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Non-alcoholic fatty liver disease (NAFLD) is associated with mutations in lipopolysaccharide-binding protein ( LBP), but the underlying epigenetic mechanisms remain understudied. Herein, LBP -/- rats with NAFLD were established and used to conduct integrative targeting-active enhancer histone H3 lysine 27 acetylation (H3K27ac) chromatin immunoprecipitation coupled with high-throughput and transcriptomic sequencing analysis to explore the potential epigenetic pathomechanisms of active enhancers of NAFLD exacerbation upon LBP deficiency. Notably, LBP -/- reduced the inflammatory response but markedly aggravated high-fat diet (HFD)-induced NAFLD in rats, with pronounced alterations in the histone acetylome and regulatory transcriptome. In total, 1â¯128 differential enhancer-target genes significantly enriched in cholesterol and fatty acid metabolism were identified between wild-type (WT) and LBP -/- NAFLD rats. Based on integrative analysis, CCAAT/enhancer-binding protein ß (C/EBPß) was identified as a pivotal transcription factor (TF) and contributor to dysregulated histone acetylome H3K27ac, and the lipid metabolism gene SCD was identified as a downstream effector exacerbating NAFLD. This study not only broadens our understanding of the essential role of LBP in the pathogenesis of NAFLD from an epigenetics perspective but also identifies key TF C/EBPß and functional gene SCD as potential regulators and therapeutic targets.
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Enfermedad del Hígado Graso no Alcohólico , Animales , Ratas , Acetilación , Histonas/metabolismo , Lípidos , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/veterinaria , Estearoil-CoA Desaturasa/metabolismoRESUMEN
Metalloenzymes are attractive research targets in fields of chemistry, biology, and medicine. Given that metalloenzymes can manifest conservation of metal-coordination and ligand binding modes, the excavation and expansion of metalloenzyme-specific knowledge is of interest in bridging metalloenzyme-related fields. Building on our previous metalloenzyme-ligand association database, MeLAD, we have expanded the scope of metalloenzyme-specific knowledge and services, by forming a versatile platform, termed the Metalloenzyme Data Bank and Analysis (MeDBA). The MeDBA provides: (i) manual curation of metalloenzymes into different categories, that this M-I, M-II and M-III; (ii) comprehensive information on metalloenzyme activities, expression profiles, family and disease links; (iii) structural information on metalloenzymes, in particular metal binding modes; (iv) metalloenzyme substrates and bioactive molecules acting on metalloenzymes; (v) excavated metal-binding pharmacophores and (vi) analysis tools for structure/metal active site comparison and metalloenzyme profiling. The MeDBA is freely available at https://medba.ddtmlab.org.
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Bases de Datos de Proteínas , Metaloproteínas , Dominio Catalítico , Ligandos , Metaloproteínas/metabolismo , Metales , EnzimasRESUMEN
The effectiveness of ß-lactam antibiotics is increasingly influenced by serine ß-lactamases (SBLs) and metallo-ß-lactamases (MBLs), which can hydrolyze ß-lactam antibiotics. The development of effective ß-lactamase inhibitors is an important direction to extend use of ß-lactam antibiotics. Although six SBL inhibitors have been approved for clinical use, but no MBL inhibitors or MBL/SBL dual-action inhibitors are available so far. Broad-spectrum targeting clinically relevant MBLs and SBLs is currently desirable, while it is not easy to achieve such a purpose owing to structural and mechanistic differences between MBLs and SBLs. In this review, we summarized recent advances of inhibitor chemotypes targeting MBLs and SBLs and their inhibition mechanisms, particularly including lead discovery and structural optimization strategies, with the aim to provide useful information for future efforts to develop new MBL and SBL inhibitors.
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Antibacterianos , Inhibidores de beta-Lactamasas , Antibacterianos/química , Antibacterianos/farmacología , Monobactamas , Serina , Inhibidores de beta-Lactamasas/química , Inhibidores de beta-Lactamasas/farmacología , beta-Lactamasas/químicaRESUMEN
Sepsis is the major culprit of death among critically ill patients who are hospitalized in intensive care units (ICUs). Although sepsis-related mortality is steadily declining year-by-year due to the continuous understanding of the pathophysiological mechanism on sepsis and improvement of the bundle treatment, sepsis-associated hospitalization is rising worldwide. Surviving Sepsis Campaign (SSC) guidelines are continuously updating, while their content is extremely complex and comprehensive for a precisely implementation in clinical practice. As a consequence, a standardized step-by-step approach for the diagnosis and treatment of sepsis is particularly important. In the present study, we proposed a standardized step-by-step approach for the diagnosis and treatment of sepsis using our daily clinical experience and the latest researches, which is close to clinical practice and is easy to implement. The proposed approach may assist clinicians to more effectively diagnose and treat septic patients and avoid the emergence of adverse clinical outcomes.
