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Molecular editing promises to facilitate the rapid diversification of complex molecular architectures by rapidly and conveniently altering core frameworks. This approach has the potential to accelerate both drug discovery and total synthesis. In this study, we present a novel protocol for the molecular editing of pyrroles. Initially, N-Boc pyrroles and alkynes are converted into N-bridged compounds through a Diels-Alder reaction. These compounds then undergo deprotection of the Boc group, nitrosylation, and cheletropic N2O extrusion to yield benzene or naphthalene products. By using benzyne as a substrate, this method can be conceptually viewed as a fusion of skeletal editing of the pyrrole ring and site-selective peripheral editing of the benzene ring. Furthermore, this proof-of-concept protocol has demonstrated its potential to transform the (hetero)arene motif from commercially available drugs, offering the possibility of generating new biologically active compounds.
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BACKGROUND: Laparoscopic surgery has been endorsed by clinical guidelines for colon cancer, but not for rectal cancer on account of unapproved oncologic equivalence with open surgery. AIMS: We started this largest-to-date meta-analysis to comprehensively evaluate the safety and efficacy of laparoscopy in the treatment of rectal cancer compared with open surgery. MATERIALS & METHODS: Both randomized and nonrandomized controlled trials comparing laparoscopic proctectomy and open surgery between January 1990 and March 2020 were searched in PubMed, Cochrane Library and Embase Databases (PROSPERO registration number CRD42020211718). The data of intraoperative, pathological, postoperative and survival outcomes were compared between two groups. RESULTS: Twenty RCTs and 93 NRCTs including 216,615 patients fulfilled the inclusion criteria, with 48,888 patients received laparoscopic surgery and 167,727 patients underwent open surgery. Compared with open surgery, laparoscopic surgery group showed faster recovery, less complications and decreased mortality within 30 days. The positive rate of circumferential margin (RR = 0.79, 95% CI: 0.72 to 0.85, p < 0.0001) and distal margin (RR = 0.75, 95% CI: 0.66 to 0.85 p < 0.0001) was significantly reduced in the laparoscopic surgery group, but the completeness of total mesorectal excision showed no significant difference. The 3-year and 5-year local recurrence, disease-free survival and overall survival were all improved in the laparoscopic surgery group, while the distal recurrence did not differ significantly between the two approaches. CONCLUSION: Laparoscopy is non-inferior to open surgery for rectal cancer with respect to oncological outcomes and long-term survival. Moreover, laparoscopic surgery provides short-term advantages, including faster recovery and less complications.
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Laparoscopía , Neoplasias del Recto , Humanos , Laparoscopía/métodos , Laparoscopía/efectos adversos , Márgenes de Escisión , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Proctectomía/métodos , Proctectomía/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Neoplasias del Recto/cirugía , Neoplasias del Recto/mortalidad , Neoplasias del Recto/patología , Resultado del TratamientoRESUMEN
The novel HLA-A*02:1144 allele differs from HLA-A*02:03:01:01 by 3 nucleotides in exon 7.
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Exones , Antígeno HLA-A2 , Humanos , Alelos , Donantes de Sangre , Pueblos del Este de Asia/genética , Antígeno HLA-A2/genética , Análisis de Secuencia de ADNRESUMEN
BACKGROUND: Internet addiction jeopardizes teenagers' physical and mental health, as well as their academic performance, and causes a variety of cognitive dysfunctions and psychological and mental health illnesses, among other things. It is a huge issue that families, schools, and society must address immediately. OBJECTIVES: This study used network meta-analysis to evaluate the impact of several interventions on college students' Internet addiction. The goal was to identify the most effective interventions and establish a reference for future interventions. We systematically searched relevant literature in domestic and international databases such as Web of Science, PubMed, EMBASE, Cochrane Library, Pro Quest, China Knowledge, Wan fang, Wipo, etc. We assessed the risk of bias according to the revised Cochrane Randomized Trials Risk of Bias Tool (RoB2) and used R Studio Software and Stata 14.0 for traditional meta-analysis and network meta-analysis. A network meta-analysis based on the IAT scale showed that comprehensive interventions had the highest probability of being the best intervention for IA (SUCRA = 90.6 % based on IAT); focused solution short-term therapy had the highest probability of being the best intervention for IA based on the CIAS-R (19 White Feather) scale (SUCRA = 100 %). CONCLUSIONS: The majority of interventions have a significant influence on the treatment of IA, and improvements in Internet addiction symptoms are more noticeable when a combination of interventions is used rather than just one.
