RESUMO
Protein-peptide interactions (PPepIs) are vital to understanding cellular functions, which can facilitate the design of novel drugs. As an essential component in forming a PPepI, protein-peptide binding sites are the basis for understanding the mechanisms involved in PPepIs. Therefore, accurately identifying protein-peptide binding sites becomes a critical task. The traditional experimental methods for researching these binding sites are labor-intensive and time-consuming, and some computational tools have been invented to supplement it. However, these computational tools have limitations in generality or accuracy due to the need for ligand information, complex feature construction, or their reliance on modeling based on amino acid residues. To deal with the drawbacks of these computational algorithms, we describe a geometric attention-based network for peptide binding site identification (GAPS) in this work. The proposed model utilizes geometric feature engineering to construct atom representations and incorporates multiple attention mechanisms to update relevant biological features. In addition, the transfer learning strategy is implemented for leveraging the protein-protein binding sites information to enhance the protein-peptide binding sites recognition capability, taking into account the common structure and biological bias between proteins and peptides. Consequently, GAPS demonstrates the state-of-the-art performance and excellent robustness in this task. Moreover, our model exhibits exceptional performance across several extended experiments including predicting the apo protein-peptide, protein-cyclic peptide and the AlphaFold-predicted protein-peptide binding sites. These results confirm that the GAPS model is a powerful, versatile, stable method suitable for diverse binding site predictions.
Assuntos
Peptídeos , Sítios de Ligação , Peptídeos/química , Peptídeos/metabolismo , Ligação Proteica , Biologia Computacional/métodos , Algoritmos , Proteínas/química , Proteínas/metabolismo , Aprendizado de MáquinaRESUMO
Inflammasomes play pivotal roles in inflammation by processing and promoting the secretion of IL-1ß. Caspase-1 is involved in the maturation of IL-1ß and IL-18, while human caspase-4 specifically processes IL-18. Recent structural studies of caspase-4 bound to Pro-IL-18 reveal the molecular basis of Pro-IL-18 activation by caspase-4. However, the mechanism of caspase-1 processing of pro-IL-1ß and other IL-1ß-converting enzymes remains elusive. Here, we observed that swine Pro-IL-1ß (sPro-IL-1ß) exists as an oligomeric precursor unlike monomeric human Pro-IL-1ß (hPro-IL-1ß). Interestingly, Seneca Valley Virus (SVV) 3C protease cleaves sPro-IL-1ß to produce mature IL-1ß, while it cleaves hPro-IL-1ß but does not produce mature IL-1ß in a specific manner. When the inflammasome is blocked, SVV 3C continues to activate IL-1ß through direct cleavage in porcine alveolar macrophages (PAMs). Through molecular modeling and mutagenesis studies, we discovered that the pro-domain of sPro-IL-1ß serves as an 'exosite' with its hydrophobic residues docking into a positively charged 3C protease pocket, thereby directing the substrate to the active site. The cleavage of sPro-IL-1ß generates a monomeric and active form of IL-1ß, initiating the downstream signaling. Thus, these studies provide IL-1ß is an inflammatory sensor that directly detects viral protease through an independent pathway operating in parallel with host inflammasomes.
Assuntos
Proteases Virais 3C , Inflamassomos , Interleucina-1beta , Picornaviridae , Proteínas Virais , Animais , Interleucina-1beta/metabolismo , Proteases Virais 3C/metabolismo , Suínos , Humanos , Proteínas Virais/metabolismo , Inflamassomos/metabolismo , Inflamação/metabolismo , Infecções por Picornaviridae/metabolismo , Infecções por Picornaviridae/virologia , Cisteína Endopeptidases/metabolismo , Especificidade da Espécie , Macrófagos Alveolares/virologia , Macrófagos Alveolares/metabolismoRESUMO
Orthocarboxylic acidsâorganic molecules carrying three hydroxyl groups at the same carbon atomâhave been distinguished as vital reactive intermediates by the atmospheric science and physical (organic) chemistry communities as transients in the atmospheric aerosol cycle. Predicted short lifetimes and their tendency to dehydrate to a carboxylic acid, free orthocarboxylic acids, signify one of the most elusive classes of organic reactive intermediates, with even the simplest representative methanetriol (CH(OH)3)âhistorically known as orthoformic acidânot previously been detected experimentally. Here, we report the first synthesis of the previously elusive methanetriol molecule in low-temperature mixed methanol (CH3OH) and molecular oxygen (O2) ices subjected to energetic irradiation. Supported by electronic structure calculations, methanetriol was identified in the gas phase upon sublimation via isomer-selective photoionization reflectron time-of-flight mass spectrometry combined with isotopic substitution studies and the detection of photoionization fragments. The first synthesis and detection of methanetriol (CH(OH)3) reveals its gas-phase stability as supported by a significant barrier hindering unimolecular decomposition. These findings progress our fundamental understanding of the chemistry and chemical bonding of methanetriol, hydroxyperoxymethane (CH3OOOH), and hydroxyperoxymethanol (CH2(OH)OOH), which are all prototype molecules in the oxidation chemistry of the atmosphere.