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Sepsis , Choque Séptico , Adhesión a Directriz , Humanos , Unidades de Cuidados Intensivos , Sepsis/diagnóstico , Sepsis/terapiaRESUMEN
Since metalloenzymes are a large collection of metal ion(s) dependent enzymes, comparison analyses of metalloenzyme active sites are critical for metalloenzyme de novo design, function investigation, and inhibitor development. Here, we report a method named MeCOM for comparing metalloenzyme active sites. It is characterized by metal ion(s) centric active site recognition and three-dimensional superimposition using α-carbon or pharmacophore features. The test results revealed that for the given metalloenzymes, MeCOM could effectively recognize the active sites, extract active site features, and superimpose the active sites; it also could correctly identify similar active sites, differentiate dissimilar active sites, and evaluate the similarity degree. Moreover, MeCOM showed potential to establish new associations between structurally distinct metalloenzymes by active site comparison. MeCOM is freely available at https://mecom.ddtmlab.org.
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Metaloproteínas , Dominio Catalítico , Metaloproteínas/química , Metales , MetiltransferasasRESUMEN
Production of metallo-ß-lactamases (MBLs) in bacterial pathogens is an important cause of resistance to the 'last-resort' carbapenem antibiotics. Development of effective MBL inhibitors to reverse carbapenem resistance in Gram-negative bacteria is still needed. We herein report X-ray structure-guided optimization of 1H-imidazole-2-carboxylic acid (ICA) derivatives by considering how to engage with the active-site flexible loops and improve penetration into Gram-negative bacteria. Structure-activity relationship studies revealed the importance of appropriate substituents at ICA 1-position to achieve potent inhibition to class B1 MBLs, particularly the Verona Integron-encoded MBLs (VIMs), mainly by involving ingenious interactions with the flexible active site loops as observed by crystallographic analyses. Of the tested ICA inhibitors, 55 displayed potent synergistic antibacterial activity with meropenem against engineered Escherichia coli strains and even intractable clinically isolated Pseudomonas aeruginosa producing VIM-2 MBL. The morphologic and internal structural changes of bacterial cells after treatment further demonstrated that 55 crossed the outer membrane and reversed the activity of meropenem. Moreover, 55 showed good pharmacokinetic and safety profile in vivo, which could be a potential candidate for combating VIM-mediated Gram-negative carbapenem resistance.
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Antibacterianos/farmacología , Ácidos Carboxílicos/farmacología , Escherichia coli/efectos de los fármacos , Imidazoles/farmacología , Pseudomonas aeruginosa/efectos de los fármacos , Inhibidores de beta-Lactamasas/farmacología , beta-Lactamasas/metabolismo , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/química , Relación Dosis-Respuesta a Droga , Escherichia coli/metabolismo , Femenino , Humanos , Imidazoles/síntesis química , Imidazoles/química , Ratones , Ratones Endogámicos ICR , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Pseudomonas aeruginosa/metabolismo , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Distribución Tisular , Inhibidores de beta-Lactamasas/síntesis química , Inhibidores de beta-Lactamasas/químicaRESUMEN
Drug repositioning is an attractive strategy for discovering new therapeutic uses for approved or investigational drugs, with potentially shorter development timelines and lower development costs. Various computational methods have been used in drug repositioning, promoting the efficiency and success rates of this approach. Recently, deep learning (DL) has attracted wide attention for its potential in target prediction and drug repositioning. Here, we provide an overview of the basic principles of commonly used DL architectures and their applications in target prediction and drug repositioning, and discuss possible ways of dealing with current challenges to help achieve its expected potential for drug repositioning.
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Aprendizaje Profundo , Reposicionamiento de Medicamentos , Biología ComputacionalRESUMEN
Metalloenzymes have critical roles in a wide range of biological processes and are directly involved in many human diseases; hence, they are considered as important targets for therapeutic intervention. The specific characteristics of metal ion(s)-containing active sites make exploitation of metal-binding pharmacophores (MBPs) critical to inhibitor development targeting metalloenzymes. This Perspective focuses on boron-containing MBPs, which display unique binding modes with metalloenzyme active sites, particularly via mimicking native substrates or tetrahedral transition states. The design concepts regarding boron-containing MBPs are highlighted through the case analyses on five distinct classes of clinically relevant nucleophilic metalloenzymes from medicinal chemistry perspectives. The challenges (e.g., selectivity) faced by some boron-containing MBPs and possible strategies (e.g., bioisosteres) for metalloenzyme inhibitor transformation are also discussed.
