A fibrilação atrial é a arritmia persistente mais comum e é o principal fator que leva ao tromboembolismo. Investigar o valor do diâmetro do átrio esquerdo combinado com o escore CHA2DS2-VASc na predição da trombose atrial esquerda/trombose de apêndice atrial esquerdo na fibrilação atrial não valvar. Trata-se de estudo retrospectivo. 238 pacientes com fibrilação atrial não valvar foram selecionados e divididos em dois grupos: trombose e não trombose. Determinou-se o escore CHA2DS2-VASc. Valores de p<0,05 foram considerados estatisticamente significativos.Receiver Operating Characteristic) revelou que a área sob a curva para o escore CHA2DS2-VASc na predição de trombose atrial esquerda/trombose de apêndice atrial esquerdo foi de 0,593 quando o escore CHA2DS2-VASc foi ≥3 pontos, e a sensibilidade e especificidade foram 86,5% e 32,6%, respectivamente, enquanto a área sob a curva para o DAE na predição de trombose atrial esquerda/trombose de apêndice atrial esquerdo foi 0,786 quando o DAE foi ≥44,17 mm, e a sensibilidade e especificidade foram 89,6% e 60,9%, respectivamente. Entre os diferentes grupos CHA2DS2-VASc, a taxa de incidência de trombose atrial esquerda/trombose de apêndice atrial esquerdo em pacientes com DAE ≥44,17 mm foi maior do que em pacientes com DAE <44,17 mm . A análise de regressão logística multivariada revelou que histórico de acidente vascular cerebral/ataque isquêmico transitório, doença vascular, escore CHA2DS2-VASc, DAE, DDFVE e FEVE foram fatores de risco independentes para trombose atrial esquerda/trombose de apêndice atrial esquerdo . A análise da curva ROC  Quando a FA ocorre, o átrio cardíaco não pode se contrair regularmente e efetivamente e o fluxo sanguíneo diminui, o que aumenta muito o risco de trombose atrial esquerda/trombose de apêndice atrial esquerdo,3 e a trombose atrial esquerda/trombose de apêndice atrial esquerdo aumenta ainda mais o risco de episódios de tromboembolismo.4 Portanto, a avaliação científica da trombose atrial esquerda/trombose de apêndice atrial esquerdo é de grande importância para orientar o tratamento e melhorar o prognóstico dos pacientes. O CHA2DS2-VASc é um escore atualmente e amplamente usado para avaliar o risco de acidente vascular cerebral em pacientes com FA não valvar, e desempenha um papel importante na determinação de fatores de alto risco e orientação do tratamento.5 No entanto, o escore depende principalmente do registro do histórico do paciente. Um estudo revelou queA fibrilação atrial (FA) é a arritmia persistente mais comum e é o principal fator que leva ao tromboembolismo.Trata-se de um estudo retrospectivo. Os dados foram coletados em prontuários médicos. No total, 238 pacientes com FA não valvar, hospitalizados no Zhengzhou Cardiovascular Hospital de fevereiro de 2012 a março de 2017, foram incluídos no estudo. Critérios de inclusão: (1) pacientes diagnosticados por eletrocardiograma (ECG) ou ECG dinâmico; (2) pacientes submetidos à ecocardiografia transesofágica. Critérios de exclusão: (1) pacientes com cardiopatia reumática, FA valvar e FA paroxística; (2) pacientes com infarto agudo do miocárdio e insuficiência cardíaca aguda descompensada em 90 dias e pacientes com histórico de cirurgia cardíaca; (3) pacientes com embolia pulmonar, trombose venosa profunda, histórico de administração de anticoagulantes, como varfarina e rivaroxabana, ou hipolipemiantes, como estatinas; (4) pacientes com tumores malignos, hipertireoidismo e disfunção hepática e renal grave. Esse estudo foi aprovado pelo Comitê de Ética do nosso hospital. Todos os pacientes forneceram consentimento informado assinado.Foram coletadas as seguintes informações de todos os pacientes: sexo, idade, curso da FA, tabagismo e alcoolismo, histórico de doença crônica, altura e peso. Calculou-se o índice de massa corporal (IMC). Além disso, glicemia em jejum (GJ), colesterol total (CT), triglicerídeos (TG), colesterol de lipoproteína de baixa densidade (LDL-c), colesterol de lipoproteína de alta densidade (HDL-c), contagem de plaquetas (Plt), ácido úrico sérico (AU) e outros indicadores bioquímicos foram coletados.Todos os exames foram realizados por um ultrassonografista experiente com o título de Médico Chefe em nosso hospital. Todos os pacientes assinaram o termo de consentimento informado antes do exame. Para realizar o exame, utilizou-se um aparelho diagnóstico de ultrassom Doppler colorido Philips iE33. Realizou-se ecocardiografia transtorácica de rotina, e a frequência da sonda foi de 2,5 MHz. Foram medidos o diâmetro atrial esquerdo (DAE), a dimensão diastólica final do ventrículo esquerdo (DDFVE) e a fração de ejeção do ventrículo esquerdo (FEVE). Posteriormente, administrou-se anestesia faríngea local com lidocaína. A seguir, a sonda foi colocada no esôfago até a localização do coração, e a frequência da sonda foi de 5,0 MHz. As seções do átrio esquerdo e do apêndice atrial esquerdo foram continuamente observadas para determinar se o trombo estava presente no átrio esquerdo/apêndice atrial esquerdo. Esses pacientes foram divididos em dois grupos: grupo trombose e grupo não trombose.7 (1) principais fatores de risco (2 pontos por item): idade ≥75 anos, AVC isquêmico e ataque isquêmico transitório; (2) fatores secundários (1 ponto por item): mulheres, com idades entre 65 e 74 