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Genome transcription and replication of influenza A virus (FluA), catalyzed by viral RNA polymerase (FluAPol), are delicately controlled across the virus life cycle. A switch from transcription to replication occurring at later stage of an infection is critical for progeny virion production and viral non-structural protein NS2 has been implicated in regulating the switch. However, the underlying regulatory mechanisms and the structure of NS2 remained elusive for years. Here, we determine the cryo-EM structure of the FluAPol-NS2 complex at ~3.0 Å resolution. Surprisingly, three domain-swapped NS2 dimers arrange three symmetrical FluPol dimers into a highly ordered barrel-like hexamer. Further structural and functional analyses demonstrate that NS2 binding not only hampers the interaction between FluAPol and the Pol II CTD because of steric conflicts, but also impairs FluAPol transcriptase activity by stalling it in the replicase conformation. Moreover, this is the first visualization of the full-length NS2 structure. Our findings uncover key molecular mechanisms of the FluA transcription-replication switch and have implications for the development of antivirals.
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Quantification of the unbound portion of platinum (Pt) in human plasma is important for assessing the pharmacokinetics of the chemotherapeutic drug cisplatin. In this study, we sought to compare the recovery of unbound Pt using Nanosep® filters to 1) traditional filters (Centrifree®, Centrisart®, Amicon®) or trichloroacetic acid (TCA) protein precipitation, and 2) unbound, bound, and total Pt concentrations in clinical specimens. For the tested filters, the impact of 1) molecular weight cut-offs, 2) centrifugation force, and 3) total Pt concentration on Pt binding in human plasma was evaluated. Pt was quantified using inductively coupled-plasma mass spectrometry. In human plasma spiked with 0.9 µg/mL Pt, the percent of unbound Pt increased at higher centrifugation speeds. By comparison, the percent of unbound Pt was highest (42.1%) following TCA protein precipitation. When total Pt was ≤0.9 µg/mL, unbound Pt (â¼20-30%) was consistent across filters. Conversely, when plasma was spiked with Pt exceeding 0.9 µg/mL, the percent of unbound Pt increased from 36.5 to 48% using ultrafiltration, compared to 63.4% to 79% with TCA precipitation. In patients receiving cisplatin-containing chemotherapy, the fraction of unbound Pt at concentrations exceeding 0.9 µg/mL ranged between 35 and 90%. Moreover, the unbound fraction of Pt in plasma correlated with the concentration of unbound (R2 = 0.738) and total Pt (R2 = 0.335). In summary, this study demonstrates that 1) the percent of unbound Pt is influenced by total and unbound Pt levels in vitro and in clinical specimens, and 2) ultrafiltration with Nanosep® filters is a feasible method for quantifying unbound Pt concentrations in human plasma.
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Precipitación Química , Cisplatino , Ultrafiltración , Humanos , Ultrafiltración/métodos , Cisplatino/sangre , Cisplatino/farmacocinética , Platino (Metal)/sangre , Platino (Metal)/farmacocinética , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Unión Proteica , Ácido Tricloroacético/sangreRESUMEN
HLA-B*40:86 differs from B*40:06:01:03 by a single nucleotide exchange in exon 3.