RESUMO
BACKGROUND & AIMS: Treatments directly targeting fibrosis remain limited. Given the unique intrinsic features of macrophages and their capacity to engraft in the liver, we genetically engineered bone marrow-derived macrophages with a chimeric antigen receptor (CAR) to direct their phagocytic activity against hepatic stellate cells (HSCs) in multiple mouse models. This study aimed to demonstrate the therapeutic efficacy of CAR macrophages (CAR-Ms) in mouse models of fibrosis and cirrhosis and to elucidate the underlying mechanisms. METHODS: uPAR expression was studied in patients with fibrosis/cirrhosis and in murine models of liver fibrosis, including mice treated with carbon tetrachloride, a 5-diethoxycarbonyl-1, 4-dihydrocollidine diet, or a high-fat/cholesterol/fructose diet. The safety and efficacy of CAR-Ms were evaluated in vitro and in vivo. RESULTS: Adoptive transfer of CAR-Ms resulted in a significant reduction in liver fibrosis and the restoration of function in murine models of liver fibrosis. CAR-Ms modulated the hepatic immune microenvironment to recruit and modify the activation of endogenous immune cells to drive fibrosis regression. These CAR-Ms were able to recruit and present antigens to T cells and mount specific antifibrotic T-cell responses to reduce fibroblasts and liver fibrosis in mice. CONCLUSION: Collectively, our findings demonstrate the potential of using macrophages as a platform for CAR technology to provide an effective treatment option for liver fibrosis. CAR-Ms might be developed for treatment of patients with liver fibrosis. IMPACT AND IMPLICATIONS: Liver fibrosis is an incurable condition that afflicts millions of people globally. Despite the clear clinical need, therapies for liver fibrosis are limited. Our findings provide the first preclinical evidence that chimeric antigen receptor (CAR)-macrophages (CAR-Ms) targeting uPAR can attenuate liver fibrosis and cirrhosis. We show that macrophages expressing this uPAR CAR exert a direct antifibrotic effect and elicit a specific T-cell response that augments the immune response against liver fibrosis. These findings demonstrate the potential of using CAR-Ms as an effective cell-based therapy for the treatment of liver fibrosis.
Assuntos
Modelos Animais de Doenças , Cirrose Hepática , Macrófagos , Receptores de Antígenos Quiméricos , Animais , Camundongos , Macrófagos/imunologia , Macrófagos/metabolismo , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Cirrose Hepática/terapia , Cirrose Hepática/imunologia , Humanos , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/imunologia , Masculino , Camundongos Endogâmicos C57BL , Feminino , Transferência Adotiva/métodosRESUMO
Circulating microRNAs (miRNAs) have recently emerged as noninvasive disease biomarkers. Quantitative detection of circulating miRNAs could offer significant information for clinical diagnosis due to its significance in the development of biological processes. In response to the current challenges of circulating miRNA detection, we introduce a sensitive, selective, and versatile circulating miRNA detection strategy using terminal deoxynucleotidyl transferase (TdT)-catalyzed RNA-primed DNA polymerization (TCRDP) coupled with semiarbitrary qPCR (SAPCR). Semiarbitrary qPCR was first developed here to detect long fragment targets with only a short-known sequence or to detect a short fragment target after extension with terminal transferase. Besides, the subsequent results show that TdT has a preference for RNA, particularly for extending RNAs with purine-rich and unstructured ends. Consequently, utilizing this assay, we have successfully applied it to the quantitative analysis of circulating miR-122 in animal models, a sensitive and informative biomarker for drug-induced liver injury, and as low as 200 zmol of the target is detected with desirable specificity and sensitivity, indicating that the TCRDP-SAPCR can offer a promising platform for nucleic acids analysis.