anos, hipertensão, diabetes, doença vascular e insuficiência cardíaca crônica; (3) escore mais baixo de 0 e escore mais alto de 9. Quanto maior o escore, maior a possibilidade de trombose.O escore CHA2DS2-VASc foi calculado de acordo com os dados clínicos básicos dos pacientes:tde Student não pareado de distribuição normal, e o teste de Kolmogorov-Smirnov (K-S) foi usado para distribuição normal. Os dados categóricos foram expressos em taxas (%) e comparados entre dois grupos usando o testeX2. Realizou-se a análise de regressão logística multivariada para analisar os fatores relacionados que afetaram a trombose atrial esquerda/trombose de apêndice atrial esquerdo. Utilizou-se a curva ROC para analisar os resultados preditivos do diâmetro atrial esquerdo e do escore CHA2DS2-VASc para trombose atrial esquerda/trombose de apêndice atrial esquerdo. Valores de p<0,05 foram considerados estatisticamente significativos.Para o agrupamento de dados e análises estatísticas, utilizou-se o programa estatístico SPSS versão 21.0. Os dados contínuos foram expressos como média±desvio padrão (x±DP) e comparados entre dois grupos usando o testeNo total, 238 pacientes com FA não valvar foram incluídos neste estudo. Entre esses pacientes, 151 pacientes eram do sexo masculino e 87 do sexo feminino, e a idade desses pacientes variou de 29 a 86, com média de 61,1±12,4 anos. Nesses 238 pacientes, ocorreu trombose atrial esquerda/trombose de apêndice atrial esquerdo em 46 pacientes, e a incidência foi de 19,3%.Diferenças de sexo, IMC, curso de FA, proporções de pacientes com histórico de tabagismo e consumo de álcool, proporções de pacientes com diabetes e doença cardíaca coronariana, escore CHA2DS2-VASc, GJ, CT, TG, LDL-c, Plt, AU e terapia medicamentosa entre o grupo trombose e o grupo não trombose não foram estatisticamente significativas . No grupo trombose, a proporção de pacientes com idade ≥75, a proporção de pacientes com hipertensão, a proporção de pacientes com insuficiência cardíaca, a proporção de pacientes com histórico de acidente vascular cerebral/ataque isquêmico transitório, a proporção de pacientes com histórico de doença vascular e o escore CHA2DS2-VASc, DAE e DDFVE foram maiores do que aqueles no grupo não trombose, enquanto o HDL-c e FEVE foram menores do que aqueles no grupo não trombose, e todas as diferenças foram estatisticamente significativas p<0,05,.Com a determinação de se a trombose atrial esquerda/trombose de apêndice atrial esquerdo existia como uma variável dependente, e as variáveis com um valor de p<0,10 como variáveis independentes, realizou-se análise de regressão logística multivariada. Os resultados revelaram que o histórico de acidente vascular cerebral/ataque isquêmico transitório, doença vascular, escore CHA2DS2-VASc, DAE, DDFVE e FEVE foram fatores de risco independentes para trombose atrial esquerda/trombose de apêndice atrial esquerdo p<0,05,.A análise da área sob a curva ROC revelou que quando o escore CHA2DS2-VASc foi usado para predizer a trombose atrial esquerda/trombose de apêndice atrial esquerdo, a área sob a curva foi de 0,593 . Quando o escore CHA2DS2-VASc foi ≥3, a sensibilidade e a especificidade foram de 86,5% e 32,6%, respectivamente. Quando o DAE foi usado para prever trombose atrial esquerda/trombose de apêndice atrial esquerdo, a área sob a curva foi de 0,786 . Quando o DAE foi ≥44,17 mm, a sensibilidade e a especificidade foram 89,6% e 60,9%, respectivamente .Nos diferentes grupos CHA2DS2-VASc, a incidência de trombose atrial esquerda/trombose de apêndice atrial esquerdo em pacientes com DAE ≥44,17 mm foi maior do que em pacientes com DAE <44,17 mm, e a diferença foi estatisticamente significativa p<0,05,.8. Em comparação com a população não FA, o risco de AVC em pacientes com FA aumenta cinco vezes.9 Além disso, um estudo revelou que10 o trombo que causou AVC em pacientes com FA veio principalmente do átrio esquerdo/apêndice atrial esquerdo. A trombose atrial esquerda/trombose de apêndice atrial esquerdo é um fator de risco independente para acidente vascular cerebral em pacientes com FA não valvar.11 Isso pode aumentar significativamente o risco de eventos tromboembólicos e é um indicador direto de terapia anticoagulante em pacientes com FA.12 Portanto, a detecção precoce da trombose atrial esquerda/trombose de apêndice atrial esquerdo ou fatores de alto risco para trombose atrial esquerda/trombose de apêndice atrial esquerdo é de grande importância para orientar o tratamento e melhorar o prognóstico de pacientes com FA. Neste estudo, 238 pacientes com FA, que não receberam anticoagulação e terapia hipolipemiante, foram incluídos. Os resultados da ecocardiografia transesofágica revelaram que a incidência de trombose atrial esquerda/trombose de apêndice atrial esquerdo foi de 19,3%. Essa porcentagem se assemelha aos 18,6% relatados por Shuanglun Xie et al.,13 e aos 20,7% relatados por Weiwei Fu et al.14 Esses resultados revelam que a incidência de trombose atrial esquerda/trombose de apêndice atrial esquerdo é relativamente alta em pacientes com FA sem anticoagulação e terapia hipolipemiante.Como o tipo de arritmia mais comum em Departamentos de Clínica Médica Cardiovascular, a FA é um fator de risco que leva ao tromboembolismo15 Um estudo revelou que16 um escore CHA2DS2-VASc ≥2 é um