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Exones , Antígeno HLA-B40 , Humanos , Alelos , Secuencia de Bases , Pueblos del Este de Asia/genética , Prueba de Histocompatibilidad , Antígeno HLA-B40/genética , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN/métodosRESUMEN
BACKGROUND: Sarcopenic obesity (SO) affects outcomes in various malignancies. However, its clinical significance in patients undergoing neoadjuvant chemotherapy (NAC) for locally advanced gastric cancer (LAGC) remains unclear. This study investigated the impact of pre- and post-NAC SO on postoperative morbidity and survival. METHODS: Data from 207 patients with LAGC, who underwent NAC followed by radical gastrectomy between January 2010 and October 2019, were reviewed. Skeletal muscle mass and visceral fat area were measured pre- and post-NAC using computed tomography to define sarcopenia and obesity, the coexistence of which was defined as SO. RESULTS: Among the patients, 52 (25.1%) and 38 (18.4%) developed SO before and after NAC, respectively. Both pre- (34.6%) and post- (47.4%) NAC SO were associated with the highest postoperative morbidity rates; however, only post-NAC SO was an independent risk factor for postoperative morbidity [hazard ratio (HR) = 9.550, 95% confidence interval (CI) = 2.818-32.369; P < .001]. Pre-NAC SO was independently associated with poorer 3-year overall [46.2% vs. 61.3%; HR = 1.258 (95% CI = 1.023-1.547); P = .049] and recurrence-free [39.3% vs. 55.4%; HR 1.285 (95% CI 1.045-1.579); P = .017] survival. CONCLUSIONS: Pre-NAC SO was an independent prognostic factor in patients with LAGC undergoing NAC; post-NAC SO independently predicted postoperative morbidity.
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BACKGROUND: Olive is an evergreen tree of Oleaceae Olea with numerous bioactive components. While the anti-inflammatory properties of olive oil and the derivatives are well-documented, there remains a dearth of in-depth researches on the immunosuppressive effects of olive fruit water extract. This study aimed to elucidate the dose-effect relationship and underlying molecular mechanisms of olive fruit extract in mediating anti-inflammatory responses. METHODS AND RESULTS: The impacts of olive fruit extract on the release of nitric oxide (NO), tumor necrosis factor (TNF-α), interleukins-6 (IL-6) and reactive oxygen species (ROS) were assessed in RAW264.7 cells induced by lipopolysaccharide (LPS). For deeper understanding, the expression of genes encoding inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-α and IL-6 was quantitatively tested. Additionally, the expression patterns of MAPK and NF-κB pathways were further observed to analyze the action mechanisms. Results suggested that olive fruit extract (200, 500, 1000 µg/mL) markedly exhibited a dose-dependent reduction in the generation of NO, TNF-α, IL-6 and ROS, as well as the expression of correlative genes studied. The activation of ERK, JNK, p38, IκB-α and p65 were all suppressed when p65 nuclear translocation was further restricted by olive fruit extract in NF-κB and MAPK signal pathways. CONCLUSIONS: Olive fruit extract targeted imposing restrictions on the signal transduction of key proteins in NF-κB and MAPK pathways, and thereby lowered the level of inflammatory mediators, which put an enormous hindrance to inflammatory development. Accordingly, it is reasonable to consider olive fruit as a potent ingredient in immunomodulatory products.
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Antiinflamatorios , Frutas , Lipopolisacáridos , FN-kappa B , Óxido Nítrico , Olea , Extractos Vegetales , Especies Reactivas de Oxígeno , Transducción de Señal , Animales , Olea/química , Ratones , Células RAW 264.7 , Extractos Vegetales/farmacología , Antiinflamatorios/farmacología , Lipopolisacáridos/farmacología , FN-kappa B/metabolismo , Frutas/química , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Óxido Nítrico/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Interleucina-6/metabolismo , Interleucina-6/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Ciclooxigenasa 2/metabolismo , Ciclooxigenasa 2/genética , Supervivencia Celular/efectos de los fármacos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismoRESUMEN
Porcine circovirus disease (PCV) causes substantial economic losses in the pig industry, primarily from porcine circovirus type 2 (PCV2) and porcine circovirus type 3 (PCV3). Novel vaccines are necessary to prevent and control PCV infections. PCV coat proteins are crucial for eliciting immunogenic proteins that induce the production of antibodies and immune responses. A vaccine platform utilizing Semliki Forest virus RNA replicons expressing vesicular stomatitis virus glycoprotein (VSV-G), was recently developed. This platform generates virus-like vesicles (VLVs) containing VSV-G exclusively, excluding other viral structural proteins. In our study, we developed a novel virus-like vesicle vaccine by constructing recombinant virus-like vesicles (rVLVs) that also express EGFP. These rVLVs were created using the RNA replicon of Venezuelan equine encephalomyelitis (VEEV) and New Jersey serotype VSV-G. The rVLVs underwent characterization and safety evaluation in vitro. Subsequently, rVLVs expressing PCV2d-Cap and PCV3-Cap proteins were constructed. Immunization of C57 mice with these rVLVs led to a significant increase in anti-porcine circovirus type 2 and type 3 capsid protein antibodies in mouse serum. Additionally, a cellular immune response was induced, as evidenced by high production of IFN-γ and IL-4 cytokines. Overall, this study demonstrates the feasibility of developing a novel porcine circovirus disease vaccine based on rVLVs.
