The Contact Interface Electronic Coupling of Cobalt and Zirconia Enables Stable and Highly Efficient 4e- Oxygen Reduction Reaction Catalysis.

Cobalt (Co) is an efficient oxygen reduction reaction (ORR) catalyst but suffers from issues of easy deactivation and instability. Here, it shows that ZrO2 can stabilize Co through interface electron coupling and enables highly efficient 4e- ORR catalysis. Porous carbon nanofibers loaded with dispersed Co-nanodots (≈10 nm, 9.63 wt%) and ZrO2 nanoparticles are synthesized as the catalyst. The electron transfer from the metallic Co to ZrO2 causes interface-oriented electron enrichment that promotes the activation and conversion of O2, improving the efficiency of 4e- transfer. Moreover, the simulation results show that ZrO2 acts like an electron reservoir to store electrons from Co and slowly release them to the interface, solving the easy deactivation problem of Co. The catalyst exhibits a high half-wave potential (E1/2) of 0.84 V, which only decreases by 3.6 mV after 10 000 cycles, showing great stability. Particularly, the enhanced spin polarization of Co in a magnetic field reinforces the interface electron coupling that increases the E1/2 to 0.864 V and decreases the energy barrier of ORR from 0.81 to 0.63 eV, confirming that the proposed strategy is effective for constructing efficient and stable ORR catalysts.

Assessment of right ventricular diastolic function in pediatric patients with repaired tetralogy of Fallot by cardiovascular magnetic resonance and echocardiography.

OBJECTIVES: Cardiovascular magnetic resonance (CMR) imaging is routinely performed for assessing right ventricular (RV) systolic but not diastolic function. We aimed to investigate CMR-based assessment of RV diastolic function in pediatric patients with repaired tetralogy of Fallot (rTOF), compared to transthoracic echocardiography (TTE) measurements. METHODS: A total of 130 consecutive pediatric patients with rTOF who underwent clinically indicated CMR and same-day TTE were included. Forty-three controls were recruited. Phase-contrast images were used to measure trans-tricuspid valve flow velocities during early (E) and late diastolic (A) phases (measured in cm/s). Feature tracking of the tricuspid annulus was performed to derive early (e') and late diastolic (a') myocardial velocities (measured in cm/s). RV diastolic function was evaluated by E/A ratio, E/e' ratio, and E-wave deceleration time (measured in milliseconds). Regression analyses were utilized to identify potential variables associated with RV diastolic dysfunction (DD). The performance of CMR-derived parameters in diagnosing RV DD was assessed using receiver-operating characteristic analyses. RESULTS: Good agreement was found between CMR and TTE measurements (ICC 0.70-0.89). Patients with RV DD (n = 67) showed significantly different CMR-derived parameters including E and e' velocities, and E/A and E/e' ratio, compared to patients without DD (n = 63) (all p < 0.05). CMR-derived E and e' velocities and E/e' ratio were independent predictors of RV DD. E/e' of 5.8 demonstrated the highest discrimination of RV DD (AUC 0.76, sensitivity 70%, specificity 86%). CONCLUSIONS: CMR-derived parameters showed good agreement with TTE parameters in determining RV DD. CMR-derived E/e' was proved to be the most effective in identifying RV DD. CLINICAL RELEVANCE STATEMENT: This study demonstrated the feasibility and efficacy of CMR in assessing diastolic function in pediatric patients. RV DD was presented in over half of patients according to current TTE guidelines, highlighting the need for assessing RV diastolic function during follow-up. KEY POINTS: • Routinely acquired cine and phase-contrast cardiovascular magnetic resonance (CMR) images yielded right ventricular (RV) diastolic parameters which demonstrated good agreement with transthoracic echocardiography (TTE) measurements. • There was a high prevalence of RV diastolic function impairment in pediatric patients with repaired tetralogy of Fallot (rTOF). • CMR is a reliable complementary modality of TTE for RV diastolic function evaluation.

Pilot-scale investigation of performance and microbial community in a novel system combining fixed and suspended activated sludge.