Assuntos
DNA Nucleotidilexotransferase , DNA , Polimerização , DNA Nucleotidilexotransferase/metabolismo , DNA Nucleotidilexotransferase/química , Humanos , DNA/química , DNA/sangue , Animais , MicroRNA Circulante/sangue , MicroRNAs/sangue , Reação em Cadeia da Polimerase em Tempo RealRESUMO
BACKGROUND: Emerging data suggested that lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerotic cardiovascular disease. Previous studies indicated fibrinogen (Fib) had synergetic effect on Lp(a)-induced events. However, combined impact of Fib and Lp(a) on ischemic stroke has not been elucidated. METHODS: In this prospective study, we consecutively enrolled 8263 patients with stable coronary artery diseases (CAD) from 2011 to 2017. Patients were categorized into three groups according to tertiles of Lp(a) levels [Lp(a)-low, Lp(a)-medium, and Lp(a)-high] and further divided into nine groups by Lp(a) and Fib levels. All subjects were followed up for the occurrence of ischemic stroke. RESULTS: During a median follow-up of 37.7 months, 157 (1.9%) ischemic strokes occurred. Stroke incidence increased by Lp(a) (1.1 vs. 2.1 vs. 2.5%, Cochran-Armitage p < .001) and Fib (1.1 vs. 2.0 vs. 2.6%, Cochran-Armitage p < .001) categories. When further classified into nine groups by Lp(a) and Fib levels, the incidence of ischemic stroke in group 9 [Lp(a)-high and Fib-high] was significantly higher than that in group 1 [Lp(a)-low and Fib-low] (3.1 vs. 6%, p < .001). The group 9 was associated with a highest risk for ischemic stroke (adjusted HR 4.907, 95% CI: 2.154-11.18, p < .001), compared with individuals in the Lp(a)-high (adjusted HR 2.290, 95% CI: 1.483-3.537, p < .001) or Fib-high (adjusted HR 1.184, 95% CI: 1.399-3.410, p = .001). Furthermore, combining Lp(a) with Fib increased C-statistics by .045 (p = .004). CONCLUSIONS: Current study first demonstrated that elevated Lp(a) combining with Fib evaluation enhanced the risk of ischemic stroke in patients with CAD beyond Lp(a) or Fib alone.
Assuntos
Doença da Artéria Coronariana , Fibrinogênio , AVC Isquêmico , Lipoproteína(a) , Humanos , Lipoproteína(a)/sangue , Lipoproteína(a)/metabolismo , Fibrinogênio/metabolismo , Masculino , Feminino , Doença da Artéria Coronariana/epidemiologia , Pessoa de Meia-Idade , Idoso , Estudos Prospectivos , AVC Isquêmico/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Incidência , Fatores de RiscoRESUMO
1,3-Enynes with conjugated alkene and alkyne moieties are attractive building blocks in synthetic chemistry. However, neither 4,1-hydrophosphination nor dihydrophosphination of 1,3-enynes has been reported. In this paper, the divalent ytterbium and calcium amide complexes supported by silaimine-functionalized cyclopentadienyl ligands (C5Me4-Si(L)=NR) were developed, which successfully catalyzed the efficient single and double hydrophosphination of 1,3-enynes with diarylphosphines. The hydrophosphination reactions selectively produced homoallenyl phosphines and (E)-propenylene diphosphines, respectively. This work demonstrated the potential of hemilabile silaimine-Cp ligands in the supporting the efficient and selective rare- and alkaline-earth catalysts.