fator de risco independente para trombose atrial esquerda/trombose de apêndice atrial esquerdo em pacientes com FA. O presente estudo revelou que o escore CHA2DS2-VASc foi maior no grupo trombose do que no grupo não trombose. No entanto, a diferença na distribuição dos escores CHA2DS2-VASc entre os dois grupos não foi estatisticamente significativa. A análise univariada e multivariada revelou que o escore CHA2DS2-VASc é um fator de risco independente para trombose atrial esquerda/trombose de apêndice atrial esquerdo. Além disso, esses resultados revelam que o escore CHA2DS2-VASc está correlacionado com a trombose atrial esquerda/trombose de apêndice atrial esquerdo. A análise da área sob a curva ROC revelou uma área sob a curva de 0,593 . Quando o escore CHA2DS2-VASc foi ≥3, a sensibilidade e a especificidade foram de 86,5% e 32,6%, respectivamente. Esses resultados mostraram que, para pacientes com escore CHA2DS2-VASc ≥3, a possibilidade de trombose atrial esquerda/trombose de apêndice atrial esquerdo deve ser altamente alertada. No entanto, este estudo também revelou que quando o escore CHA2DS2-VASc era 0 ou 1, a trombose atrial esquerda/trombose de apêndice atrial esquerdo ainda ocorria em 9 e 15 pacientes, respectivamente. Além disso, esses resultados revelaram que, para pacientes de baixo risco com escore CHA2DS2-VASc de 0 ou 1, ainda havia risco de acidente vascular cerebral. Esses resultados sugeriram que o escore CHA2DS2-VASc tem algumas limitações na predição de trombose atrial esquerda/trombose de apêndice atrial esquerdo.O escore CHA2DS2-VASc foi estabelecido otimizando ainda mais o escore CHADS2, que é um método clínico comumente usado para avaliar o risco de acidente vascular cerebral em pacientes com FA atualmente, sendo também usado para orientar o tratamento clínico.17 alterações morfológicas no átrio esquerdo e no apêndice atrial esquerdo podem aumentar o risco de tromboembolismo em pacientes com FA. Quando a FA ocorre, quanto maior o átrio cardíaco, mais facilmente se forma a trombose.18 Neste estudo, comparou-se o DAE em pacientes com FA. Os resultados revelaram um DAE maior no grupo trombose do que no grupo não trombose, sendo um fator de risco independente para trombose atrial esquerda/trombose de apêndice atrial esquerdo. A análise da curva ROC revelou que quando o DAE foi usado para predizer a trombose atrial esquerda/trombose de apêndice atrial esquerdo, a área sob a curva foi 0,786 , e quando o DAE era ≥44,17 mm, a sensibilidade e a especificidade eram 89,6% e 60,9%, respectivamente. Esses resultados revelaram que o tamanho do DAE se correlacionou com a trombose atrial esquerda/trombose de apêndice atrial esquerdo. Portanto, quando o DAE era ≥44,17 mm, apresentava boa sensibilidade e especificidade na predição de trombose atrial esquerda/trombose de apêndice atrial esquerdo. Neste estudo, usamos o DAE como o índice para prever trombose atrial esquerda/trombose de apêndice atrial esquerdo. Recentemente, o volume atrial esquerdo tem sido usado como medida do aumento atrial esquerdo.19 Esse índice pode ser incluído em estudos futuros. Neste estudo, os pacientes foram estratificados de acordo com o escore CHA2DS2-VASc, a fim de analisar o efeito do DAE na trombose atrial esquerda/trombose de apêndice atrial esquerdo. Esses resultados revelaram que, independentemente de o escore CHA2DS2-VASc ser 0, 1 ou ≥2, um DAE ≥44,17 mm aumentou significativamente o risco de trombose atrial esquerda/trombose de apêndice atrial esquerdo. Esses resultados revelaram que uma avaliação adicional do DAE com base no escore CHA2DS2-VASc seria útil para avaliar o risco de trombose atrial esquerda/trombose de apêndice atrial esquerdo e orientar a terapia de anticoagulação.Um estudo revelou queNo entanto, considerando que este é um estudo unicêntrico e com amostra pequena, pode haver algumas deficiências na representatividade da amostra. Portanto, estudos de coorte multicêntricos e com amostras maiores são necessários para esclarecer ainda mais a relação entre o escore CHA2DS2-VASc e o DAE na predição de trombose atrial esquerda/trombose de apêndice atrial esquerdo e orientação da terapia de anticoagulação.Em resumo, o escore CHA2DS2-VASc e o DAE estão correlacionados à trombose atrial esquerda/trombose de apêndice atrial esquerdo em pacientes com FA não valvar. Para pacientes com escore CHA2DS2-VASc de 0 ou 1, o tamanho do DAE deve ser considerado. Quando o DAE era ≥44,17 mm, o risco de trombose atrial esquerda/trombose de apêndice atrial esquerdo ainda é relativamente alto, sendo necessário conduzir terapias de anticoagulação adicionais. 