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Biological networks serve a crucial role in elucidating intricate biological processes. While interspecies environmental interactions have been extensively studied, the exploration of gene interactions within species, particularly among individual microorganisms, is less developed. The increasing amount of microbiome genomic data necessitates a more nuanced analysis of microbial genome structures and functions. In this context, we introduce a complex structure using higher-order network theory, "Solid Motif Structures (SMS)", via a hierarchical biological network analysis of genomes within the same genus, effectively linking microbial genome structure with its function. Leveraging 162 high-quality genomes of Microcystis, a key freshwater cyanobacterium within microbial ecosystems, we established a genome structure network. Employing deep learning techniques, such as adaptive graph encoder, we uncovered 27 critical functional subnetworks and their associated SMSs. Incorporating metagenomic data from seven geographically distinct lakes, we conducted an investigation into Microcystis' functional stability under varying environmental conditions, unveiling unique functional interaction models for each lake. Our work compiles these insights into an extensive resource repository, providing novel perspectives on the functional dynamics within Microcystis. This research offers a hierarchical network analysis framework for understanding interactions between microbial genome structures and functions within the same genus.
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Genoma Bacteriano , Microcystis , Microcystis/genética , Lagos/microbiología , Redes Reguladoras de Genes , Metagenómica/métodos , Metagenoma , Genoma Microbiano , Genómica/métodos , Aprendizaje ProfundoRESUMEN
Background: The improvement rate and predictors of secondary mitral regurgitation in patients with aortic regurgitation undergoing transcatheter aortic valve replacement (TAVR) remain unclear. This study aimed to identify predictors of persistent moderate to severe secondary mitral regurgitation after TAVR in patients with aortic regurgitation by assessing mitral valve geometry with computed tomography (CT). Methods: This retrospective cohort study reviewed 242 consecutive patients with aortic regurgitation who underwent TAVR between May 2014 and December 2022. Patients with primary or less than moderate mitral regurgitation were excluded. Mitral annular dimensions (area, perimeter, anteroposterior, intercommissural, and trigone-to-trigone diameter), mitral valve tenting geometry (mitral valve tenting area [MVTA] and mitral valve tenting height [MVTH]), and papillary muscle displacement were systematically measured at CT. Mitral regurgitation improvement was assessed at 3 months after TAVR by echocardiography. Logistic regression was performed to explore the association of mitral valve geometry with mitral regurgitation improvement after TAVR. Results: A total of 75 patients (mean age, 74 ± 7 years; 32.0% female) with moderate to severe secondary mitral regurgitation were included in the final analysis. Mitral regurgitation improved in 49 patients and remained unchanged in 26 patients. Mitral annular dimensions, including area, perimeter, anteroposterior, and intercommissural diameter, were associated with mitral regurgitation improvement. MVTA and MVTH were risk factors for sustained mitral regurgitation. In addition, QRS duration > 120 ms and atrial fibrillation had an impact on the mitral regurgitation improvement. Mitral annular area (odds ratio [OR], 1.41; 95% confidence interval [CI]: 1.05, 1.90; p = 0.02) and MVTA (OR, 7.24; 95% CI: 1.72, 30.44; p = 0.007) were independent predictors of persistent secondary mitral regurgitation after TAVR. Conclusions: Mitral annular area and MVTA were independent predictors of persistent secondary mitral regurgitation after TAVR.