RESUMO
Osteocalcin is the most abundant noncollagenous bone protein and the functions in bone remineralization as well as in inhibition of bone growth have remained unclear. In this contribution, we explain the dual role of osteocalcin in the nucleation of new calcium phosphate during bone remodeling and in the inhibition of hydroxyapatite crystal growth at the molecular scale. The mechanism was derived using pH-resolved all-atom models for the protein, phosphate species, and hydroxyapatite, along with molecular dynamics simulations and experimental and clinical observations. Osteocalcin binds to (hkl) hydroxyapatite surfaces through multiple residues, identified in this work, and the fingerprint of binding residues varies as a function of the (hkl) crystal facet and pH value. On balance, the affinity of osteocalcin to hydroxyapatite slows down crystal growth. The unique tricalcium γ-carboxylglutamic acid (Gla) domain hereby rarely adsorbs to hydroxyapatite surfaces and faces instead toward the solution. The Gla domain enables prenucleation of calcium phosphate for new bone formation at a slightly acidic pH of 5. The growth of prenucleation clusters of calcium phosphate continues upon increase in pH value from 5 to 7 and is much less favorable, or not observed, on the native osteocalcin structure at and above neutral pH values of 7. The results provide mechanistic insight into the early stages of bone remodeling from the molecular scale, help inform mutations of osteocalcin to modify binding to apatites, support drug design, and guide toward potential cures for osteoporosis and hyperosteogeny.
Assuntos
Osso e Ossos , Durapatita , Osteocalcina/genética , Osteocalcina/química , Osteocalcina/metabolismo , Osso e Ossos/metabolismo , Fosfatos de Cálcio/farmacologiaRESUMO
The interlayer strategy has emerged as an effective approach for modulating the interfacial polymerization process and improving the permeability and selectivity of polyamide membranes. However, the underlying mechanisms by which charged interlayers influence the interfacial polymerization process remain inadequately understood. In this study, we utilized two distinct charged cellulose nanofibers, namely, carboxylated cellulose (â-CNF) and quaternized cellulose ([Formula: see text]-CNF), as interlayers to regulate the interfacial polymerization process. Through simulation results, isothermal titration calorimetry (ITC) and UV tests, we demonstrated that the [Formula: see text]-CNF interlayer, which possesses stronger hydration capability and better piperazine affinity, enhanced the diffusion of piperazine across the reaction interface compared with the â-CNF interlayer. This led to an acceleration of the interfacial polymerization process and the formation of a denser membrane structure. Further investigation revealed that the charged interlayers significantly influenced the surface charging properties of the resulting nanofiltration membranes within a 30 nm range of electrostatic effects. Specifically, the â-CNF interlayer conferred a higher negative charge to the membrane surface, while the [Formula: see text]-CNF interlayer endowed the membranes with a lower surface negative charge. Leveraging these differences, the â-i-TFC membranes exhibited exceptional separation performance for divalent anions, achieving a SO42-/Cl- selectivity of 136. Conversely, the [Formula: see text]-i-TFC membrane demonstrated an enhanced separation of divalent cations, displaying a Mg2+/Na+ selectivity of 3.5. This study lays the groundwork for regulating the surface charging properties of polyamide membranes, offering potential advancements in nanofiltration applications.
RESUMO
Epidermal growth factor receptor (EGFR) is one of the most studied drug targets for treating non-small-cell lung cancer (NSCLC). However, there are no approved inhibitors for the C797S resistance mutation caused by the third-generation EGFR inhibitor (Osimertinib). Therefore, the development of fourth-generation EGFR inhibitors is urgent. In this study, we clarified the structure-activity relationship of several synthesized compounds as fourth-generation inhibitors against human triple (Del19/T790M/C797S) mutation. Representative compound 52 showed potent inhibitory activity against EGFRL858R/T790M/C797S with an IC50 of 0.55 nM and significantly inhibited the proliferation of the Ba/F3 cell line harboring EGFRL858R/T790M/C797S with an IC50 of 43.28 nM. Moreover, 52 demonstrated good pharmacokinetic properties and excellent in vivo efficacy. Overall, the compound 52 can be considered a promising candidate for overcoming EGFR C797S-mediated mutations.