1In recent years, with the aging of the population in China, the incidence of this disease has increased.2Therefore, this disease represents a serious threat to people’s life and health. When AF occurs, the cardiac atrium cannot regularly and effectively constrict, and blood flow slows down, which greatly increases the risk of left atrial/left atrial appendage thrombosis,3and left atrial/left atrial appendage thrombosis further increases the risk of thromboembolism events.4Therefore, scientific evaluation of left atrial/left atrial appendage thrombosis is of great significance for guiding treatment and improving the prognosis of patients. CHA2DS2-VASc is a presently and widely used scoring system to assess the risk of stroke in patients with non-valvular AF, and plays an important role in determining high-risk factors and guiding treatment.5However, the scoring system relies mainly on patient’s history record. A study revealed that6left atrial size was closely correlated to left atrial/left atrial appendage thrombosis. However, it remains unclear whether the left atrial diameter combined with the CHA2DS2-VASc scoring system can improve the predictive results of left atrial/left atrial appendage thrombosis. The objective of this study was to analyze the factors related to left atrial/left atrial appendage thrombosis in patients with non-valvular AF, and explore the value of left atrial diameter combined with the CHA2DS2-VASc score in predicting left atrial/left atrial appendage thrombosis, in order to provide reference for clinical practice.Atrial fibrillation (AF) is the most common persistent arrhythmia, and is the major factor that leads to thromboembolism.This was a retrospective study. Data was collected from medical records. A total of 238 patients with non-valvular AF, who were hospitalized in Zhengzhou Cardiovascular Hospital from February 2012 to March 2017, were enrolled into the study. Inclusion criteria: (1) patients diagnosed by electrocardiogram (ECG) or dynamic ECG; (2) patients who underwent transesophageal echocardiography. Exclusion criteria: (1) patients with rheumatic heart disease, valvular AF and paroxysmal AF; (2) patients with acute myocardial infarction and acute decompensated heart failure within 90 days, and patients with previous history of cardiac surgery; (3) patients with pulmonary embolism, deep venous thrombosis, history of administration of anticoagulant drugs, such as warfarin and rivaroxaban, or lipid-lowering drugs, such as statins; (4) patients with malignant tumors, hyperthyroidism, and severe liver and kidney dysfunction. This study was approved by the Ethics Committee of our hospital. All patients provided a signed informed consent.Gender, age, course of AF, smoking and alcohol addiction, chronic disease history, height and weight of all patients were collected, and the body mass index (BMI) was calculated. In addition, fasting blood glucose (FBG), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), platelet count (Plt), serum uric acid (UA) and other biochemical indicators were collected.All examinations were performed by an experienced sonographer with the title of Chief Physician in our hospital. All patients were routinely informed and signed an informed consent before examination. A Philips iE33 color Doppler ultrasound diagnostic apparatus was used to complete the examination. Transthoracic echocardiography was routinely performed, and the probe frequency was 2.5 MHz. Left atrial diameter (LAD), left ventricular end-diastolic dimension (LVEDD), and left ventricular ejection fraction (LVEF) were measured. Subsequently, local pharyngeal anesthesia with lidocaine was administered. Then, the probe was placed into the esophagus up to the location of the heart, and the probe frequency was 5.0 MHz. The left atrial and left atrial appendage sections were continuously observed to determine whether thrombus was present in the left atrial/left atrial appendage. These patients were divided into two groups: thrombosis group and non-thrombosis group.7(1) major risk factors (2 points per item): age of ≥75 years old, ischemic stroke, and transient ischemic attack; (2) secondary factors (1 point per item): female, aged 65–74, hypertension, diabetes, vascular disease, and chronic heart failure; (3) a lowest score of 0 and a highest score of 9. The higher the score was, the greater the possibility of thrombosis.The CHA2DS2-VASc score was calculated according to the basic clinical data of patients:t-test of normal distribution, and Kolmogorov-Smirnov (K-S) test was used for normal distribution. Categorical data were expressed in rate (%), and compared between two groups usingX2-test. Multivariate logistic regression analysis was performed to analyze related factors that affected the left atrial/left atrial appendage thrombosis. The receiver operating characteristic (ROC) curve was used to analyze the predictive results of left atrial diameter and CHA2DS2-VASc score for left atrial/left atrial appendage thrombosis. p<0.05 was considered statistically significant.Data collation and statistical analyses were conducted using the statistical software SPSS 21.0. Continuous data were expressed as mean±standard deviation (x±SD), and compared between two groups using Student’s unpairedA total of 238 patients with non-valvular AF were enrolled in this study. Among these patients, 151 patients were male and 87 patients were female, and the age of these patients ranged from 29 to 86, with an average age of 61.1±12.4. In these 238 patients, left atrial/left atrial appendage thrombosis occurred in 46 patients, and the incidence was 19.3%.Differences in gender, BMI, course of AF, proportions of patients with a history of smoking and alcohol consumption, proportions of patients with diabetes and coronary heart disease, CHA2DS2-VASc score, FBG, TC, TG, LDL-C, Plt, UA and drug therapy between the thrombosis group and non-thrombosis group were not statistically significant (p>0.05). In the thrombosis