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Candida albicans (C. albicans), a microbe commonly isolated from Candida vaginitis patients with vaginal tract infections, transforms from yeast to hyphae and produces many toxins, adhesins, and invasins, as well as C. albicans biofilms resistant to antifungal antibiotic treatment. Effective agents against this pathogen are urgently needed. Antimicrobial peptides (AMPs) have been used to cure inflammation and infectious diseases. In this study, we isolated whole housefly larvae insect SVWC peptide 1 (WHIS1), a novel insect single von Willebrand factor C-domain protein (SVWC) peptide from whole housefly larvae. The expression pattern of WHIS1 showed a response to the stimulation of C. albicans. In contrast to other SVWC members, which function as antiviral peptides, interferon (IFN) analogs or pathogen recognition receptors (PRRs), which are the prokaryotically expressed MdWHIS1 protein, inhibit the growth of C. albicans. Eukaryotic heterologous expression of WHIS1 inhibited C. albicans invasion into A549 and HeLa cells. The heterologous expression of WHIS1 clearly inhibited hyphal formation both extracellularly and intracellularly. Furthermore, the mechanism of WHIS1 has demonstrated that it downregulates all key hyphal formation factors (ALS1, ALS3, ALS5, ECE1, HWP1, HGC1, EFG1, and ZAP1) both extracellularly and intracellularly. These data showed that heterologously expressed WHIS1 inhibits C. albicans invasion into epithelial cells by affecting hyphal formation and adhesion factor-related gene expression. These findings provide new potential drug candidates for treating C. albicans infection.
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Almost all the neutralizing antibodies targeting the receptor-binding domain (RBD) of spike (S) protein show weakened or lost efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged or emerging variants, such as Omicron and its sub-variants. This suggests that highly conserved epitopes are crucial for the development of neutralizing antibodies. Here, we present one nanobody, N235, displaying broad neutralization against the SARS-CoV-2 prototype and multiple variants, including the newly emerged Omicron and its sub-variants. Cryo-electron microscopy demonstrates N235 binds a novel, conserved, cryptic epitope in the N-terminal domain (NTD) of the S protein, which interferes with the RBD in the neighboring S protein. The neutralization mechanism interpreted via flow cytometry and Western blot shows that N235 appears to induce the S1 subunit shedding from the trimeric S complex. Furthermore, a nano-IgM construct (MN235), engineered by fusing N235 with the human IgM Fc region, displays prevention via inducing S1 shedding and cross-linking virus particles. Compared to N235, MN235 exhibits varied enhancement in neutralization against pseudotyped and authentic viruses in vitro. The intranasal administration of MN235 in low doses can effectively prevent the infection of Omicron sub-variant BA.1 and XBB in vivo, suggesting that it can be developed as a promising prophylactic antibody to cope with the ongoing and future infection.