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Boro/química , Inhibidores Enzimáticos/farmacología , Metaloproteínas/antagonistas & inhibidores , Metales/química , Inhibidores Enzimáticos/química , Estructura MolecularRESUMEN
BACKGROUND: Acute kidney injury (AKI) is one of the most common acute pancreatitis (AP)-associated complications that has a significant effect on AP, but the factors affecting the AP patients' survival rate remains unclear. AIM: To assess the influences of AKI on the survival rate in AP patients. METHODS: A total of 139 AP patients were included in this retrospective study. Patients were divided into AKI group (n = 72) and non-AKI group (n = 67) according to the occurrence of AKI. Data were collected from medical records of hospitalized patients. Then, these data were compared between the two groups and further analysis was performed. RESULTS: AKI is more likely to occur in male AP patients (P = 0.009). AP patients in AKI group exhibited a significantly higher acute physiologic assessment and chronic health evaluation II score, higher Sequential Organ Failure Assessment score, lower Glasgow Coma Scale score, and higher demand for mechanical ventilation, infusion of vasopressors, and renal replacement therapy than AP patients in non-AKI group (P < 0.01, P < 0.01, P = 0.01, P = 0.001, P < 0.01, P < 0.01, respectively). Significant differences were noted in dose of norepinephrine and adrenaline, duration of mechanical ventilation, maximum and mean values of intra-peritoneal pressure (IPP), maximum and mean values of procalcitonin, maximum and mean serum levels of creatinine, minimum platelet count, and length of hospitalization. Among AP patients with AKI, the survival rate of surgical intensive care unit and in-hospital were only 23% and 21% of the corresponding rates in AP patients without AKI, respectively. The factors that influenced the AP patients' survival rate included body mass index (BMI), mean values of IPP, minimum platelet count, and hospital day, of which mean values of IPP showed the greatest impact. CONCLUSION: AP patients with AKI had a lower survival rate and worse relevant clinical outcomes than AP patients without AKI, which necessitates further attention to AP patients with AKI in surgical intensive care unit.
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Lesión Renal Aguda , Pancreatitis , Enfermedad Aguda , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/etiología , Lesión Renal Aguda/terapia , Humanos , Unidades de Cuidados Intensivos , Masculino , Pancreatitis/complicaciones , Pancreatitis/diagnóstico , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
The major drawbacks of P-glycoprotein (P-gp) inhibitors at the clinical stage make the development of new P-gp inhibitors challenging and desirable. In this study, we reported our structure-activity relationship studies of 4-indolyl quinazoline, which led to the discovery of a highly effective and orally active P-gp inhibitor, YS-370. YS-370 effectively reversed multidrug resistance (MDR) to paclitaxel and colchicine in SW620/AD300 and HEK293T-ABCB1 cells. YS-370 bound directly to P-gp, did not alter expression or subcellular localization of P-gp in SW620/AD300 cells, but increased the intracellular accumulation of paclitaxel. Furthermore, YS-370 stimulated the P-gp ATPase activity and had moderate inhibition against CYP3A4. Significantly, oral administration of YS-370 in combination with paclitaxel achieved much stronger antitumor activity in a xenograft model bearing SW620/Ad300 cells than either drug alone. Taken together, our data demonstrate that YS-370 is a promising P-gp inhibitor capable of overcoming MDR and represents a unique scaffold for the development of new P-gp inhibitors.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Antineoplásicos/farmacología , Descubrimiento de Drogas , Quinazolinas/farmacología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Disponibilidad Biológica , Línea Celular , Línea Celular Tumoral , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Células HEK293 , Humanos , Ratones , Simulación del Acoplamiento Molecular , Quinazolinas/administración & dosificación , Quinazolinas/química , Relación Estructura-Actividad , Fracciones Subcelulares/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Human sirtuin 5 (SIRT5) plays pivotal roles in metabolic pathways and other biological processes, and is involved in several human diseases including cancer. Development of new potent and selective SIRT5 inhibitors is currently desirable to provide potential therapeutics for related diseases. Herein, we report a series of new 3-thioureidopropanoic acid derivatives, which were designed to mimic the binding features of SIRT5 glutaryl-lysine substrates. Structure-activity relationship studies revealed several compounds with low micromolar inhibitory activities to SIRT5. Computational and biochemical studies indicated that these compounds exhibited competitive SIRT5 inhibition with respect to the glutaryl-lysine substrate rather than nicotinamide adenine dinucleotide cofactor. Moreover, they showed high selectivity for SIRT5 over SIRT1-3 and 6 and could stabilize SIRT5 proteins as revealed by thermal shift analyses. This work provides an effective substrate-mimicking strategy for future inhibitor design, and offers new inhibitors to investigate their therapeutic potentials in SIRT5-associated disease models.