group, the proportion of patients aged ≥75, the proportion of patients with hypertension, the proportion of patients with heart failure, the proportion of patients with a history of stroke/transient ischemic attack, the proportion of patients with a history of vascular disease, and the CHA2DS2-VASc score, LAD and LVEDD were higher than those in the non-thrombosis group, while HDL-C and LVEF were lower than those in the non-thrombosis group, and all differences were statistically significant p<0.05,.With the determination of whether the left atrial/left atrial appendage thrombosis existed as a dependent variable, and the variables with a p-value <0.10 as independent variables, multivariate logistic regression analysis was performed. The results revealed that the history of stroke/transient ischemic attack, vascular disease, CHA2DS2-VASc score, LAD, LVEDD and LVEF were independent risk factors for left atrial/left atrial appendage thrombosis p<0.05,.The ROC curve analysis revealed that when the CHA2DS2-VASc score was used to predict left atrial/left atrial appendage thrombosis, the area under the curve (AUC) was 0.593 (95% CI: 0.495–0.690). When the CHA2DS2-VASc score was ≥3, sensitivity and specificity were 86.5% and 32.6%, respectively. When LAD was used to predict left atrial/left atrial appendage thrombosis, the AUC was 0.786 (95% CI: 0.704–0.868). When LAD was ≥44.17 mm, sensitivity and specificity were 89.6% and 60.9%, respectively .In the different CHA2DS2-VASc groups, the incidence of left atrial/left atrial appendage thrombosis in patients with LAD ≥44.17 mm was higher than that in patients with LAD <44.17 mm, and the difference was statistically significant p<0.05,.8Compared with the non-AF population, the risk of stroke in patients with AF is increased by five times.9In addition, a study revealed that10the thrombus that caused stroke in AF patients mostly came from the left atrial /left atrial appendage. Left atrial/left atrial appendage thrombosis is an independent risk factor for stroke in patients with non-valvular AF.11This may significantly increase the risk of thromboembolic events, and is a direct indicator of anticoagulant therapy in AF patients.12Therefore, early detection of left atrial/left atrial appendage thrombosis or high-risk factors for left atrial/left atrial appendage thrombosis is of great significance for guiding treatment and improving the prognosis of AF patients. In this study, 238 AF patients, who did not receive anticoagulation and lipid-lowering therapy, were enrolled. The transesophageal echocardiography results revealed that the incidence of left atrial/left atrial appendage thrombosis was 19.3%. This is similar to 18.6%, reported by Shuanglun Xie et al.,13and 20.7%, reported by Weiwei Fu et al.14These results reveal that the incidence of left atrial/left atrial appendage thrombosis is relatively high in AF patients without anticoagulation and lipid-lowering therapy.As the most common arrhythmia type in the Internal Medicine-Cardiovascular Department, AF is a risk factor that leads to thromboembolism.15A study revealed that16a CHA2DS2-VASc score of ≥2 is an independent risk factor for left atrial/left atrial appendage thrombosis in AF patients. This study revealed that the CHA2DS2-VASc score was higher in the thrombosis group than in the non-thrombosis group. However, the difference in the distribution of CHA2DS2-VASc scores between the two groups was not statistically significant. Univariate and multivariate analysis revealed that the CHA2DS2-VASc score is an independent risk factor for left atrial/left atrial appendage thrombosis. Furthermore, these results reveal that the CHA2DS2-VASc score is correlated to left atrial/left atrial appendage thrombosis. The ROC curve analysis revealed that the AUC was 0.593 (95% CI: 0.495–0.690). When the CHA2DS2-VASc score was ≥3, sensitivity and specificity were 86.5% and 32.6%, respectively. These results showed that for patients with a CHA2DS2-VASc score of ≥3, the possibility of left atrial/left atrial appendage thrombosis should be highly alerted. However, this study also revealed that when the CHA2DS2-VASc score was 0 or 1, left atrial/left atrial appendage thrombosis still occurred in 9 and 15 patients, respectively. Furthermore, these results revealed that for low-risk patients with a CHA2DS2-VASc score of 0 or 1, there was still a risk of stroke. These results suggested that the CHA2DS2-VASc score has some limitations in predicting left atrial/left atrial appendage thrombosis.The CHA2DS2-VASc scoring system was established by further optimizing the CHADS2 scoring system, which is a clinical method commonly used to assess the risk of stroke in AF patients at present, and also used to guide clinical treatment.17morphological changes in the left atrium and left atrial appendage might increase the risk of thromboembolism in AF patients. When AF occurs, the bigger the cardiac atrium, the more easily thrombosis forms.18In this study, LAD in AF patients was compared. The results revealed that LAD was greater in the thrombosis group than in the non-thrombosis group, which was an independent risk factor for left atrial/left atrial appendage thrombosis. The ROC curve analysis revealed that when LAD was used to predict left atrial/left atrial