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Anticuerpos Neutralizantes , Anticuerpos Antivirales , COVID-19 , Epítopos , Inmunoglobulina M , SARS-CoV-2 , Anticuerpos de Dominio Único , Glicoproteína de la Espiga del Coronavirus , SARS-CoV-2/inmunología , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/química , Humanos , Anticuerpos de Dominio Único/inmunología , Anticuerpos de Dominio Único/genética , Anticuerpos de Dominio Único/química , Anticuerpos de Dominio Único/farmacología , Epítopos/inmunología , Epítopos/genética , Epítopos/química , Animales , COVID-19/inmunología , COVID-19/virología , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/química , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/química , Anticuerpos Neutralizantes/genética , Inmunoglobulina M/inmunología , Inmunoglobulina M/genética , Ratones , Dominios Proteicos , Microscopía por CrioelectrónRESUMEN
BACKGROUND: Rectal mucinous adenocarcinoma (MAC) is a rare pathological type of rectal cancer with unique pathological features and a poor prognosis. It is difficult to diagnose and treat early because of the lack of specific manifestations in some aspects of the disease. The common metastatic organs of rectal cancer are the liver and lung; however, rectal carcinoma with metastasis to subcutaneous soft tissue is a rare finding. CASE SUMMARY: In this report, the clinical data, diagnosis and treatment process, and postoperative pathological features of a patient with left waist subcutaneous soft tissue masses were retrospectively analyzed. The patient underwent surgical treatment after admission and recovered well after surgery. The final pathological diagnosis was rectal MAC with left waist subcutaneous soft tissue metastasis. CONCLUSION: Subcutaneous soft tissue metastasis of rectal MAC is rare, and it can suggest that the tumor is disseminated, and it can appear even earlier than the primary malignant tumor, which is occult and leads to a missed diagnosis and misdiagnosis clinically. When a subcutaneous soft tissue mass of unknown origin appears in a patient with rectal cancer, a malignant tumor should be considered.
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The sensitive and reliable nanozyme-based sensor enables the detection of low concentrations of H2O2 in biological microenvironments, it has potential applications as an in-situ monitoring platform for cellular H2O2 release. The uniformly dispersed bimetallic sulfide (Zn2SnS4) nanoflowers were synthesized via a one-pot hydrothermal method and the two kinds of metal ions can serve as morphology and structure directing agents for each other in the synthetic process. The nanoparticles were utilized as nanozyme materials to fabricate a novel electrochemical sensor, and it exhibits a distinct electrochemical response towards H2O2 with excellent stability and detection capability (with a minimum detection limit of 1.79â nM (S/N=3)), the excellent characteristics facilitate the precise detection of low concentrations of H2O2 in biological microenvironments. Use the macrophages differentiated from leukemia THP-1 cells as a representative sensing model, the sensor was successfully utilized for real-time monitoring of the release of H2O2 induced by living cells, which has significant potential applications in clinical diagnosis and cancer treatment.
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Técnicas Electroquímicas , Peróxido de Hidrógeno , Límite de Detección , Sulfuros , Peróxido de Hidrógeno/química , Humanos , Técnicas Electroquímicas/métodos , Sulfuros/química , Zinc/química , Células THP-1 , Macrófagos/metabolismoRESUMEN
Insect visual electrophysiological techniques are important to study the electrical characteristics of photoreceptor cells and visual neurons in insects, including electroretinography (ERG) and microelectrode intracellular recording (MIR). ERG records the changes of voltage or electric current in the retina of insects in response to different light stimuli, which occurs outside the cell. MIR records the changes in individual photoreceptor cells or visual neurons of an insect exposed to different lights, which occurs inside the cell. Insect visual electrophysiological techniques can explore the mechanism of electrophysiological response of insects' vision to light and reveal their sensitive light spectra and photoreceptor types. This review introduced the basic structure and the principle of ERG and MIR, and summarized their applications in insect researches in the past 20 years, which would provide references for elucidating the mechanism of light perception in insects and the use of insect phototropism to control pests.