Assuntos
Acrilamidas , Compostos de Anilina , Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Proliferação de Células , Relação Dose-Resposta a Droga , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB , Neoplasias Pulmonares , Inibidores de Proteínas Quinases , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Receptores ErbB/genética , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Acrilamidas/farmacologia , Acrilamidas/química , Acrilamidas/síntese química , Relação Estrutura-Atividade , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Compostos de Anilina/farmacologia , Compostos de Anilina/química , Compostos de Anilina/síntese química , Compostos de Anilina/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Estrutura Molecular , Animais , Camundongos , Linhagem Celular Tumoral , Mutação , Indóis , PirimidinasRESUMO
Tendon injuries are common orthopedic ailments with a challenging healing trajectory, especially in cases like the Achilles tendon afflictions. The healing trajectory of tendon injuries is often suboptimal, leading to scar formation and functional impairment due to the inherent low metabolic activity and vascularization of tendon tissue. As pressing is needed for effective interventions, efforts are made to explore biomaterials to augment tendon healing. However, tissue engineering approaches face hurdles in optimizing tissue scaffolds and nanomedical strategies. To navigate these challenges, an injectable hydrogel amalgamated with human umbilical vein endothelial cells-derived exosomes (HUVECs-Exos) was prepared and named H-Exos-gel in this study, aiming to enhance tendon repair. In our research involving a model of Achilles tendon injuries in 60 rats, we investigated the efficacy of H-Exos-gel through histological assessments performed at 2 and 4 weeks and behavioral assessments conducted at the 4-week mark revealed its ability to enhance the Achilles tendon's mechanical strength, regulate inflammation and facilitate tendon regeneration and functional recovery. Mechanically, the H-Exos-gel modulated the cellular behaviors of macrophages and tendon-derived stem cells (TDSCs) by inhibiting inflammation-related pathways and promoting proliferation-related pathways. Our findings delineate that the H-Exos-gel epitomizes a viable bioactive medium for tendon healing, heralding a promising avenue for the clinical amelioration of tendon injuries.
Assuntos
Tendão do Calcâneo , Exossomos , Células Endoteliais da Veia Umbilical Humana , Hidrogéis , Regeneração , Traumatismos dos Tendões , Cicatrização , Animais , Exossomos/metabolismo , Hidrogéis/química , Hidrogéis/farmacologia , Ratos , Humanos , Tendão do Calcâneo/lesões , Traumatismos dos Tendões/terapia , Cicatrização/efeitos dos fármacos , Masculino , Ratos Sprague-Dawley , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Engenharia Tecidual/métodos , Alicerces Teciduais/química , InflamaçãoRESUMO
BACKGROUND: Despite the higher sensitivity of melanoma towards ferroptosis and photodynamic therapy (PDT), the lack of efficient ferroptosis inducers and the poor solubility of photosensitizers restrict their synergistic strategies. With unique advantages, carbon dots (CDs) are expected to serve as innovative building blocks for combination therapy of cancers. RESULTS: Herein, an ferroptosis/PDT integrated nanoplatform for melanoma therapy is constructed based on chlorin e6-modified Fe ions-doped carbon dots (Fe-CDs@Ce6). As a novel type of iron-carbon hybrid nanoparticles, the as-prepared Fe-CDs can selectively activate ferroptosis, prevent angiogenesis and inhibit the migration of mouse skin melanoma cells (B16), but have no toxicity to normal cells. The nano-conjugated structures facilitate not only the aqueous dispersibility of Ce6, but also the self-accumulation ability of Fe-CDs@Ce6 within melanoma area without requiring extra targets. Moreover, the therapeutic effects of Fe-CDs@Ce6 are synergistically enhanced due to the increased GSH depletion by PDT and the elevated singlet oxygen (1O2) production efficiency by Fe-CDs. When combined with laser irradiation, the tumor growth can be significantly suppressed by Fe-CDs@Ce6 through cyclic administration. The T2-weighted magnetic resonance imaging (MRI) capability of Fe-CDs@Ce6 also reveals their potentials for cancer diagnosis and navigation therapy. CONCLUSIONS: Our findings indicate the multifunctionality of Fe-CDs@Ce6 in effectively combining ferroptosis/PDT therapy, tumor targeting and MRI imaging, which enables Fe-CDs@Ce6 to become promising biocompatible nanoplatform for the treatment of melanoma.