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The inflammation-related tumor microenvironment (TME) is one of the major driving forces of hepatocarcinogenesis. We aimed to investigate cell-to-cell communication among Hepatocellular Carcinoma (HCC) through re-analyzing HCC single-cell RNA-seq data, and to confirm such cellular interaction through in vitro and in vivo study. We found a subset of Regulatory B cells with PD-L1 expression (PD-L1+ Bregs), mainly located in adjacent HCC tissues. In co-localization with PD-L1+ Bregs, a subset of Tumor Associated Macrophages with high expression of CXCL12 (CXCL12+ TAMs) was also mainly located in adjacent HCC tissues. Moreover, CXCL12+ TAMs can be stimulated in vitro using an HCC conditional medium. Using CellChat analysis and Multiplex Immunohistochemistry staining (mIHC), CXCL12+ TAMs were found to be first recruited by Cancer-Associated Fibroblasts (CAFs) through a CD74/macrophage migration inhibitory factor (MIF) pattern, and further differentiated into TGF-ß-enriched tissues. Furthermore, CXCL12+ TAMs recruited PD-L1+ Bregs via the CXCL12/CXCR4 axis, and CXCR4 expression was significantly positively correlated to PD-L1 expression in PD-L1+ Bregs. At last, we confirmed the communications among CAFs, Macrophages and B cells and their tumor-promoting effects by using an orthotopic mouse model of HCC. Immunosuppressive HCC TME involving cell-to-cell communications comprised MIF-secreting CAFs, CXCL12-secreting TAMs, and PD-L1-producing Bregs, and their regulation could be promising therapeutic targets in future immunotherapy for human HCC.
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Figla is one of the earliest expressed genes in the oocyte during ovarian development. In this study, Figla was characterized in C. maculata, one of the main aquaculture species in China, and designated as CmFigla. The length of CmFigla cDNA was 1303 bp, encoding 197 amino acids that contained a conserved bHLH domain. CmFigla revealed a female-biased expression patterns in the gonads of adult fish, and CmFigla expression was far higher in ovaries than that in testes at all gonadal development stages, especially at 60~180 days post-fertilization (dpf). Furthermore, a noteworthy inverse relationship was observed between CmFigla expression and the methylation of its promoter in the adult gonads. Gonads at 90 dpf were used for in situ hybridization (ISH), and CmFigla transcripts were mainly concentrated in oogonia and the primary oocytes in ovaries, but undetectable in the testes. These results indicated that Figla would play vital roles in the ovarian development in C. maculata. Additionally, the frame-shift mutations of CmFigla were successfully constructed through the CRISPR/Cas9 system, which established a positive foundation for further investigation on the role of Figla in the ovarian development of C. maculata. Our study provides valuable clues for exploring the regulatory mechanism of Figla in the fish ovarian development and maintenance, which would be useful for the sex control and reproduction of fish in aquaculture.
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Transapical beating-heart mitral repair with chordal implantation system has been considered as an alternative treatment for degenerative mitral regurgitation. This study aimed to assess the feasibility and safety of the E-Chord system (Med-Zenith Medical, Beijing, China) for transapical beating-heart mitral valve repair in a porcine model. Artificial chordae were transapically implanted on the mitral valves of 12 anesthetized pigs under epicardial echocardiographic guidance and secured outside the left ventricular apex. The study endpoints included procedural success, device durability, and tissue response to the device. The procedural success rate was 100% (12/12). All animals were implanted with E-Chord in the anterior and posterior leaflets, respectively, and survived uneventfully until euthanized as planned. During the 180-day follow-up, no animal had significant mitral valve dysfunction. The gross observation showed no evidence of anchor detachment and chordal rupture, and there was no obvious damage or changes to mitral leaflets. Microscopic evaluation revealed that the endothelialization of anchor and chordae was completed 90 days after implantation and there was no evidence of chordal rupture, thrombosis, or infection during the 180-day follow-up. The E-Chord system was found to be feasible and safe for heart-beating mitral chordal implantation in a porcine model. The findings of this study suggest that the E-Chord system may be a potential alternative for the treatment of degenerative mitral regurgitation in humans.