The conventional activated sludge (CAS) process is a widely used method for wastewater treatment due to its effectiveness and affordability. However, it can be prone to sludge abnormalities such as sludge bulking/foaming and sludge loss, which can lead to a decrease in treatment efficiency. To address these issues, a novel bag-based fixed activated sludge (BBFAS) system utilizing mesh bags to contain the sludge was developed for low carbon/nitrogen ratio wastewater treatment. Pilot-scale experiments demonstrated that the BBFAS system could successfully avoid the sludge abnormalities. Moreover, it was not affected by mass transfer resistance and exhibited significantly higher nitrogen removal efficiency, surpassing that of the CAS system by up to 78%. Additionally, the BBFAS system demonstrated comparable organic matter removal efficiency to CAS system. 16S rRNA gene high-throughput sequencing revealed that the bacterial community structure within the BBFAS system was significantly different from that of the CAS system. The bacteria associated with ammonium removal were more abundant in the BBFAS system than in the CAS system. The abundance of Nitrospira in the BBFAS could reach up to 6% and significantly higher than that in the CAS system, and they were likely responsible for both ammonia-oxidizing and nitrite-oxidizing functions. Clear stratification of microbial communities was observed from the outer to inner layers of the bag components due to the gradients of dissolved oxygen and other substrates. Overall, this study presents a promising approach for avoiding activated sludge abnormalities while maintaining high pollutant removal performance.

Metal ions-anchored bacterial outer membrane vesicles for enhanced ferroptosis induction and immune stimulation in targeted antitumor therapy.

The activation of ferroptosis presents a versatile strategy for enhancing the antitumor immune responses in cancer therapy. However, developing ferroptosis inducers that combine high biocompatibility and therapeutic efficiency remains challenging. In this study, we propose a novel approach using biological nanoparticles derived from outer membrane vesicles (OMVs) of Escherichia coli for tumor treatment, aiming to activate ferroptosis and stimulate the immune responses. Specifically, we functionalize the OMVs by anchoring them with ferrous ions via electrostatic interactions and loading them with the STING agonist-4, followed by tumor-targeting DSPE-PEG-FA decoration, henceforth referred to as OMV/SaFeFA. The anchoring of ferrous ions endows the OMVs with peroxidase-like activity, capable of inducing cellular lipid peroxidation by catalyzing H2O2 to •OH. Furthermore, OMV/SaFeFA exhibits pH-responsive release of ferrous ions and the agonist, along with tumor-targeting capabilities, enabling tumor-specific therapy while minimizing side effects. Notably, the concurrent activation of the STING pathway and ferroptosis elicits robust antitumor responses in colon tumor-bearing mouse models, leading to exceptional therapeutic efficacy and prolonged survival. Importantly, no acute toxicity was observed in mice receiving OMV/SaFeFA treatments, underscoring its potential for future tumor therapy and clinical translation.

Transcatheter Aortic Valve Replacement and Coronary Protection Guided by Deep Learning and 3-Dimensional Printing.

OBJECTIVE: In this case report, the auxiliary role of deep learning and 3-dimensional printing technology in the perioperative period was discussed to guide transcatheter aortic valve replacement and coronary stent implantation simultaneously. CASE PRESENTATION: A 68-year-old man had shortness of breath and chest tightness, accompanied by paroxysmal nocturnal dyspnea, 2 weeks before presenting at our hospital. Echocardiography results obtained in the outpatient department showed severe aortic stenosis combined with regurgitation and pleural effusion. The patient was first treated with closed thoracic drainage. After 800 mL of pleural effusion was collected, the patient's symptoms were relieved and he was admitted to the hospital. Preoperative transthoracic echocardiography showed severe bicuspid aortic valve stenosis combined with calcification and aortic regurgitation (mean pressure gradient, 42 mmHg). Preoperative computed tomography results showed a type I bicuspid aortic valve with severe eccentric calcification. The leaflet could be seen from the left coronary artery plane, which indicated an extremely high possibility of coronary obstruction. After preoperative imaging assessment, deep learning and 3-dimensional printing technology were used for evaluation and simulation. Guided transcatheter aortic valve replacement and a coronary stent implant were completed successfully. Postoperative digital subtraction angiography showed that the bioprosthesis and the chimney coronary stent were in ideal positions. Transesophageal echocardiography showed normal morphology without paravalvular regurgitation. CONCLUSION: The perioperative guidance of deep learning and 3-dimensional printing are of great help for surgical strategy formulation in patients with severe bicuspid aortic valve stenosis with calcification and high-risk coronary obstruction.

[Clinical and genetic analysis of a child with Canavan disease due to compound heterozygous variants of ASPA gene].