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Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Lisina/antagonistas & inhibidores , Propionatos/farmacología , Sirtuinas/antagonistas & inhibidores , Tiourea/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Lisina/metabolismo , Estructura Molecular , Propionatos/síntesis química , Propionatos/química , Sirtuinas/metabolismo , Relación Estructura-Actividad , Especificidad por Sustrato , Tiourea/síntesis química , Tiourea/químicaRESUMEN
BACKGROUND: As a highly contagious disease, coronavirus disease 2019 (COVID-19) is wreaking havoc around the world due to continuous spread among close contacts mainly via droplets, aerosols, contaminated hands or surfaces. Therefore, centralized isolation of close contacts and suspected patients is an important measure to prevent the transmission of COVID-19. At present, the quarantine duration in most countries is 14 d due to the fact that the incubation period of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is usually identified as 1-14 d with median estimate of 4-7.5 d. Since COVID-19 patients in the incubation period are also contagious, cases with an incubation period of more than 14 d need to be evaluated. CASE SUMMARY: A 70-year-old male patient was admitted to the Department of Respiratory Medicine of The First Affiliated Hospital of Harbin Medical University on April 5 due to a cough with sputum and shortness of breath. On April 10, the patient was transferred to the Fever Clinic for further treatment due to close contact to one confirmed COVID-19 patient in the same room. During the period from April 10 to May 6, nucleic acid and antibodies to SARS-CoV-2 were tested 7 and 4 times, respectively, all of which were negative. On May 7, the patient developed fever with a maximum temperature of 39â, and his respiratory difficulties had deteriorated. The results of nucleic acid and antibody detection of SARS-CoV-2 were positive. On May 8, the nucleic acid and antibody detection of SARS-CoV-2 by Heilongjiang Provincial Center for Disease Control were also positive, and the patient was diagnosed with COVID-19 and reported to the Chinese Center for Disease Control and Prevention. CONCLUSION: This case highlights the importance of the SARS-CoV-2 incubation period. Further epidemiological investigations and clinical observations are urgently needed to identify the optimal incubation period of SARS-CoV-2 and formulate rational and evidence-based quarantine policies for COVID-19 accordingly.
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The large global outbreak of coronavirus disease 2019 (COVID-19) has seriously endangered the health care system in China and globally. The sudden surge of patients with severe acute respiratory syndrome coronavirus 2 infection has revealed the shortage of critical care medicine resources and intensivists. Currently, the management of non-critically ill patients with COVID-19 is performed mostly by non-intensive care unit (ICU) physicians, who lack the required professional knowledge, training, and practice in critical care medicine, especially in terms of continuous monitoring of the respiratory function, intervention, and feedback on treatment effects. This clinical problem needs an urgent solution. Therefore, here, we propose a series of clinical strategies for non-ICU physicians aimed at the standardization of the management of non-critically ill patients with COVID-19 from the perspective of critical care medicine. Isolation management is performed to facilitate the implementation of hierarchical monitoring and intervention to ensure the reasonable distribution of scarce critical care medical resources and intensivists, highlight the key patients, timely detection of disease progression, and early and appropriate intervention and organ function support, and thus improve the prognosis. Different management objectives are also set based on the high-risk factors and the severity of patients with COVID-19. The approaches suggested herein will facilitate the timely detection of disease progression, and thus ensure the provision of early and appropriate intervention and organ function support, which will eventually improve the prognosis.