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Implantación de Prótesis de Válvulas Cardíacas , Insuficiencia de la Válvula Mitral , Prolapso de la Válvula Mitral , Humanos , Porcinos , Animales , Insuficiencia de la Válvula Mitral/cirugía , Estudios de Factibilidad , Válvula Mitral/diagnóstico por imagen , Válvula Mitral/cirugía , Cuerdas Tendinosas/cirugía , Resultado del TratamientoRESUMEN
BACKGROUND: Transcatheter mitral valve replacement (TMVR) has become an alternative for high-risk patients with severe mitral regurgitation (MR). The aim of this study was to evaluate the safety and feasibility of the Mi-thos TMVR system (NewMed Medical) for high-risk patients with severe MR. METHODS: This was a prospective, two-center, single-arm early feasibility study. Baseline characteristics, procedural data and 30-day follow-up outcomes were collected and analyzed. The primary endpoint was intraoperative success rate of device implantation. The second endpoints were all-cause mortality and major post-procedural complications. Echocardiographic data were evaluated by an independent core laboratory. Clinical events were adjudicated by a clinical events committee. RESULTS: Ten high-risk patients with severe MR were enrolled at two sites from August 2021 to November 2022. The median age was 70.5 years, and 60% of patients were female. The median Society of Thoracic Surgeons Predicted Risk of Mortality was 9.5%. The Mi-thos TMVR system was successfully implanted via transapical access in all patients. There was no pericedural mortality or major postpericedural complications during the 30-day follow-up. All implanted prosthetic valves had no or trace valvular or paravalvular MR, and the median mitral valve gradient at 30 days was 2.0 mmHg (IQR: 2.0-3.0 mmHg). There was one mild left ventricular outflow tract obstruction. CONCLUSIONS: The favorable short-term outcomes of the Mi-thos TMVR system demonstrated that it might be a feasible and safe therapeutic alternative for high-risk patients with severe MR. Nevertheless, further evaluation of the Mi-thos TMVR system is warranted.
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Implantación de Prótesis de Válvulas Cardíacas , Prótesis Valvulares Cardíacas , Insuficiencia de la Válvula Mitral , Humanos , Femenino , Anciano , Masculino , Válvula Mitral/diagnóstico por imagen , Válvula Mitral/cirugía , Insuficiencia de la Válvula Mitral/diagnóstico por imagen , Insuficiencia de la Válvula Mitral/cirugía , Insuficiencia de la Válvula Mitral/etiología , Prótesis Valvulares Cardíacas/efectos adversos , Estudios Prospectivos , Cateterismo Cardíaco , Resultado del TratamientoRESUMEN
Background: Acute Stanford type A aortic dissection (ATAAD) is characterized by intimal tearing and false lumen formation containing large amounts of erythrocytes with heme. Heme oxygenase 1 (HO-1) is the key enzyme to degrade heme for iron accumulation and further ferroptosis. The current study aimed at investigating the role of HO-1 in the dissection progression of ATAAD. Methods: Bioinformatic analyses and experimental validation were performed to reveal ferroptosis and HO-1 expression in ATAAD. Human aortic vascular smooth muscle cell (HA-VSMC) was used to explore underlying molecular mechanisms and the role of HO-1 overexpression in ATAAD. Results: Ferroptosis was identified as a critical manner of regulated cell death in ATAAD. HO-1 was screened as a key signature of ferroptosis in ATAAD, which was closely associated with oxidative stress. Single cell/nucleus transcriptomic analysis and histological staining revealed that HO-1 and HIF-1α were upregulated in vascular smooth muscle cell (VSMC) of ATAAD. Further in vitro experiments showed that H2O2-induced oxidative stress increased VSMC ferroptosis with the overexpression of HO-1, which could be suppressed by HIF-1α inhibitor PX-478. HIF-1α could transcriptionally regulate the expression of HO-1 through binding to its promoter region. Pharmacological inhibition of HO-1 by zinc protoporphyrin (ZnPP) did not reduce H2O2-induced HA-VSMC damage without heme co-incubation. However, H2O2-induced HA-VSMC damage was worsened when heme was added into the medium, and ZnPP could reduce HA-VSMC damage in this condition. Conclusion: HO-1 is a key signature of VSMC ferroptosis in ATAAD. HIF-1α/HO-1 mediated ferroptosis might participate in oxidative stress induced VSMC damage.