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Electrorretinografía , Insectos , Células Fotorreceptoras de Invertebrados , Animales , Insectos/fisiología , Electrorretinografía/métodos , Células Fotorreceptoras de Invertebrados/fisiología , Visión Ocular/fisiología , Microelectrodos , Fenómenos Electrofisiológicos , Electrofisiología/métodosRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a wide range of hosts, including hippopotami, which are semi-aquatic mammals and phylogenetically closely related to Cetacea. In this study, we characterized the binding properties of hippopotamus angiotensin-converting enzyme 2 (hiACE2) to the spike (S) protein receptor binding domains (RBDs) of the SARS-CoV-2 prototype (PT) and variants of concern (VOCs). Furthermore, the cryo-electron microscopy (cryo-EM) structure of the SARS-CoV-2 PT S protein complexed with hiACE2 was resolved. Structural and mutational analyses revealed that L30 and F83, which are specific to hiACE2, played a crucial role in the hiACE2/SARS-CoV-2 RBD interaction. In addition, comparative and structural analysis of ACE2 orthologs suggested that the cetaceans may have the potential to be infected by SARS-CoV-2. These results provide crucial molecular insights into the susceptibility of hippopotami to SARS-CoV-2 and suggest the potential risk of SARS-CoV-2 VOCs spillover and the necessity for surveillance. IMPORTANCE: The hippopotami are the first semi-aquatic artiodactyl mammals wherein SARS-CoV-2 infection has been reported. Exploration of the invasion mechanism of SARS-CoV-2 will provide important information for the surveillance of SARS-CoV-2 in hippopotami, as well as other semi-aquatic mammals and cetaceans. Here, we found that hippopotamus ACE2 (hiACE2) could efficiently bind to the RBDs of the SARS-CoV-2 prototype (PT) and variants of concern (VOCs) and facilitate the transduction of SARS-CoV-2 PT and VOCs pseudoviruses into hiACE2-expressing cells. The cryo-EM structure of the SARS-CoV-2 PT S protein complexed with hiACE2 elucidated a few critical residues in the RBD/hiACE2 interface, especially L30 and F83 of hiACE2 which are unique to hiACE2 and contributed to the decreased binding affinity to PT RBD compared to human ACE2. Our work provides insight into cross-species transmission and highlights the necessity for monitoring host jumps and spillover events on SARS-CoV-2 in semi-aquatic/aquatic mammals.
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Enzima Convertidora de Angiotensina 2 , Artiodáctilos , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Animales , Humanos , Enzima Convertidora de Angiotensina 2/metabolismo , Enzima Convertidora de Angiotensina 2/química , Enzima Convertidora de Angiotensina 2/genética , Artiodáctilos/virología , Betacoronavirus/genética , Betacoronavirus/metabolismo , Sitios de Unión , COVID-19/virología , COVID-19/metabolismo , Microscopía por Crioelectrón , Unión Proteica , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , Glicoproteína de la Espiga del Coronavirus/metabolismo , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genéticaRESUMEN
Cultural relics as the crystallization of human history are non-renewable and irreplaceable resources. Microorganisms are widely colonized on ancient wall paintings, stone cultural relics, and other types of cultural heritages to cause harm. The dominant disease fungus, Parengyodontium album, is extensively distributed and can seriously threaten the long-term preservation of precious cultural heritage due to surviving in various cultural relics and extreme environments. The classification and nomenclature of P. album have undergone several changes, so its impact on cultural relic received little attention. Here, we summarized the brief histories of its classification and development, distribution range, and cultural heritage preference of P. album. We further analyzed the physiological, biochemical, and ecological characteristics and potential biological degradation mechanism. We proposed that P. album could be used as an indicative species of microbial hazardous effects on cultural heritage. We discussed the prevention and control countermeasures of such typical mural microorganisms and pointed out key research directions in this field.
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Cultura , HumanosRESUMEN
Developing mechanistic non-animal testing methods based on the adverse outcome pathway (AOP) framework must incorporate molecular and cellular key events associated with target toxicity. Using data from an in vitro assay and chemical structures, we aimed to create a hybrid model to predict hepatotoxicants. We first curated a reference dataset of 869 compounds for hepatotoxicity modeling. Then, we profiled them against PubChem for existing in vitro toxicity data. Of the 2560 resulting assays, we selected the mitochondrial membrane potential (MMP) assay, a high-throughput screening (HTS) tool that can test chemical disruptors for mitochondrial function. Machine learning was applied to develop quantitative structure-activity relationship (QSAR) models with 2536 compounds tested in the MMP assay for screening new compounds. The MMP assay results, including QSAR model outputs, yielded hepatotoxicity predictions for reference set compounds with a Correct Classification Ratio (CCR) of 0.59. The predictivity improved by including 37 structural alerts (CCR = 0.8). We validated our model by testing 37 reference set compounds in human HepG2 hepatoma cells, and reliably predicting them for hepatotoxicity (CCR = 0.79). This study introduces a novel AOP modeling strategy that combines public HTS data, computational modeling, and experimental testing to predict chemical hepatotoxicity.