appendage thrombosis, the AUC was 0.786 (95% CI: 0.704–0.868), and when LAD was ≥44.17 mm, sensitivity and specificity were 89.6% and 60.9%, respectively. These results revealed that LAD size was correlated to left atrial/left atrial appendage thrombosis. Hence, when LAD was ≥44.17 mm, this had good sensitivity and specificity in predicting left atrial/left atrial appendage thrombosis. In this study, we used LAD as the index to predict left atrial/left atrial appendage thrombosis. Recently, left atrial volume has been used as a measure of left atrial enlargement.19This index might be included in future studies. In this study, patients were further stratified according to the CHA2DS2-VASc score, in order to analyze the effect of LAD on left atrial/left atrial appendage thrombosis. These results revealed that regardless of whether the CHA2DS2-VASc score was 0, 1 or ≥2, LAD ≥44.17 mm significantly increased the risk of left atrial/left atrial appendage thrombosis. These results revealed that further assessment of LAD on the basis of the CHA2DS2-VASc score would be helpful for evaluating the risk of left atrial/left atrial appendage thrombosis and guiding anticoagulation therapy.A study revealed thatHowever, considering that this study is a single-center, small-sample size study, there may be some shortcomings in sample representativeness. Hence, multi-center and large-sample size cohort studies are needed to further clarify the relationship between the CHA2DS2-VASc score and LAD in predicting left atrial/left atrial appendage thrombosis and guiding anticoagulation therapy.In summary, the CHA2DS2-VASc score and LAD are correlated to left atrial/left atrial appendage thrombosis in patients with non-valvular AF. For patients with a CHA2DS2-VASc score of 0 or 1, LAD size should be further considered. When LAD was ≥44.17 mm, the risk of left atrial/left atrial appendage thrombosis is still relatively high, and it is necessary to conduct further anticoagulation therapy.


T) is calculated by using the Fisher–Lee relationship. Consequently, the thermal and electrical transport properties such as S), Fano factor (F), electrical conductance (G), thermal conductance (Q), and merit number -9H-fluorene aromatic system as a prototype of a molecular switch. Variations of the dihedral angles between the two Benzene rings at each end of the molecule have been considered, thus determining the dependence on the structural variation of the molecule when the aromatic system is connected between metal contacts. The molecule is modeled through a Tight-Binding Hamiltonian where—from the analytical process of decimation and using Green’s functions—the probability of transmission ( Given the current rate of technological advancement, the smallest components that begin to be functional such as individual molecules and small groups of molecules  are taking great steps to be used in molecular electronics and consequently contribute to the development of nanoscience. The first theoretical and experimental efforts in this field began in the 1970s with the work of Aviram and Ratner who described how a modified salt can work as a traditional diode in an electrical circuit ,11,12.Molecular systems based on benzene rings have become important devices that can be used in molecular electronics. They have been characterized with superconducting properties as well as with special characteristics to be used in solar cells, nanotransistors, organic light-emitting diode (OLED), to name a few ,14. In pOver the past few years, researchers in chemistry, physics, and nanotechnology have begun to understand stereoelectronics adequately. This is the means through which it is possible to interpret how and why the electronic properties of molecules vary and can be modified in the process of shaping physical–chemical systems. With the appearance of single-molecule techniques, the necessary instruments and technology have been created to follow the conformation of molecules step by step. By introducing the stereoscopic effect, for example, in the aromatic structure of biphenyl, it is possible to modify the structural and physical properties of an organic functional molecule. Aiming to investigate the process of intramolecular conformation of biphenyl and how this affects the dynamics of its transport properties at the level of an isolated molecule, Xin et al.  designedIn this work, we consider the theoretical and analytical study of thermal and electrical properties through the aromatic 2,7-Di-9H-fluorene system as a prototype of a molecular switch wire, by including the dependence on the dihedral angles between the two external benzene rings at each end and the interactions between the molecule and the contacts see . Such ef) limits ,32,33. IThe renormalization method is a method that transforms the real space into an effective space that generates the systematic reduction of the Hamiltonian dimension, i.e., the set of linear equations that characterize the system becomes a set of nonlinear equations with effective energies and couplings with fewer degrees of freedom. The renormalization method is a highly efficient and very low computational cost  methods). For this reason, to calculate the transport properties in this work, the renormalization process is done under the