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PURPOSE: Temozolomide resistance remains a major obstacle in the treatment of glioblastoma (GBM). The combination of temozolomide with another agent could offer an improved treatment option if it could overcome chemoresistance and prevent side effects. Here, we determined the critical drug that cause ferroptosis in GBM cells and elucidated the possible mechanism by which drug combination overcomes chemoresistance. EXPERIMENTAL DESIGN: Haloperidol/temozolomide synergism was assessed in GBM cell lines with different dopamine D2 receptor (DRD2) expression in vitro and in vivo. Inhibitors of ferroptosis, autophagy, endoplasmic reticulum (ER) stress and cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) were used to validate the specific mechanisms by which haloperidol and temozolomide induce ferroptosis in GBM cells. RESULTS: In the present work, we demonstrate that the DRD2 level is increased by temozolomide in a time-dependent manner and is inversely correlated with temozolomide sensitivity in GBM. The DRD2 antagonist haloperidol, a butylbenzene antipsychotic, markedly induces ferroptosis and effectively enhances temozolomide efficacy in vivo and in vitro. Mechanistically, haloperidol suppressed the effect of temozolomide on cAMP by antagonizing DRD2 receptor activity, and the increases in cAMP/PKA triggered ER stress, which led to autophagy and ferroptosis. Furthermore, elevated autophagy mediates downregulation of FTH1 expression at the posttranslational level in an autophagy-dependent manner and ultimately leads to ferroptosis. CONCLUSIONS: Our results provide experimental evidence for repurposing haloperidol as an effective adjunct therapy to inhibit adaptive temozolomide resistance to enhance the efficacy of chemoradiotherapy in GBM, a strategy that may have broad prospects for clinical application.
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Neoplasias Encefálicas , Ferroptosis , Glioblastoma , Humanos , Temozolomida/farmacología , Temozolomida/uso terapéutico , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , Haloperidol/farmacología , Haloperidol/uso terapéutico , Antagonistas de los Receptores de Dopamina D2/farmacología , Línea Celular Tumoral , Autofagia , Estrés del Retículo Endoplásmico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Resistencia a Antineoplásicos/genética , Receptores de Dopamina D2/genéticaRESUMEN
AIM: Our aim was to conduct a systematic review and meta-analysis to examine the efficacy and safety of oliceridine in patients with postoperative pain. METHODS: Four databases were searched from the beginning of the database to the present. We included all randomized controlled trials (RCT) that evaluated the efficacy and safety of oliceridine in patients with postoperative pain. Our endpoints were the proportion of treatment responders to the oliceridine regimen and the incidence of adverse effects such as nausea and vomiting. RESULTS: The analysis showed that more patients responded significantly with oliceridine compared to placebo. The proportion of treatment responders to oliceridine was comparable to that of morphine. Oliceridine had analgesia effects similar to morphine compared to placebo. The incidence of respiratory safety events was significantly lower with oliceridine compared to morphine. Oliceridine was significantly associated with more adverse events such as nausea and vomiting compared to placebo. The safety profile of oliceridine was superior to morphine compared to morphine. CONCLUSIONS: Our systematic review and meta-analysis showed that oliceridine is an effective and safe intravenous analgesic in patients with postoperative pain, producing rapid postoperative analgesic and usually well tolerated, and reducing incidence of adverse events compared to morphine. PROSPERO REGISTRATION: CRD42023391581.
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Analgésicos Opioides , Morfina , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Morfina/efectos adversos , Analgésicos/uso terapéutico , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/etiología , Vómitos/inducido químicamente , Náusea/inducido químicamenteRESUMEN
For treatment of glioblastoma (GBM), temozolomide (TMZ) and radiotherapy (RT) exert antitumor effects by inducing DNA double-strand breaks (DSBs), mainly via futile DNA mismatch repair (MMR) and inducing apoptosis. Here, we provide evidence that RBBP4 modulates glioblastoma resistance to chemotherapy and radiotherapy by recruiting transcription factors and epigenetic regulators that bind to their promoters to regulate the expression of the Mre11-Rad50-NBS1(MRN) complex and the level of DNA-DSB repair, which are closely associated with recovery from TMZ- and radiotherapy-induced DNA damage in U87MG and LN229 glioblastoma cells, which have negative MGMT expression. Disruption of RBBP4 induced GBM cell DNA damage and apoptosis in response to TMZ and radiotherapy and enhanced radiotherapy and chemotherapy sensitivity by the independent pathway of MGMT. These results displayed a possible chemo-radioresistant mechanism in MGMT negative GBM. In addition, the RBBP4-MRN complex regulation axis may provide an interesting target for developing therapy-sensitizing strategies for GBM.