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The shortage of personal protective equipment and lack of proper nursing training have been endangering health care workers dealing with coronavirus disease 2019 (COVID-19). In our treatment center, the implementation of a holistic care model of time-sharing management for severe and critical COVID-19 patients has further aggravated the shortage of intensive care unit (ICU) professional nurses. Therefore, we developed a short-term specialized and targeted nursing training program to help ICU nurses to cope with stress and become more efficient, thus reducing the number of nurses required in the ICU. In order to avoid possible human-to-human spread, small teaching classes and remote training were applied. The procedural training mode included four steps: preparation, plan, implementation, and evaluation. An evaluation was conducted throughout the process of nursing training. In this study, we documented and shared experiences in transitioning from traditional face-to-face programs to remote combined with proceduralization nursing training mode from our daily work experiences during the COVID-19 pandemic, which has shown to be helpful for nurses working in the ICU.
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The rapid global outbreak of coronavirus disease 2019 (COVID-19) and the surge of infected patients have led to the verge of exhaustion of critical care medicine resources worldwide, especially with regard to critical care staff. A holistic care model on time-sharing management for severe and critical COVID-19 patients is proposed, which includes formulation of individualized care objectives and plans, identification of care tasks in each shift and making detailed checklist, and management of quality of care. This study was conducted in the COVID-19 treatment center of Harbin, Heilongjiang Province. The data collected from the treatment center were recorded and analyzed. From the results we can deduce that it is especially suitable for non-intensive care unit (non-ICU) nurses to adapt care management mode of ICU as soon as possible and ensure the quality and efficiency of care during the epidemic. The holistic care model on time-sharing management for severe and critical cases with COVID-19 proposed based on our daily work experiences can assist in improving the quality and efficiency of care, thus reducing the mortality rate of patients in ICU.
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BACKGROUND: A large number of pneumonia cases due to coronavirus disease 2019 (COVID-19) have been first reported in China. Meanwhile, the virus is sweeping all around the world and has infected millions of people. Fever and pulmonary symptoms have been noticed as major and early signs of infection, whereas gastrointestinal symptoms were also observed in a significant portion of patients. The clinical investigation of disease onset was underestimated, especially due to the neglection of cases presenting with gastrointestinal symptoms. AIM: To characterize the clinical features of coronavirus-infected patients with gastrointestinal symptoms as initial symptoms. METHODS: This is a retrospective, single-center case series of the general consecutive hospitalized patients with confirmed COVID-19 at Wuhan Union Hospital from February 2, 2020 to February 13, 2020. According to their initial symptoms, these patients were classified into two groups. Patients in group one presented with pulmonary symptoms (PS) as initial symptoms, and group two presented with gastrointestinal symptoms (GS). Epidemiological, demographic, clinical, laboratory, and treatment data were collected for analysis. RESULTS: Among the 50 patients recruited, no patient has been admitted to intensive care units, and no patient died during the study. The duration of hospitalization was longer in the GS group than in the PS group (12.13 ± 2.44 vs 10.00 ± 2.13, P < 0.01). All of the 50 patients exhibited decreased lymphocytes. However, lymphocytes in the GS group were significantly lower compared to those in the PS group (0.94 ± 0.06 vs 1.04 ± 0.15, P < 0.01). Procalcitonin and hs-CRP were both significantly higher in the GS group than in the PS group. Accordingly, the duration of viral shedding was significantly longer in the GS group compared to the PS group (10.22 ± 1.93 vs 8.15 ± 1.87, P < 0.01). CONCLUSION: COVID-19 patients presenting with gastrointestinal symptoms as initial symptoms need more days of viral shedding and hospitalization than the patients presenting with pulmonary symptoms.
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To investigate the right heart function in coronavirus disease 2019 (COVID-19) patients with acute respiratory distress syndrome (ARDS), a retrospective analysis of 49 COVID-19 patients with ARDS was performed. Patients were divided into severe group and critically-severe group according to the severity of illness. Age-matched healthy volunteers were recruited as a control group. The cardiac cavity diameters, tricuspid annular plane systolic excursion (TAPSE), tricuspid valve regurgitation pressure gradient biggest (TRPG), pulmonary arterial systolic pressure (PASP), maximum inferior vena cava diameter (IVCmax) and minimum diameter (IVCmin), and inferior vena cava collapse index (ICV-CI) were measured using echocardiography. We found that the TAPSE was significantly decreased in pneumonia patients compared to healthy subjects (P < 0.0001), and it was significantly lower in critically-severe patients (P = 0.0068). The TAPSE was less than 17 mm in three (8.6%) severe and five (35.7%) critically-severe patients. In addition, the TAPSE was significantly decreased in severe ARDS patients than in mild ARDS patients. The IVCmax and IVCmin were significantly increased in critically-severe patients compared to healthy subjects and severe patients (P < 0.01), whereas the ICV-CI was significantly decreased (P < 0.05). COVID-19 patients had significantly larger right atrium and ventricle than healthy controls (P < 0.01). The left ventricular ejection fraction (LVEF) in critically-severe patients was significantly lower than that in severe patients and healthy controls (P < 0.05). Right ventricular function was impaired in critically-severe COVID-19 patients. The assessment and protection of the right heart function in COVID-19 patients should be strengthened.