OBJECTIVE: To analyze the clinical phenotype and genetic characteristics for a child with Canavan disease. METHODS: A child who was admitted to the Children's Hospital Affiliated to Shandong University on April 9, 2021 for inability to uphold his head for 2 months and increased muscle tone for one week was subjected to whole exome sequencing, and candidate variants were verified by Sanger sequencing. RESULTS: Genetic testing revealed that the child has harbored compound heterozygous variants of the ASPA gene, including a paternally derived c.556_559dupGTTC (p. L187Rfs*5) and a maternally derived c.919delA (p. S307Vfs*24). Based on the guidelines from the American College of Medical Genetics and Genomics, both variants were predicted to be pathogenic (PVS1+PM2_Supporting+PM3). CONCLUSION: The c.556_559dupGTTC (p.L187Rfs*5) and c.919delA (p.S307Vfs*24) compound heterozygous variants of the ASPA gene probably underlay the pathogenesis of Canavan disease in this child.

KAT2A-mediated succinylation modification of notch1 promotes the proliferation and differentiation of dental pulp stem cells by activating notch pathway.

BACKGROUND: Dental pulp stem cells (DPSCs) are a kind of undifferentiated dental mesenchymal stem cells with strong self-renewal ability and multi-differentiation potential. This study aimed to investigate the regulatory functions of succinylation modification in DPSCs. METHODS: DPSCs were isolated from the dental pulp collected from healthy subjects, and then stem cell surface markers were identified using flow cytometry. The osteogenic differentiation ability of DPSCs was verified by alkaline phosphatase (ALP) and alizarin red staining methods, while adipogenic differentiation was detected by oil red O staining. Meanwhile, the mRNA of two desuccinylases (SIRT5 and SIRT7) and three succinylases (KAT2A, KAT3B, and CPT1A) in DPSCs before and after mineralization induction were detected using quantitative real-time PCR. The cell cycle was measured by flow cytometry, and the expression of bone-specific genes, including COL1a1 and Runx2 were evaluated by western blotting and were combined for the proliferation and differentiation of DPSCs. Co-immunoprecipitation (co-IP) and immunofluorescence were combined to verify the binding relationship between proteins. RESULTS: The specific markers of mesenchymal stem cells were highly expressed in DPSCs, while the osteogenic differentiation ability of isolated DPSCs was confirmed via ALP and alizarin red staining. Similarly, the oil red O staining also verified the adipogenic differentiation ability of DPSCs. The levels of KAT2A were found to be significantly upregulated in mineralization induction, which significantly decreased the ratio of G0/G1 phase and increased S phase cells; converse results regarding cell cycle distribution were obtained when KAT2A was inhibited. Moreover, overexpression of KAT2A promoted the differentiation of DPSCs, while its inhibition exerted the opposite effect. The elevated KAT2A was found to activate the Notch1 signaling pathway, which succinylated Notch1 at the K2177 site to increase their corresponding protein levels in DPSCs. The co-IP results showed that KAT2A and Notch1 were endogenously bound to each other, while inhibition of Notch1 reversed the effects of KAT2A overexpression on the DPSCs proliferation and differentiation. CONCLUSION: KAT2A interacted directly with Notch1, succinylating the Notch1 at the K2177 site to increase their corresponding protein levels in DPSCs. Similarly, KAT2A-mediated succinylation modification of Notch1 promotes the DPSCs proliferation and differentiation, suggesting that targeting KAT2A and Notch1 may contribute to tooth regeneration.

DENTAL AND SKELETAL CHANGES OF LONG-TERM USE OF MANDIBULAR ADVANCEMENT DEVICES FOR THE TREATMENT OF ADULT OBSTRUCTIVE SLEEP APNEA: A SYSTEMATIC REVIEW AND META-ANALYSIS.