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Roturas del ADN de Doble Cadena , Glioblastoma , Humanos , Glioblastoma/patología , Enzimas Reparadoras del ADN/genética , Proteína Homóloga de MRE11/genética , Reparación del ADN , Temozolomida/uso terapéutico , Factores de Transcripción/genética , ADN , Quimioradioterapia , Proteínas de Ciclo Celular/metabolismo , Proteínas de Unión al ADN/genética , Ácido Anhídrido Hidrolasas/metabolismo , Proteína 4 de Unión a Retinoblastoma/genética , Proteína 4 de Unión a Retinoblastoma/metabolismoRESUMEN
BACKGROUND: Our previous study suggested that atlanto-occipital instability (AOI) is common in patients with type II basilar invagination (II-BI). OBJECTIVE: To further understand the pathogenesis of AOI in Chiari malformations (CM) and CM + II-BI through systematic measurements of the bone structure surrounding the craniocervical junction. METHODS: Computed tomography data from 185 adults (80 controls, 63 CM, and 42 CM + II-BI) were collected, and geometric models were established for parameter measurement. Canonical correlation analysis was used to evaluate the morphological and positional relationships of the atlanto-occipital joint (AOJ). RESULTS: Among the 3 groups, the length and height of the condyle and superior portion of the lateral masses of the atlas (C1-LM) were smallest in CM + II-BI cases; the AOJ had the shallowest depth and the lowest curvature in the same group. AOJs were divided into 3 morphological types: type I, the typical ball-and-socket joint, mainly in the control group (100%); type II, the shallower joint, mainly in the CM group (92.9%); and type III, the abnormal flat-tilt joint, mainly in the CM + II-BI group (89.3%). Kinematic computed tomography revealed AOI in all III-AOJs (100%) and some II-AOJs (1.5%) but not in type I-AOJs (0%). Morphological parameters of the superior portion of C1-LM positively correlated with those of C0 and the clivus and significantly correlated with AOI. CONCLUSION: Dysplasia of the condyle and superior portion of C1-LM exists in both CM and II-BI cases yet is more obvious in type II-BI. Unstable movement caused by AOJ deformation is another pathogenic factor in patients with CM + II-BI.
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Malformación de Arnold-Chiari , Articulación Atlantoaxoidea , Articulación Atlantooccipital , Inestabilidad de la Articulación , Adulto , Humanos , Articulación Atlantoaxoidea/diagnóstico por imagen , Articulación Atlantoaxoidea/anomalías , Malformación de Arnold-Chiari/complicaciones , Malformación de Arnold-Chiari/diagnóstico por imagen , Malformación de Arnold-Chiari/patología , Inestabilidad de la Articulación/diagnóstico por imagen , Inestabilidad de la Articulación/etiología , Tomografía Computarizada por Rayos X , Fosa Craneal Posterior , Articulación Atlantooccipital/diagnóstico por imagen , Articulación Atlantooccipital/patologíaRESUMEN
Accurate anatomical matching for patient-specific electromyographic (EMG) mapping is crucial yet technically challenging in various medical disciplines. The fixed electrode construction of multielectrode arrays (MEAs) makes it nearly impossible to match an individual's unique muscle anatomy. This mismatch between the MEAs and target muscles leads to missing relevant muscle activity, highly redundant data, complicated electrode placement optimization, and inaccuracies in classification algorithms. Here, we present customizable and reconfigurable drawn-on-skin (DoS) MEAs as the first demonstration of high-density EMG mapping from in situ-fabricated electrodes with tunable configurations adapted to subject-specific muscle anatomy. The DoS MEAs show uniform electrical properties and can map EMG activity with high fidelity under skin deformation-induced motion, which stems from the unique and robust skin-electrode interface. They can be used to localize innervation zones (IZs), detect motor unit propagation, and capture EMG signals with consistent quality during large muscle movements. Reconfiguring the electrode arrangement of DoS MEAs to match and extend the coverage of the forearm flexors enables localization of the muscle activity and prevents missed information such as IZs. In addition, DoS MEAs customized to the specific anatomy of subjects produce highly informative data, leading to accurate finger gesture detection and prosthetic control compared with conventional technology.