Assuntos
Ferroptose , Melanoma , Nanopartículas , Fotoquimioterapia , Camundongos , Animais , Fotoquimioterapia/métodos , Melanoma/tratamento farmacológico , Carbono/farmacologia , Carbono/química , Linhagem Celular Tumoral , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Fármacos Fotossensibilizantes/química , Imageamento por Ressonância Magnética , Nanopartículas/químicaRESUMO
BACKGROUND: Immune checkpoint inhibitors (ICIs) can improve survivals of metastatic triple negative breast cancer (mTNBC); however, we still seek circulating blood biomarkers to predict the efficacy of ICIs. MATERIALS AND METHODS: In this study, we analyzed the data of ICIs treated mTNBC collected in Anhui Medical University affiliated hospitals from 2018 to 2023. The counts of lymphocytes, monocytes, platelets, and ratio indexes (NLR, MLR, PLR) in peripheral blood were investigated via the Kaplan-Meier curves and the Cox proportional-hazards model. RESULTS: The total of 50 mTNBC patients were treated with ICIs. High level of peripheral lymphocytes and low level of NLR and MLR at baseline and post the first cycle of ICIs play the predictable role of immunotherapies. Lymphocytes counts (HR = 0.280; 95% CI: 0.095-0.823; p = 0.021) and NLR (HR = 1.150; 95% CI: 1.052-1.257; p = 0.002) are significantly correlated with overall survival. High NLR also increases the risk of disease progression (HR = 2.189; 95% CI:1.085-4.414; p = 0.029). When NLR at baseline ≥ 2.75, the hazard of death (HR = 2.575; 95% CI:1.217-5.447; p = 0.013) and disease progression (HR = 2.189; 95% CI: 1.085-4.414; p = 0.029) significantly rise. HER-2 expression and anti-tumor therapy lines are statistically correlated with survivals. CONCLUSIONS: Before the initiation of ICIs, enriched peripheral lymphocytes and poor neutrophils and NLR contribute to the prediction of survivals.
Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Prognóstico , Biomarcadores , Linfócitos/patologia , Progressão da Doença , Estudos Retrospectivos , Biomarcadores TumoraisRESUMO
OBJECTIVE: We aimed to develop a tool for virtual orthodontic bracket removal based on deep learning algorithms for feature extraction from bonded teeth and to demonstrate its application in a bracket position assessment scenario. MATERIALS AND METHODS: Our segmentation network for virtual bracket removal was trained using dataset A, containing 978 bonded teeth, 20 original teeth, and 20 brackets generated by scanners. The accuracy and segmentation time of the network were tested by dataset B, which included an additional 118 bonded teeth without knowing the original tooth morphology. This tool was then applied for bracket position assessment. The clinical crown center, bracket center, and orientations of separated teeth and brackets were extracted for analyzing the linear distribution and angular deviation of bonded brackets. RESULTS: This tool performed virtual bracket removal in 2.9 ms per tooth with accuracies of 98.93% and 97.42% (P < 0.01) in datasets A and B, respectively. The tooth surface and bracket characteristics were extracted and used to evaluate the results of manually bonded brackets by 49 orthodontists. Personal preferences for bracket angulation and bracket distribution were displayed graphically and tabularly. CONCLUSIONS: The tool's efficiency and precision are satisfactory, and it can be operated without original tooth data. It can be used to display the bonding deviation in the bracket position assessment scenario. CLINICAL SIGNIFICANCE: With the aid of this tool, unnecessary bracket removal can be avoided when evaluating bracket positions and modifying treatment plans. It has the potential to produce retainers and orthodontic devices prior to tooth debonding.
Assuntos
Aprendizado Profundo , Colagem Dentária , Braquetes Ortodônticos , Colagem Dentária/métodos , Descolagem Dentária/métodos , Microscopia Eletrônica de VarreduraRESUMO
In order to solve the problem of low recognition accuracy of traditional pig sound recognition methods, deep neural network (DNN) and Hidden Markov Model (HMM) theory were used as the basis of pig sound signal recognition in this study. In this study, the sounds made by 10 landrace pigs during eating, estrus, howling, humming and panting were collected and preprocessed by Kalman filtering and an improved endpoint detection algorithm based on empirical mode decomposition-Teiger energy operator (EMD-TEO) cepstral distance. The extracted 39-dimensional mel-frequency cepstral coefficients (MFCCs) were then used as a dataset for network learning and recognition to build a DNN- and HMM-based sound recognition model for pig states. The results show that in the pig sound dataset, the recognition accuracy of DNN-HMM reaches 83%, which is 22% and 17% higher than that of the baseline models HMM and GMM-HMM, and possesses a better recognition effect. In a sub-dataset of the publicly available dataset AudioSet, DNN-HMM achieves a recognition accuracy of 79%, which is 8% and 4% higher than the classical models SVM and ResNet18, respectively, with better robustness.