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Alternativas a las Pruebas en Animales , Enfermedad Hepática Inducida por Sustancias y Drogas , Aprendizaje Automático , Potencial de la Membrana Mitocondrial , Relación Estructura-Actividad Cuantitativa , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Pruebas de Toxicidad , Ensayos Analíticos de Alto Rendimiento , Hígado/efectos de los fármacos , Células Hep G2RESUMEN
The aim of this study was to evaluate the role of angiotensin-converting enzyme 1 (ACE1) in H2O2-induced trophoblast cell injury and the potential molecular mechanisms. Oxidative stress was modeled by exposing HTR-8/SVneo cells to 200 µM H2O2. Western blot and real-time quantitative PCR methods were used to detect protein and mRNA expression level of ACE1 in chorionic villus tissue and trophoblast HTR-8/SVneo cell. Inhibition of ACE1 expression was achieved by transfection with small interfering RNA. Then flow cytometry, Cell Counting Kit-8, and Transwell assay was used to assess apoptosis, viability, and migration ability of the cells. Reactive oxygen species (ROS) were detected by fluorescent probes, and malondialdehyde (MDA), superoxide dismutase (SOD), and reduced glutathione (GSH) activities were determined by corresponding detection kits. Angiotensin-converting enzyme 1 expression was upregulated in chorionic villus tissue of patients with missed abortion (MA) compared with individuals with normal early pregnancy abortion. H2O2 induced elevated ACE1 expression in HTR-8/SVneo cells, promoted apoptosis, and inhibited cell viability and migration. Knockdown of ACE1 expression inhibited H2O2-induced effects to enhance cell viability and migration and suppress apoptosis. Additionally, H2O2 stimulation caused increased levels of ROS and MDA and decreased SOD and GSH activity in the cells, whereas knockdown of ACE1 expression led to opposite changes of these oxidative stress indicators. Moreover, knockdown of ACE1 attenuated the inhibitory effect of H2O2 on the Nrf2/HO-1 pathway. Angiotensin-converting enzyme 1 was associated with MA, and it promoted H2O2-induced injury of trophoblast cells through inhibiting the Nrf2 pathway. Therefore, ACE1 may serve as a potential therapeutic target for MA.
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Aborto Retenido , Peróxido de Hidrógeno , Peptidil-Dipeptidasa A , Trofoblastos , Humanos , Trofoblastos/metabolismo , Trofoblastos/efectos de los fármacos , Peróxido de Hidrógeno/farmacología , Peptidil-Dipeptidasa A/genética , Peptidil-Dipeptidasa A/metabolismo , Femenino , Embarazo , Aborto Retenido/genética , Aborto Retenido/metabolismo , Apoptosis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Línea Celular , Especies Reactivas de Oxígeno/metabolismo , Supervivencia Celular/efectos de los fármacos , Adulto , Movimiento Celular/efectos de los fármacosRESUMEN
BACKGROUND: This study aimed to explore the possible etiology and treatment of severe fetal tachycardia in the absence of organic disease and provide a reference for clinical management of severe fetal tachycardia. CASE SUMMARY: A 29-year-old pregnant woman, with a gravidity 1 parity 0, presented with a fetal heart rate (FHR) of 243 beats per minute during a routine antenatal examination at 31 + 2 wk of gestation. Before termination of pregnancy at 38 wk of gestation, the FHR repeatedly showed serious abnormalities, lasting more than 30 min. However, the pregnant woman and the fetus had no clinical symptoms, and repeated examination revealed no organic lesions. The mother and the baby were regularly followed up. CONCLUSION: This was a case of severe fetal tachycardia with no organic lesions and management based on clinical experience.