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Switch/sucrose-nonfermenting (SWI/SNF) complexes play a key role in chromatin remodeling. Recent studies have found that SMARCC2, as the core subunit of the fundamental module of the complex, plays a key role in its early assembly. In this study, we found a unique function of SMARCC2 in inhibiting the progression of glioblastoma by targeting the DKK1 signaling axis. Low expression of SMARCC2 is found in malignant glioblastoma (GBM) compared with low-grade gliomas. SMARCC2 knockout promoted the proliferation of glioblastoma cells, while its overexpression showed the opposite effect. Mechanistically, SMARCC2 negatively regulates transcription by dynamically regulating the chromatin structure and closing the promoter region of the target gene DKK1, which can be bound by the transcription factor EGR1. DKK1 knockdown significantly reduced the proliferation of glioblastoma cell lines by inhibiting the PI3K-AKT pathway. We also studied the functions of the SWIRM and SANT domains of SMARCC2 and found that the SWIRM domain plays a more important role in the complete chromatin remodeling function of SMARCC2. In addition, in vivo studies confirmed that overexpression of SMARCC2 could significantly inhibit the size of intracranial gliomas in situ in nude mice. Overall, this study shows that SMARCC2, as a tumor suppressor, inhibits the proliferation of glioblastoma by targeting the transcription of the oncogene DKK1 through chromatin remodeling, indicating that SMARCC2 is a potentially attractive therapeutic target in glioblastoma.
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Ensamble y Desensamble de Cromatina , Glioblastoma , Animales , Ratones , Ensamble y Desensamble de Cromatina/genética , Proteína 1 de la Respuesta de Crecimiento Precoz/genética , Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Glioblastoma/genética , Ratones Desnudos , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND: Microsurgical techniques are increasingly being recommended for the treatment of symptomatic Tarlov cysts (TCs) due to improved long-term outcomes compared to those of other strategies. However, these techniques are associated with a high risk of cyst recurrence and cerebrospinal fluid (CSF) leakage, resulting in the surgical strategy of TCs remaining controversial. We hypothesize that incomplete closure of the ostium between the cyst and the subarachnoid space is the probable cause of surgical failure. Accordingly, we present a novel method of cyst separation and ostium closure that aims to block the ostium more firmly and reliably. METHODS: Thirty-five consecutive patients (21 females) underwent the modified ostium obstruction surgery due to symptomatic TCs. We collected and compared their outcomes at the final follow-up to evaluate the surgical effect. RESULTS: Thirty-five patients had 74 TCs (S2 level, 48.7%; mean diameter, 2.0 ± 1.0 cm); ostia nerve root fibers were found in all TCs. The mean follow-up duration was 37.8 (range, 13.5-76.8) months. At the final follow-up, 33 patients experienced complete or substantial resolution of the preoperative symptoms. The symptom with the highest improvement rate was radicular pain. Both the modified evaluation criteria for the efficacy of lumbar function criterion and Japanese Orthopedic Association score 29 showed an overall improvement rate of 94.3%. Two patients experienced surgery-related neurological dysfunction. No cyst recurrence or CSF leakage was observed. Magnetic resonance imaging showed that all cysts disappeared or significantly reduced postoperatively. CONCLUSIONS: The microscopic fenestration of cysts and modified ostium obstruction described herein is a safe and effective strategy for management of patients with symptomatic TCs and is associated with a low incidence of cyst recurrence and CSF leakage since it achieves complete closure of cyst ostium.