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COVID-19/complicaciones , Ventrículos Cardíacos/fisiopatología , Pandemias , Disfunción Ventricular Derecha/etiología , Función Ventricular Derecha/fisiología , COVID-19/epidemiología , Ecocardiografía Doppler , Femenino , Estudios de Seguimiento , Ventrículos Cardíacos/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Disfunción Ventricular Derecha/diagnóstico , Disfunción Ventricular Derecha/fisiopatologíaRESUMEN
MOTIVATION: Metalloenzymes are attractive targets for therapeutic intervention owing to their central roles in various biological processes and pathological situations. The fast-growing body of structural data on metalloenzyme-ligand interactions is facilitating efficient drug discovery targeting metalloenzymes. However, there remains a shortage of specific databases that can provide centralized, interconnected information exclusive to metalloenzyme-ligand associations. RESULTS: We created a Metalloenzyme-Ligand Association Database (MeLAD), which is designed to provide curated structural data and information exclusive to metalloenzyme-ligand interactions, and more uniquely, present expanded associations that are represented by metal-binding pharmacophores (MBPs), metalloenzyme structural similarity (MeSIM) and ligand chemical similarity (LigSIM). MeLAD currently contains 6086 structurally resolved interactions of 1416 metalloenzymes with 3564 ligands, of which classical metal-binding, non-classical metal-binding, non-metal-binding and metal water-bridging interactions account for 63.0%, 2.3%, 34.4% and 0.3%, respectively. A total of 263 monodentate, 191 bidentate and 15 tridentate MBP chemotypes were included in MeLAD, which are linked to different active site metal ions and coordination modes. 3726 and 52 740 deductive metalloenzyme-ligand associations by MeSIM and LigSIM analyses, respectively, were included in MeLAD. An online server is provided for users to conduct metalloenzyme profiling prediction for small molecules of interest. MeLAD is searchable by multiple criteria, e.g. metalloenzyme name, ligand identifier, functional class, bioinorganic class, metal ion and metal-containing cofactor, which will serve as a valuable, integrative data source to foster metalloenzyme related research, particularly involved in drug discovery targeting metalloenzymes. AVAILABILITY AND IMPLEMENTATION: MeLAD is accessible at https://melad.ddtmlab.org. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Metaloproteínas , Dominio Catalítico , Descubrimiento de Drogas , Ligandos , MetalesRESUMEN
BACKGROUND: Schistosomiasis is one of the most devastating tropical diseases in the world. Oncomelania hupensis is the only intermediate host of Schistosoma japonicum, and its growth and development are sensitive to environmental factors. The Three Gorges Dam has substantially altered the water level in the Yangtze River. This study focused on the impact of the flooding time on the occurrence of Oncomelania snails in Hunan Province, China. METHODS: The data regarding Oncomelania snails were collected from the Schistosomiasis Atlas of the People's Republic of China. Air temperature, hours of daylight and relative humidity from 1995 to 2002 were collected from the China Meteorological Data Sharing Service System. The data for rainfall and days inundated with water were collected from the Hunan flood control information system and hydrological stations in Hunan Province. A generalized additive model was used to estimate the impact of these factors on the presence or absence of snails. RESULTS: The number of days inundated with water in the areas with snails ranged from 56 to 212 days. However, 82 percent of the areas without snails were inundated with water less than 60 days. The lowest air temperature in a year in the areas without snails ranges from -2.88 °C to -2.10 °C, and the range was from -2.88 °C to -2.34 °C for areas with snails. Annual rainfall in the areas with snails ranged from 989 to 1565 mm, and the range was from 1230 mm to 1647 mm for the areas without snails. The results from the generalized additive model showed that the number of days inundated with water, lowest air temperature in a year, annual rainfall, days of daily rainfall greater than 0.1 mm, and hours of daylight were the factors that significantly affect the occurrence of snails in Hunan Province, China. CONCLUSIONS: The number of days inundated with water may be a key factor determining the geographical distribution of Oncomelania snails in Hunan Province and the favorable number of days inundated with water for the survival of snails ranges from about 2 to 7 months.