Assuntos
Algoritmos , Redes Neurais de Computação , Feminino , Suínos , Animais , Som , Cadeias de MarkovRESUMO
BACKGROUND: Significant individual differences exist in the insight of patients with obsessive-compulsive disorder (OCD), and the clinical characteristics of OCD patients with varying levels of insight are not entirely uniform. This study aims to investigate disparities in disease severity, anxiety, and depression status among OCD patients with differing levels of insight, with the goal of generating novel treatment strategies for OCD. METHODS: A total of 114 patients diagnosed with OCD were recruited from the Department of Psychology at Affiliated Mental Health Center & Hangzhou Seventh People's Hospital to participate in this research. Based on their Total Insight and Treatment Attitude Questionnaire (ITAQ) scores, the patients were divided into two groups: Group OCD with high insight (referred to as Group OCD-HI, ITAQ score ≥20 points, n = 80) and Group OCD with low insight (referred to as Group OCD-LI, ITAQ score <20 points, n = 34). Subsequently, the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), Hamilton Anxiety Scale (HAMA), and Hamilton Depression Scale (HAMD) scores were compared between the two groups. All questionnaires for this study were completed by experienced psychiatrists. RESULTS: The Y-BOCS scores for YB1, YB2, YB4, YB5, YB6, YB9, and the total Y-BOCS scores in Group OCD-HI were significantly higher than those in Group OCD-LI (p < 0.05). Conversely, Group OCD-HI exhibited significantly lower HAMA and HAMD scores compared to Group OCD-LI (p < 0.05). Furthermore, the total ITAQ score displayed a significant negative correlation with the total Y-BOCS, HAMA, and HAMD scores (p < 0.05). CONCLUSIONS: This study revealed that certain OCD patients exhibit incomplete insight, and this lack of insight is strongly associated with increased disease severity and heightened levels of anxiety and depression. It is hoped that by enhancing the insight of OCD patients, the goal of ameliorating disease symptoms and alleviating negative emotions can be attained.
Assuntos
Depressão , Transtorno Obsessivo-Compulsivo , Humanos , Transtorno Obsessivo-Compulsivo/complicações , Transtorno Obsessivo-Compulsivo/diagnóstico , Transtornos de Ansiedade , Ansiedade , Gravidade do PacienteRESUMO
OBJECTIVES: To investigate the clinical phenotypes and genotypes of children with congenital fibrinogen disorder (CFD). METHODS: A retrospective analysis was conducted on the clinical data of 16 children with CFD. Polymerase chain reaction was used to amplify all exons and flanking sequences of the FGA, FGB, and FGG genes, and sequencing was performed to analyze mutation characteristics. RESULTS: Among the 16 children, there were 9 boys (56%) and 7 girls (44%), with a median age of 4 years at the time of attending the hospital. Among these children, 9 (56%) attended the hospital due to bleeding events, and 7 (44%) were diagnosed based on preoperative examination. The children with bleeding events had a significantly lower fibrinogen activity than those without bleeding events (P<0.05). Genetic testing was conducted on 12 children and revealed a total of 12 mutations, among which there were 4 novel mutations, i.e., c.80T>C and c.1368delC in the FGA gene and c.1007T>A and C.1053C>A in the FGG gene. There were 2 cases of congenital afibrinogenemia caused by null mutations of the FGA gene, with relatively severe bleeding symptoms. There were 7 cases of congenital dysfibrinogenemia mainly caused by heterozygous missense mutations of the FGG and FGA genes, and their clinical phenotypes ranged from asymptomatic phenotype to varying degrees of bleeding. CONCLUSIONS: The clinical phenotypes of children with CFD are heterogeneous, and the severity of bleeding is associated with the level of fibrinogen activity, but there is a weak association between clinical phenotype and genotype.