BACKGROUND: Mandibular advancement devices (MADs) are indicated for use in patients with mild to moderate obstructive sleep apnea (OSA). Long-term use of MADs has been found to be associated with dental and skeletal changes. This study aims to conduct a systematic review and meta-analysis to improve knowledge about the dental and skeletal changes of long-term (>1 year) use of MADs for the treatment of OSA. MATERIAL AND METHODS: Electronic databases were systematically searched. Two reviewers conducted screening, quality assessment, and data extraction independently. Thirty-four studies were included in the systematic review and 23 in the meta-analysis. RESULTS: The mean change of overjet and overbite was -0.77mm (95%CI -1.01 to -0.53, P < .00001) and -0.64mm (95%CI -0.85 to -0.43, P < .00001), with progressive change over the treatment duration. The inclination of the upper incisor (U1/SN) and the lower incisor (L1/MP) showed a mean change of retroclined -2.10° (95%CI -3.93 to -0.28, P = .02) and proclined 1.78° (95%CI 0.63 to 2.92, P = .002), respectively. The mean change of the anteroposterior position of the mandible (SNB) was -0.33° posteriorly (95%CI -0.65 to -0.02, P = .04). CONCLUSIONS: The meta-analysis showed a gradual decrease in overjet and overbite with treatment duration with long-term use of MADs for the treatment of OSA. Upper and lower incisors retroclined and proclined, respectively. The skeletal changes might include the mandibular position. Patients treated with MADs need to be continuously monitored over time.

Genome-wide analysis of the metallothionein gene family in cassava reveals its role in response to physiological stress through the regulation of reactive oxygen species.

BACKGROUND: Cassava (Manihot esculenta Crantz) is widely planted in tropical and several subtropical regions in which drought, high temperatures, and other abiotic stresses occur. Metallothionein (MT) is a group of conjugated proteins with small molecular weight and rich in cysteine. These proteins play a substantial role in response to physiological stress through the regulation of reactive oxygen species (ROS). However, the biological functions of MT genes in cassava are unknown. RESULTS: A total of 10 MeMT genes were identified in the cassava genome. The MeMTs were divided into 3 groups (Types 2-4) based on the contents and distribution of Cys residues. The MeMTs exhibited tissue-specific expression and located on 7 chromosomes. The MeMT promoters contain some hormones regulatory and stresses responsiveness elements. MeMTs were upregulated under hydrogen peroxide (H2O2) treatment and in respond to post-harvest physiological deterioration (PPD). The results were consistent with defense-responsive cis-acting elements in the MeMT promoters. Further, four of MeMTs were selected and silenced by using the virus-induced gene silencing (VIGS) method to evaluate their functional characterization. The results of gene-silenced cassava suggest that MeMTs are involved in oxidative stress resistance, as ROS scavengers. CONCLUSION: We identified the 10 MeMT genes, and explore their evolutionary relationship, conserved motif, and tissue-specific expression. The expression profiles of MeMTs under three kinds of abiotic stresses (wounding, low-temperature, and H2O2) and during PPD were analyzed. The tissue-specific expression and the response to abiotic stresses revealed the role of MT in plant growth and development. Furthermore, silenced expression of MeMTs in cassava leaves decreased its tolerance to ROS, consistent with its predicted role as ROS scavengers. In summary, our results suggest an important role of MeMTs in response to physiological stress as well as species adaptation via the regulation of ROS homeostasis.

Transcatheter Mitral Valve-in-Valve Implantation Applying a Long Pre-Curved Sheath for Patients with Degenerated Bioprosthetic Mitral Valve.

Backgrounds: Percutaneous transseptal transcatheter mitral valve-in-valve implantation (TMViV) has become an alternative minimally invasive treatment choice for patients with degenerated mitral bioprosthesis and high surgical risk. However, transseptal approach is more technically challenging than transapical approach in TMViV procedures. Objective: The objective of this study was to introduce the experience of applying long pre-curved sheaths in transseptal TMViV procedures and to evaluate the effect of long pre-curved sheath techniques in TMViV procedures. Methods: Between January 2020 and December 2021, 27 patients with degenerated bioprosthetic mitral valve underwent TMViV procedures using a balloon-expandable valve via the transseptal approach. The regular 14/16F expandable sheath were used for low-profile delivery in first 10 cases, and 22F long pre-curved sheath were used in the next 17 cases during procedures. We retrospectively reviewed the catheter techniques, perioperative characteristics, and prognosis. The median follow-up time was 12 (1-21) months. To further scrutinize our data, we divided the group into the early 10 patients using 14/16F expandable sheath and the subsequent 17 patients with long pre-curved sheath in order to assess the impact of different sheaths and procedural details on outcomes. Results: Procedural success was obtained in all patients with no in-hospital mortality. Seventeen patients received 26 mm prostheses; the remaining ten patients received 29 mm prostheses. Post balloon dilatation was performed in one case. Total procedure time was (96.1 ± 28.2) min, the fluoroscopic time was (27.4 ± 6.5) min, and total contrast volume was (50.7 ± 10.1) mL. One patient received blood transfusion because of hemorrhage at the femoral puncture site. One patient received a permanent pacemaker implantation due to high-degree atrioventricular block at postoperative day 3. There were no other major post-procedure complications and the median length of hospital stay was 4 days. Twenty-five (92.6%) patients improved by ≥ 1 New York Heart Association (NYHA) functional class at 30 days. In subsequent sub analysis, there were shorter procedural time [(85.2 ± 24.3) vs. (115.2 ± 25.6) min, p = 0.0048] and shorter fluoroscopic time [(24.3 ± 5.2) vs. (31.3 ± 5.1) min, p = 0.0073] in cases with the long pre-curved sheath than ones with regular expandable sheath. The iatrogenic atrial septal defect (ASD) closure was performed because of the transeptal large right to left shunt in 2 cases with regular expandable sheath, but no patient needed intraoperative ASD closure in cases with the long pre-curved sheath. Conclusions: Transseptal TMViV using long pre-curved sheath could simplify transseptal approach with reliable outcomes for patients of degenerated mitral bioprosthesis.