inclusion of Feynman paths using Green’s functions, which can be considered as propagators (Dyson’s equation) that carry the charge transport information through the molecular system and provide an alternative in the solution of the Schrödinger equation in a numerical and analytically stable way. It is important to note that the renormalization method used in this work has been implemented in the calculation of quantum transport properties through quantum wire systems, aromatic molecular systems, DNA molecules, among others, and have been compared with transport properties through similar systems, determined by DFT calculations and/or experimental results ,30,31,34The manuscript is organized as follows: In To describe the molecular system as an electronic device, which is connected to two metal contacts See , we intrn, respectively. Moreover, Here, z is a complex term given by G can be calculated by using the Dyson equation, given byUsing the Landauer formalism, we study the fluctuations in both current and temperature through molecular wire composed of benzene rings connected to two semi-infinite leads ,32,33. TDue to the high complexity while describing the 2,7-Di-9H-fluorene molecular structure by the Hamiltonian, its solution is rather complicated. Therefore, in order to numerically solve the transport properties on this system, we perform the Decimation process as a valid approximation. It is based on considering the molecular system into an effective linear chain, such as that shown the Then, the transmission probability for the new one-dimensional effective molecular system can be written asThe Equation  as(9)TIS) and the total current flowing through the aromatic molecules, the Fano factor can be evaluated via the following relationship [The noise power of current fluctuations (NPCF) is calculated by the following expression ,34,35:(1S=S0∫−∞∞Ttionship :(12)F=S2When carriers ,37.e is the electronic charge, and h represents the Plank’s constant. The Landauer integrals used in Equation (13) have the formTo complete the full landscape of electrical conduction in these systems, we evaluate the of merit ,39,40,41The next section describes the analytical and numerical results obtained from the application of the decimation method and Landauer’s formalism for molecular systems connected to terminal electrodes.The calculation of the N resonances shown in the transmission profile  and the molecule-contact bonding energy  and the lowest unoccupied molecular orbital (LUMO) are located on the edges of these zones and the band gap. The bandwidth of the gap is ∼2.0 eV, which is in good accordance with the work of Na Xin et al. [In n et al. .I), the shot noise (S), and the Fano factor (F) are calculated as functions of the coupling V). The current flow occurs due to an imbalance between the chemical potentials of the electrodes  which depends on the weak or strong coupling that exists with the molecular system. As we can see in V), for any value of In n et al.  for the Equation . Figure The ductance a is propductance ; therefoncreases . It incrComplementary to the above, we can observe that the width of the energy bands and the antiresonance or band-gap in the  similar b to thosance in G. The zert figure d, and weIn this section, we analyze the electrical and thermal properties of the 2,7-Di-9H-fluorene molecule, taking into account the variation of the dihedral angle between the two extreme benzene rings of the molecule. We only take into account a fixed value for affected ,42,45,46S-quantum noise and the F-Fano factor behave similar to the flat molecule, except for the fact that the quantum noise decreases or increases when there is a change in the molecular structure and goes from a Poisson limit  b. Calculated see b. The foFinally, it can also be inferred that when determining the thermal properties increase .The electrical properties such as transmission probability, n et al.  and our It was demonstrated that the analytical renormalization treatment of the system has presented a reliable approach, giving results that allowed understanding phenomena such as the stereoelectronic effect of molecular conductance. It was also shown that the change in charge transport through the molecule depends on the temperature, the


CD99, a leukocyte surface molecule, reportedly plays an important role in several cellular processes. However, the role of CD99 in T cell regulation remains unclear, as the CD99 ligand associated with T-cell regulation has not yet been identified. Our previous study showed that recombinant CD99 bound to CD99 ligands was expressed on monocytes, NK cells and dendritic cells. This interaction regulates the expression of IL-6 and TNF-α in CD3 + T cells following T cell activation. In the present study, we confirmed the presence of CD99 ligands in immune cells.A recombinant CD99-human IgG fusion protein, CD99HIgG, was produced and used to search for CD99 ligand expression in various hematopoietic cell lines. Among several cell lines, THP-1 monocytic cell line showed strong positive reaction for CD99HIgG, and CD99 and CD99 ligand complexes were pulled-down using a DTSSP cross-linker. The study demonstrated the presence of the membrane bound CD99 ligand, and CD99 ligand candidates were identified via LC–MS/MS. These