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Quistes , Quistes de Tarlov , Femenino , Humanos , Quistes de Tarlov/diagnóstico por imagen , Quistes de Tarlov/cirugía , Quistes de Tarlov/patología , Estudios Retrospectivos , Microcirugia/métodos , Quistes/cirugía , Imagen por Resonancia MagnéticaRESUMEN
10-Hydroxy-2-decenoic acid (10-HDA) is a principal active ingredients of royal jelly. Several recent studies demonstrated that 10-HDA has potential anti-type 2 diabetes mellitus (T2DM) properties. To evaluate the anti-T2DM effect of 10-HDA and explore its underlying molecular mechanisms, we used high fat diet (HFD) combined with streptozotocin (STZ) injection to establish a diabetes model. Mice were randomly divided into four groups (8 mice per group): control group, 10-HDA group, T2DM group, and T2DM + 10-HDA group. The 10-HDA and T2DM + 10-HDA groups were administered intragastric 10-HDA (100 mg per kg body weight), while the control and T2DM groups were administered a vehicle, daily for 4 weeks. Our analysis indicated that there was no significant difference in body weight between T2DM + 10-HDA and control group mice (P > 0.05). Treatment with 10-HDA reduced fasting blood glucose and increased insulin levels in diabetic mice (P < 0.05), as well as increasing the area of pancreatic islets (P < 0.05), and alleviating vacuolar degeneration in the liver. Further, 10-HDA intervention increased superoxide dismutase, catalase, and glutathione peroxidase activities in diabetic mouse liver, alleviated lipid peroxidation, inhibited liver NF-κB nuclear translocation, decreased IL-6 and TNF-α content, and increased P-PI3K, P-AKT, and P-GSK3ß protein levels (all P < 0.05). Fifteen potential biomarkers were screened by analysis of liver metabolomics data, of which hexadecanamide, stearamide, pentadecanoic acid, and fatty acid esters of hydroxy fatty acids (16:0/18:1) were highly abundant. In conclusion, 10-HDA has clear hypoglycemic effects on diabetic mice, through the PI3K/AKT/GSK3ß signaling pathway.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Animales , Biomarcadores , Glucemia/metabolismo , Peso Corporal , Catalasa/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Dieta Alta en Grasa/efectos adversos , Ácidos Grasos/farmacología , Ácidos Grasos Monoinsaturados , Glutatión Peroxidasa/metabolismo , Glucógeno Sintasa Quinasa 3 beta/genética , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Hipoglucemiantes/farmacología , Insulina/metabolismo , Interleucina-6 , Ratones , FN-kappa B/genética , FN-kappa B/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Estreptozocina , Superóxido Dismutasa/metabolismo , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
BACKGROUND: Treatment of Chiari malformation (CM) is controversial, especially when it coexists with "stable" or Type II basilar invagination (CM + II-BI). Precise evaluation of craniovertebral junction (CVJ) stability is crucial in such patients; however, this has never been validated. This study aimed to dynamically evaluate atlanto-condyle and atlantoaxial stability by kinematic computed tomography (CT) and report its surgical treatment. METHODS: The study recruited 101 patients (control, CM, and CM + II-BI groups: 48, 34, and 19 patients, respectively). During kinematic CT, the CVJ stability-related parameters were measured and compared between the 3 groups. The surgical strategy for treating CM + II-BI was based on these results. Preoperative and postoperative images were acquired, and functional scores were used to assess the outcome. RESULTS: Among the 3 groups, the length of the clivus and the height of the condyle were the shortest in the CM + II-BI group, which was accompanied by the greatest rotation of the atlas and atlanto-condyle facet movement on cervical flexion and extension. Moreover, in such patients, increased Chamberlain's baseline violation indicated the aggregate invagination of the odontoid in the flexed position, and asymmetric displacement of atlantoaxial facets was observed. Seventeen CM + II-BI patients underwent surgical treatment with atlantoaxial distraction and occipitocervical fusion. The syringomyelia width and tonsillar herniation decreased significantly, and functional scores indicated symptom relief and good outcomes. CONCLUSIONS: CVJ instability, especially the ultramovement of atlanto-condyle facets, commonly exists in II-BI as evaluated using kinematic CT. The surgical strategy of atlantoaxial distraction and occipitocervical fusion should be considered to treat such patients.