Transcatheter Closure of a Paravalvular Leak After Transcatheter Aortic Valve Replacement With 3-Dimensional Printing Guidance: A Case Report.

PURPOSE: Our goal was to report the transcatheter closure of a paravalvular leak after transcatheter aortic valve replacement (TAVR) using 3-dimensional (3D) printing. CASE REPORT: A 66-year-old man who had undergone transapical and TAVR 2 years ago due to aortic regurgitation, presented with palpitations and shortness of breath owing to exacerbation of paravalvular regurgitation. Echocardiography suggested that the stented aortic valve was fixed securely in place and the valve leaflets moved normally after TAVR, but there was severe paravalvular regurgitation (3 bundles, volume 11.0 mL). Due to the high surgical risk, we closed the transcatheter paravalvular leak using preprocedural guidance with 3D printing and intraprocedural guidance with digital subtraction angiography. Postoperative echocardiography showed that the paravalvular leak was significantly reduced. 3D construction showed that the occluders and the stent valve were well placed. CONCLUSION: Transcatheter closure of a paravalvular leak of the aortic valve may be feasible with appropriate pre- and intraoperative 3D printing guidance. CLINICAL IMPACT: 3D printing technology may help surgeons to make accurate preoperative strategy before occlusion procedures.

The role of prevertebral soft tissue swelling in dysphagia after anterior cervical corpectomy fusion: change trends and risk factors.

OBJECTIVES: This study aimed to analyze the change trends of prevertebral soft tissue swelling (PSTS) for anterior cervical corpectomy fusion(ACCF) and to evaluate the risk factors of PSTS for postoperative dysphagia. METHODS: There were 309 patients with degenerative cervical diseases who were treated with ACCF from November 2015 and September 2019 in our hospital. According to the symptom of swallowing function after ACCF, those were divided into the dysphagia group and the normal-swallowing function group. Cervical computed tomography(CT) was analyzed, and radiological evaluation of the prevertebral soft tissue was measured between the antero-inferior corner of each vertebral body and the air shadow of the airway through CT mid-sagittal slice images before operation and after operation(one week, one month, eight months and twelve months). RESULTS: The incidence of dysphagia after ACCF was 41.1%. 120 of 127(94.5%) patients had dysphagia disappeared at the 8 months after ACCF, and all disappeared at the 12 months. In both groups, PSTS would be biggest at 1 week postoperatively comparing to the preoperative, and then get smaller from 1 week to 12 months postoperatively (p < 0.05). After 12 months of operation, the PSTS of all cervical spinal levels would get equal to the preoperative size in the normal-swallowing function group, while the PSTS in dysphagia group would get equal only in C5-7 levels. The PSTS of preoperative C6 level and postoperative C2 level were more closely related to the present of postoperative dysphagia (OR: 9.403, 95%CI: 2.344-37.719, OR: 3.187, 95%CI: 1.78-5.705). It was more important to predict postoperative dysphagia using the value of PSTS at preoperative C6 level and postoperative C2 level, with the cutoff threshold for the PSTS of preoperative C6 level ≦1.51 cm and postoperative C2 level ≦1.3915 cm, which could get sensitivity & specificity 66.929% and 61.54%, 77.17% and 64.29%, respectively. CONCLUSION: Our study showed that the increasing of the PSTS after ACCF should be considered as a risk factor of dysphagia after surgery. With the recovery of PSTS over time, the incidence of postoperative dysphagia decreases. The PSTS of preoperative C6 level and and postoperative C2 level should play an important part in predicting the risk of postoperative dysphagia.