Assuntos
Afibrinogenemia , Fibrinogênio , Genótipo , Mutação , Fenótipo , Humanos , Masculino , Feminino , Afibrinogenemia/genética , Pré-Escolar , Criança , Fibrinogênio/genética , Lactente , Estudos Retrospectivos , Adolescente , Hemorragia/genética , Hemorragia/etiologiaRESUMO
Background: Transradial artery (TRA) access for percutaneous coronary intervention (PCI) was associated with lower risks of major bleeding and vascular complications compared to transfemoral artery access. Use of large-bore ( ≥ 7-Fr) guiding catheters through TRA approach increased the likelihood of radial artery occlusion (RAO). This study aimed to investigate whether use of the thin-walled 7-Fr Glidesheath Slender, allowing PCI with large-caliber guiding catheters, is superior to standard 7-Fr Cordis sheath with respect to periprocedural RAO within 24 hours after transradial coronary intervention (TRI) in complex lesions. Methods: A prospective randomized, controlled, single-blinded (patient-blinded) trial was conducted, randomizing 504 patients with TRI for complex lesions to either 7-Fr Glidesheath Slender or conventional 7-Fr Cordis sheath. The primary outcome was defined as the incidence of periprocedural RAO with Doppler ultrasound during the first 24 hours after TRI. Results: The incidence of early RAO was 10.3% for 7-Fr Glidesheath Slender and 13.5% for conventional 7-Fr sheath (p = 0.271). The procedural success rate for Glidesheath Slender was 92.9% and for Cordis sheath was 93.7% (p = 0.722). There was no signficiant difference between treatment arms in terms of local hematoma and radial spasm, whereas use of the Glidesheath Slender was associated with significantly less pain during the procedure (numeric rating scale [NRS], 2.27 ± 0.75 vs. 2.45 ± 0.95, p = 0.017). The assessment of radial artery in ultrasound parameters after complex TRI was improved with Glidesheath Slender. Conclusions: Among patients with complex coronary lesions undergoing TRI, 7-Fr Glidesheath Slender was not superior to conventional 7-Fr in the prevention of periprocedural RAO within 24 hours following complex PCI, without reducing RAO occurrence. Clinical Trial Registration: NCT04748068.
RESUMO
BACKGROUND: Multiple primary malignant tumors (MPMTs) was first described by Billroth as early as 1889, with the first report published by Warren and Gates in 1932. Since then, numerous cases have been reported. A literature review of 1104269 patients with cancer revealed that the incidence of MPMTs ranged from 0.73 to 11.7%. In recent years, however, there has been a significant upward trend in the incidence of this phenomenon, which may be associated with many different factors, including the advancement of modern diagnostic procedures facilitating the examination and diagnosis of more MPMTs, increased exposure to chemotherapy and radiotherapy that exacerbate the risk of new malignant tumors in patients with cancer, and prolonged survival of patients with cancer allowing sufficient time for the development of new primary cancers. AIM: To analyze the incidence, clinical features, treatment factors, prevalence, and prognosis of patients with MPMTs in the gastrointestinal tract treated in a single center. Additionally, we analyzed the different tumor combinations, time interval between the occurrence of tumors, and staging. METHODS: This retrospective cohort study analyzed 8059 patients with pathologically confirmed gastrointestinal malignant tumors treated at the Gansu Province Hospital in Lanzhou, Gansu, China between June 2011 and June 2020. Of these, 85 patients had MPMTs. The clinical features, treatment factors, prevalence, and prognosis of this latter cohort were analyzed. RESULTS: The incidence of MPMTs in patients with gastrointestinal malignant tumors was 1.05% (85/8059), including 83 double primary malignant tumors and two triple primary malignant tumors of which 57 (67.06%) were synchronous MPMTs (SMPMTs) and 28 (32.94%) were metachronous MPMTs (MMPMTs). The most frequent associations were found between the rectum colon cancers within the SMPMT category and the gastric-colon cancers within the MMPMT category. For the MMPMTs, the median interval was 53 months. The overall 1-, 3- and 5-year survival rates from diagnosis of the first primary cancer were 91.36%, 65.41%, and 45.97%, respectively; those from diagnosis of the second primary cancer were 67.90%, 29.90%, and 17.37%, respectively. CONCLUSION: MPMTs in the gastrointestinal tract have a high incidence and poor prognosis. Thus, it is necessary to perform both gastroscopy and colonoscopy in patients with gastrointestinal tumors. Multidisciplinary comprehensive diagnosis and treatment may improve the diagnosis rate and treatment efficiency of MPMTs.