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Malformación de Arnold-Chiari , Articulación Atlantoaxoidea , Platibasia , Fusión Vertebral , Malformación de Arnold-Chiari/complicaciones , Malformación de Arnold-Chiari/diagnóstico por imagen , Malformación de Arnold-Chiari/cirugía , Articulación Atlantoaxoidea/anomalías , Articulación Atlantoaxoidea/diagnóstico por imagen , Articulación Atlantoaxoidea/cirugía , Fenómenos Biomecánicos , Descompresión Quirúrgica/métodos , Humanos , Platibasia/complicaciones , Platibasia/diagnóstico por imagen , Platibasia/cirugía , Fusión Vertebral/métodos , Tomografía Computarizada por Rayos XRESUMEN
With the rapid development of sequencing technology, completed genomes of microbes have explosively emerged. For a newly sequenced prokaryotic genome, gene functional annotation and metabolism pathway assignment are important foundations for all subsequent research work. However, the assignment rate for gene metabolism pathways is lower than 48% on the whole. It is even lower for newly sequenced prokaryotic genomes, which has become a bottleneck for subsequent research. Thus, the development of a high-precision metabolic pathway assignment framework is urgently needed. Here, we developed PPA-GCN, a prokaryotic pathways assignment framework based on graph convolutional network, to assist functional pathway assignments using KEGG information and genomic characteristics. In the framework, genomic gene synteny information was used to construct a network, and ideas of self-supervised learning were inspired to enhance the framework's learning ability. Our framework is applicable to the genera of microbe with sufficient whole genome sequences. To evaluate the assignment rate, genomes from three different genera (Flavobacterium (65 genomes) and Pseudomonas (100 genomes), Staphylococcus (500 genomes)) were used. The initial functional pathway assignment rate of the three test genera were 27.7% (Flavobacterium), 49.5% (Pseudomonas) and 30.1% (Staphylococcus). PPA-GCN achieved excellence performance of 84.8% (Flavobacterium), 77.0% (Pseudomonas) and 71.0% (Staphylococcus) for assignment rate. At the same time, PPA-GCN was proved to have strong fault tolerance. The framework provides novel insights into assignment for metabolism pathways and is likely to inform future deep learning applications for interpreting functional annotations and extends to all prokaryotic genera with sufficient genomes.
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Patients with aortic stenosis and low left ventricular ejection fraction (LVEF) would benefit from transcatheter aortic valve replacement. However, the safety and efficacy of transcatheter aortic valve replacement in patients with aortic regurgitation and left ventricular dysfunction remains unknown.We defined LVEF < 50% as left ventricular dysfunction. A total of 27 symptomatic patients with aortic regurgitation and ejection fraction < 50% underwent transcatheter aortic valve replacement using the J-Valve™ system (JieCheng Medical Technology Co, Ltd, Suzhou, China) in Zhongshan Hospital, Fudan University, from May 2014 to June 2019. Procedural and postoperative clinical outcomes were analyzed according to Valve Academic Research Consortium-2 (VARC-2) criteria.All patients (eight females; 70.6 ± 7.1 years) were considered to be at least intermediate surgical risk and/or severe comorbidity precluding for surgical aortic valve replacement (logistic European System for Cardiac Operative Risk Evaluation, 16.8 ± 9.5%, range 4.6% to 37.9%) by a multidisciplinary heart team. Transapical implantations were successful in 26 (96.3%) patients. All-cause mortality was 3.7% in the latest follow-up (25-590 days, median 369 days). Significant improvements in LVEF, left ventricular end-diastolic, and systolic dimensions were observed after procedure (from 40.3 ± 6.7% to 50.8 ± 10.5%, P < 0.001; from 65.1 ± 8.9 mm to 56.0 ± 9.6 mm, P = 0.002; from 52.2 ± 9.8 mm to 35.9 ± 13.4 mm, P < 0.001, respectively). No patient had aortic stenosis and paravalvular leak more than moderate and heart function improvement was obtained in the majority of patients at 1-year follow-up.Transcatheter aortic valve replacement using the J-Valve™ system is a reasonable alternative for patients with aortic regurgitation and left ventricular dysfunction regarding promising short-term outcomes.