Role of craniofacial phenotypes in the response to oral appliance therapy for obstructive sleep apnea.

BACKGROUND: Mandibular advancement device (MAD) is a good alternative for patients with obstructive sleep apnea (OSA). However, the treatment response varies amongst individuals. OBJECTIVE: This study aimed to explore the role of craniofacial features in the response to MADs to improve prognostication and patient selection. METHODS: The retrospective trial contained 42 males aged 41.5 ± 9.0 years, and with an apnea-hypopnea index (AHI) of 21.5 ± 13.8 events/h. According to the mandibular plane angle, participants were divided into three groups: low angle (n = 13), average angle (n = 14) and high angle (n = 15). Under the monitoring of home sleep testing, adjustable MADs were used to titrate the mandible forward from 0 mm with an increment of 0.5 mm every day. The polysomnography outcomes, mandibular protrusion amounts, changes in upper airway MRI measurements and nasal resistance were compared amongst the three groups. RESULTS: The normalisation rate (AHI <5 /h) was 92.3%, 57.1% and 46.7%, respectively, in the low-, average- and high-angle groups (p = .027). The effective protrusion where AHI was reduced by half was 20 (11.3 ~ 37.5) %, 31.3 (23.6 ~ 50) % and 50 (36.9 ~ 64.9) % of the maximal mandibular protrusion, in the low-, average- and high-angle groups (p = .004). Multivariate logistic regression revealed that increased gonion angle (OR = 0.878) and baseline AHI(OR = 0.868) can reduce the probability of normalisation. CONCLUSION: The high mandibular plane angle might be an unfavourable factor to MAD treatment and more protrusion was needed to achieve a 50% reduction in AHI. Vertical craniofacial pattern (gonion angle) and baseline AHI constituted the model for predicting the effect of MADs.

Detection of Various Traditional Chinese Medicinal Metabolites as Angiotensin-Converting Enzyme Inhibitors: Molecular Docking, Activity Testing, and Surface Plasmon Resonance Approaches.

Angiotensin-converting enzyme 1 (ACE1) is a peptide involved in fluid and blood pressure management. It regulates blood pressure by converting angiotensin I to angiotensin II, which has vasoconstrictive effects. Previous studies have shown that certain compounds of natural origin can inhibit the activity of angiotensin-converting enzymes and exert blood pressure-regulating effects. Surface Plasmon Resonance (SPR) biosensor technology is the industry standard method for observing biomolecule interactions. In our study, we used molecular simulation methods to investigate the docking energies of various herbal metabolites with ACE1 proteins, tested the real-time binding affinities between various herbal metabolites and sACE1 by SPR, and analyzed the relationship between real-time binding affinity and docking energy. In addition, to further explore the connection between inhibitor activity and real-time binding affinity, several herbal metabolites' in vitro inhibitory activities were tested using an ACE1 activity test kit. The molecular docking simulation technique's results and the real-time affinity tested by the SPR technique were found to be negatively correlated, and the virtual docking technique still has some drawbacks as a tool for forecasting proteins' affinities to the metabolites of Chinese herbal metabolites. There may be a positive correlation between the enzyme inhibitory activity and the real-time affinity detected by the SPR technique, and the results from the SPR technique may provide convincing evidence to prove the interaction between herbal metabolites and ACE1 target proteins.

Rationally Screened and Designed ABCG2-Binding Aptamers for Targeting Cancer Stem Cells and Reversing Multidrug Resistance.

The ATP-binding cassette, subfamily G, isoform 2 protein (ABCG2), as an important member of ABC transporters, plays a key role in multidrug resistance (MDR) in cancer and has been widely considered as a marker of cancer stem cells (CSC). Reagents capable of simultaneously targeting ABCG2 and reversing MDR have great clinical application values, but their development is highly challenging. Herein, ABCG2 glycosylated extracellular region-binding aptamers were efficiently screened by a cladded molecularly imprinted polymer (cMIP)-based in vitro screening method and further rationally engineered into cyclic bivalent aptamers. Experiments showed that both the monovalent and cyclic bivalent aptamers could specifically bind ABCG2 and thereby specially target CSC of human colorectal carcinomas (CoCSC), while the latter could effectively reverse MDR in drug-resistant liver cancer cells (HepG2/ADR). Different from currently predominant small molecule inhibitors, the reversal of MDR relied on a different mechanism; the cyclic bivalent aptamers bound the two monomers of ABCG2 dimers simultaneously and thereby blocked the ABCG2-mediated drug-pumping channel, resulting in increased intracellular accumulation of substrate drugs. This study opened a new access to the development of affinity reagents for targeting CSC and reversing MDR, holding great prospects in cancer diagnosis and treatment.

