or without BG45 treatment. Further verification demonstrated that the effect of BG45 on synapses and learning and memory may involve the CaMKII/ITPKA/Ca2+ pathway. These results suggest that class I HDACI BG45 might be a promising drug for the early clinical treatment of AD.

The use of a technology-assisted and teacher-supervised online discussion platform to promote academic progress in blended embryology courses.

BACKGROUND: Students' engagement with learning materials and discussions with teachers and peers before and after lectures are among the keys to the successful implementation of blended programs. Mixed results have been reported by previous studies on blended learning. This study evaluated the effectiveness of embedding a teacher-supervised online discussion platform in a blended embryology course in terms of its impact on students' capabilities to handle difficult and cognitively challenging tasks. METHODS: Two forms of blended learning were investigated and compared in this study. Students in the control group (n = 85) learned online materials before each class, followed by classroom instruction and activities in which face-to-face discussion and communication between students were encouraged. Students in the experimental group (n = 83) followed a similar procedure with an additional teacher-supervised online discussion platform to guide, supervise and evaluate their learning progress. All participants were first-year medical students in clinical medicine at Dalian Medical University who had enrolled in 2017. All participants took the final exam to test their learning outcomes. RESULTS: The embryology grades of students in the experimental group were significantly higher than those of students in the control group (p = 0.001). Additionally, the scores of students in the experimental group on questions with a high difficulty level (p = 0.003) and questions assessing high-order cognitive skills (p = 0.003) were higher than those of students in the control group; the effect size was moderate (η2 > 0.05). CONCLUSIONS: In blended embryology courses, compared with learner-led and face-to-face discussion, the teacher-supervised online discussion platform has great potential to enable students to achieve higher grades and solve difficult and cognitively challenging tasks.

A Class I HDAC Inhibitor Rescues Synaptic Damage and Neuron Loss in APP-Transfected Cells and APP/PS1 Mice through the GRIP1/AMPA Pathway.

As a neurodegenerative disease, Alzheimer's disease (AD) seriously affects the health of older people. Changes in synapses occur first over the course of the disease, perhaps even before the formation of Aß plaques. Histone deacetylase (HDAC) mediates the damage of Aß oligomers to dendritic spines. Therefore, we examined the relationship between HDAC activity and synaptic defects using an HDAC inhibitor (HDACI), BG45, in the human neuroblastoma SH-SY5Y cell line with stable overexpression of Swedish mutant APP (APPsw) and in APP/PS1 transgenic mice during this study. The cells were treated with 15 µM BG45 and the APP/PS1 mice were treated with 30 mg/kg BG45. We detected the levels of synapse-related proteins, HDACs, tau phosphorylation, and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors using Western blotting and immunohistochemistry. We also measured the expression of cytoskeletal proteins in the cell model. The mRNA levels of the glutamate ion receptor alginate subunit 2 (GRIK2), sodium voltage-gated channel beta subunit (SCN3B), synaptophysin (SYP), Grm2 (the gene encoding glutamate receptor subunit 2 (GluR2)), Grid2IP, glutamate receptor interacting protein 1 (GRIP1), and GRIP2 were detected to explore the effects of the HDACI on regulating the expression of synaptic proteins and AMPA receptors. According to our studies, the expressions of HDAC1, HDAC2, and HDAC3 were increased, which were accompanied by the downregulation of the synapse-related proteins SYP, postsynaptic dendritic protein (PSD-95), and spinophilin as early as 24 h after transfection with the APPsw gene. BG45 upregulated the expression of synapse-related proteins and repaired cytoskeletal damage. In vivo, BG45 alleviated the apoptosis-mediated loss of hippocampal neurons, upregulated synapse-related proteins, reduced Aß deposition and phosphorylation of tau, and increased the levels of the synapse-related genes GRIK2, SCN3B, SYP, Grm2, and Grid2IP. BG45 increased the expression of the AMPA receptor subunits GluA1, GluA2, and GluA3 on APPsw-transfected cells and increased GRIP1 and GRIP2 expression and AMPA receptor phosphorylation in vivo. Based on these results, HDACs are involved in the early process of synaptic defects in AD models, and BG45 may rescue synaptic damage and the loss of hippocampal neurons by specifically inhibiting HDAC1, HDAC2, and HDAC3, thereby modulating AMPA receptor transduction, increasing synapse-related gene expression, and finally enhancing the function of excitatory synapses. BG45 may be considered a potential drug for the treatment of early AD in further studies.

Identification of Potential Core Genes for the Rupture of Intracranial Aneurysms by a Bioinformatics Analysis.

Background: Previous studies, using autopsy and angiography, have shown that 3.6-6% of the population have intracranial aneurysms, and the rupture of aneurysm can lead to brain dysfunction or even death in patients. Methods: To explore potential preventional target genes for the ruptured of aneurysm, we analyze three gene expression datasets (GSE13353, GSE15629 and GSE54083) derived from the GEO database. We confirm DEGs associated with the unrupture of aneurysms by R package. DAVID version provides functional classification and annotation analyses of associated genes, including GO and KEGG pathway. PPI of these DEGs is analyzed based on the string database and visualized by Cytoscape software. DEGs are verified by qRT-PCR using samples isolated from the patients. Results: 249 overlapping DEGs, including 96 up-regulated genes and 153 down-regulated genes are screened using the Venn diagram webtool. The GO term and KEGG pathways analysis results indicate that these DEGs are mainly enriched in protein phosphorylation, apoptotic process and inflammatory response in the BP term and focal adhesion, thyroid hormone signaling pathway, ErbB signaling pathway, cytokine-cytokine receptor interaction and some disease processes in the KEGG pathways. 6 candidates are confirmed by Cytoscape software and qRT-PCR, including APP, JUN, GSK3B, ErbB2, PPBP and THBS1. Conclusions: Our data and previous studies show that ErbB2 and THBS1 are crucial to prevent aneurysm rupture, while APP, JUN, GSK3B and PPBP performs the opposite role, and further experiments are needed to verify these findings.