Genome-wide survey and functional analysis reveal TCF21 promotes chicken preadipocyte differentiation by directly upregulating HTR2A.

BACKGROUND/AIM: Previously, we showed that transcription factor 21 (TCF21) promotes chicken preadipocyte differentiation. However, the genome-wide TCF21 binding sites and its downstream target genes in chicken adipogenesis were unknown. METHODS: ChIP-Seq and RNA-Seq were used to screen candidate targets of TCF21. qPCR and luciferase reporter assay were applied to verify the sequencing results. Western blotting, oil red-O staining and pharmacological treatments were performed to investigate the function of 5-hydroxytryptamine receptor 2A (HTR2A), one of the bonafide direct downstream binding targets of TCF21. RESULTS: A total of 94 candidate target genes of TCF21 were identified. ChIP-qPCR, RT-qPCR, and luciferase reporter assay demonstrated that HTR2A is one of the bonafide direct downstream binding targets of TCF21. HTR2A expression in adipose tissue was upregulated in fat line broilers. Also, the abundance of HTR2A gradually increased during the adipogenesis process. Interestingly, pharmacological enhancement or inhibition of HTR2A promoted or attenuated the differentiation of preadipocytes, respectively. Furthermore, HTR2A inhibition impaired the TCF21 promoted adipogenesis. CONCLUSIONS: We profiled the genome-wide TCF21 binding sites in chicken differentiated preadipocytes revealing HTR2A as the direct downstream target of TCF21 in adipogenesis.

Identification of target and pathway of aspirin combined with Lipitor treatment in prostate cancer through integrated bioinformatics analysis.

PURPOSE: Our previous studies have confirmed that aspirin combined with Lipitor inhibited the development of prostate cancer (PCa), but the mechanisms need to be comprehensively expounded. The study aims to screen out the hub genes of combination therapy and to explore their association with the pathogenesis and prognosis of PCa. METHODS: Gene expressions were quantified by RNA sequencing (RNA-seq). Altered biological function, pathways of differentially expressed genes (DEGs), protein-protein interaction network, the filtering of hub genes, gene co-expression and the pathogenesis and prognosis were revealed by bioinformatics analysis. The correlation between hub gene expression and patient survival was validated by Kaplan-Meier. The effects of silent DNA replication and sister chromatid cohesion 1 (siDSCC1) combined with Lipitor and aspirin on DSCC1 expression, viability, invasion and migration of PCa cells were detected by qRT-PCR, Wound healing and transwell assays. RESULTS: 157 overlapped DEGs involved in FoxO, PI3K-Akt and p53 signaling pathways were identified. Ten hub genes (NEIL3, CDC7, DSCC1, CDC25C, PRIM1, MCM10, FBXO5, DTL, SERPINE1, EXO1) were verified to be correlated with the pathology and prognosis of PCa. DSCC1 silencing not only inhibited the viability, migration and invasion of PCa cells, but also strengthened the suppressing effects of Lipitor and aspirin alone or in combination on PCa cells. CONCLUSION: The enrichment pathways and targets of Lipitor combined with aspirin in PCa are discovered, and DSCC1 silencing can potentiate the effect of Lipitor combined with aspirin in the treatment of PCa.

Cognition, motor symptoms, and glycolipid metabolism in Parkinson's disease with depressive symptoms.

Depressive symptoms and abnormal glycolipid metabolisms are common in patients with Parkinson's disease (PD), but their relationship has not been fully reported. It is not clear whether glycolipid impairments lead to poor cognitive and motor function, and aggravate depressive symptoms. Therefore, we aimed to explore the relationships between glycolipid variables, cognition, motor and depressive symptoms in PD patients cross-sectionally. Two hundred ten PD patients were recruited. Glycolipid parameters and Uric acid (UA) were measured. Depressive symptoms, cognitive function and motor symptoms were assessed using the Hamilton Depression Rating Scale-17 (HAMD-17), the Montreal Cognitive Assessment (MOCA) and the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part-III (UPDRS-III). Depressive PD patients had significantly worse motor symptoms and higher levels of fasting plasma glucose (FPG) than those in non-depressive patients (F = 24.145, P < 0.001). Further, logistic regression analysis indicated that UPDRS-III (OR = 1.039, 95% CI 1.019-1.057, P = 0.044), FPG (OR = 1.447, 95% CI 1.050-1.994, P = 0.024) were independently associated with depression. In PD patients without depression, UA (ß = - 0.068, t = - 2.913, P = 0.005) and cholesterol (CHOL) (ß = - 3.941, t = - 2.518, P = 0.014) were independent predictors of the UPDRS-III score; in addition, UPDRS-III score was negatively associated with MOCA score (ß = - 0.092, t = - 2.791, P = 0.007). FPG levels and motor symptoms were related to depressive symptoms in PD patients. Further, in non-depressive PD patients, UA and CHOL showed putative biomarkers of motor symptoms.

Polymorphisms of COMT and CREB1 are associated with treatment-resistant depression in a Chinese Han population.

Genetic factors play a crucial role for the pathophysiology of treatment-resistant depression (TRD). It has been established that Catechol-O-methyltransferase (COMT) and cyclic amp-response element-binding protein (CREB) are associated with antidepressant response. The aim of this study was to explore the association between single nucleotide polymorphisms (SNPs) in COMT and CREB1 genes and TRD in a Chinese population. We recruited 181 patients with major depressive disorder (MDD) and 80 healthy controls, including 81 TRD patients. Depressive symptoms were assessed with the Hamilton Depression Rating Scale-17 (HDRS). Genotyping was performed using mass spectrometry. Genetic analyses were conducted by PLINK Software. The distribution of COMT SNP rs4818 allele and genotypes were significantly different between TRD and controls. Statistical differences in allele frequencies were observed between TRD and non-TRD groups, including rs11904814 and rs6740584 in CREB1 gene, rs4680 and rs4818 in COMT gene. There were differences in the distribution of HDRS total scores among different phenotypes of CREB1 rs11904814, CREB1 rs6740584, COMT rs4680 and rs4818. Gene-gene interaction effect of COMT-CREB1 (rs4680 × rs6740584) revealed significant epistasis in TRD. There findings indicate that COMT and CREB1 polymorphisms influence the risk of TRD and affect the severity of depressive symptoms of MDD.

Labor characteristics and intrapartum interventions in women with vaginal birth after cesarean section.

BACKGROUND: With the development of China's two-child-policy, vaginal birth after cesarean section (VBAC) has aroused public concern. It is important to understand the labour characteristics and intrapartum management of women attempting VBAC to enhance the rates of successful VBAC. The purpose of our research was to investigate the differences in the characteristics of labor, intervention measures and perinatal outcomes between women who had a VBAC and primiparas or multiparas not undergoing VBAC, providing clinical references of intrapartum management for women who are planning a VBAC. MATERIAL AND METHODS: This observational retrospective study enrolled all women who laboured spontaneously and who had a VBAC (n = 139) at the Second Affiliated Hospital of Wenzhou Medical University in China between 2016 and 2019. They were allocated into VBAC group A (the previous cesarean section was performed before dilation of the cervix) and VBAC group B (the previous cesarean section was performed after dilation of the cervix). The primipara control group included 149 primiparae, and the multipara control group included 155 multiparae with second vaginal birth. Durations of labor, intervention measures and perinatal outcomes were compared among the groups. RESULTS: The durations of labor, intrapartum interventions and maternal and neonatal outcomes in VBAC group A were similar to those of the VBAC group B. However, all women who had a VBAC and those in VBAC group A had shorter first, second and the total stages of labor than primiparae. All women with VBAC and those in VBAC group B had longer second stage of labor, but shorter third stage of labor than multiparae. Oxytocin, labor analgesia and artificial rupture of membranes were administered less often in women with VBAC than in primiparae, while phloroglucinol was administered more often in women with VBAC than in multiparae. Women who had a VBAC were more likely to receive episiotomy and had higher incidences of postpartum hemorrhage than primipara and multipara women. CONCLUSIONS: Labor characteristics, intrapartum interventions and perinatal outcomes in women who had a VBAC with cervical dilation were similar to those in women who had a VBAC without cervical dilation before the previous cesarean section, but differed significantly from those of multiparae and primiparae who did not undergo VBAC.