results may be useful to further identify the CD99 ligands, and to fully comprehend the role of CD99 in immunoregulation. CD99 is a heavily O-linked type I transmembrane glycoprotein expressed on both hematopoietic and non-hematopoietic cells –3. Up-reRecently, we demonstrated that putative CD99 ligands were expressed on the surfaces of monocytes, NK cells and dendritic cells, but not on those of B and T cells . RecombiHEK293T cells stably expressing CD99HIgG were generated in our laboratory . Large sTo validate the binding activity of purified CD99HIgG, PBMCs were stained with 20 μg/mL of biotinylated CD99HIgG or CD147ExHIgG control as described in [3. Cells were stained with 10 μg/mL of CD99HIgG or CD147ExHIgG control on ice for 1 h. Next, 2 mM DTSSP ; Pierce) was added, followed by further incubation for 2 h. Then, DTSSP was neutralized by adding 20% FBS and the un-crosslinked proteins were washed out. The bound proteins was determined using rabbit anti-human immunoglobulins antibodies-FITC and analysed via a FACSort flow cytometer (BD Biosciences).To study the cellular distribution of CD99 ligands, Fc receptors of various human hematopoietic cell lines were blocked using 20% FBS-PBS-0.02% NaN8) were stained with 10 μg of CD99HIgG or CD147ExHIgG control in 500 μl of PBS and incubated at 4˚C for 3 h. Next, an equal volume of 4 mM DTSSP was added, and further incubated for 2 h. Subsequently, 50 mM glycine in PBS was added at a final concentration of 20 mM. Cells were washed, then lysed using 1 mL of 1% lauryl maltoside containing protease inhibitors. Recombinant proteins-ligand complexes were isolated from cell lysate using protein G agarose beads (Pierce), eluted via 0.5% sodium dodecyl sulphate (SDS), and further investigated using western blotting. Molecular weight shifts of the complex were detected using anti-CD99 mAb or anti-CD147 mAb followed by rabbit anti-mouse immunoglobulins antibodies-HRP. This complex was subjected to LC–MS/MS.THP-1 cells  that was seen in the pre-pull-down lysate (lane 3) was not seen in the flow though lysate (lane 4);  were used as controls in LC–MS/MS analysis. The peptide finger prints obtained via LC–MS/MS were searched for batch protein sequences in the NCBI database. Protein identification of BSA control showed that most proteins were bovine serum albumin [see Additional file For the purpose of on-membrane digestion following electroblotting, protein bands corresponding to CD99 ligand-CD99HIgG complexes on the PVDF membrane were subjected to an on-membrane digestion protocol prior to LC–MS/MS analysis Fig. a; the rePossible CD99 ligands of interest, as indicated by the results of both in-gel and on membrane digestions, are listed to facilitate identification of CD99 ligands.CD99 plays the vital role in immunoregulation, with particular reference to T cell regulation. However, the precise function of CD99 in T cell regulation remains unclear. As a result, CD99 ligand remains undefined. Therefore, identification of the CD99 ligand is necessary. Interestingly, as our previously reported, the putative CD99 ligand is a membrane protein. It was found that CD99HIgG with a DTSSP cross-linker bound specifically to the surfaces of monocytes, NK cells and dendritic cells, but not to those of B and T cells . In the The pull-down method, which involves recombinant CD99 protein and a DTSSP cross-linker, was utilized to identify the amino acid sequences of CD99 ligands. THP-1 cells were used to represent CD99 ligand expressing cells. CD99HIgG was used as a bait protein and DTSSP was added to crosslink recombinant CD99 and its ligands on THP-1 cell surface. According to the properties of DTSSP, molecular weight shifts due to crosslinking between CD99 and CD99 ligands was observed in the pull-downs by western blotting under non-reducing conditions. The results indicated that recombinant CD99 was able to pull-down CD99 ligands from the surface of THP-1 cells. This is the first experiment that concretely demonstrated the presence of membrane CD99 ligand proteins. The samples obtained by the pull-down method were prepared for identification of CD99 ligands via LC–MS/MS.Two methods, in-gel digestion and on-membrane digestion, were utilized to prepare samples for LC–MS/MS analysis. Several unnamed proteins and some surface receptors were obtained. These proteins were potential CD99 ligands. The unnamed protein products, in particular, should be the focus of attention, as no CD99 ligand has been identified so far. We speculated that the CD99 ligand may be a novel, un-defined protein. The possibility of heterophilic interaction of CD99 is suggested.To the best of our knowledge, our experiments, are the first to confirm the presence of putative CD99 ligands on the surfaces of leukocytes. Several proteins that had been predicted to be CD99 ligand candidates were also included in the results of this study.CD99 ligand candidates identified by LC–MS/MS have not yet been further confirmed. Additional investigations using different method i.e. Genome-scale receptor array (GSRA) technology are required to clarify CD99 ligands, in order to fully comprehend the role of CD99 in immunoregulation. Several specific antibodies to un-defined proteins are also required for confirming the CD99 ligand.Additional file 1. Methods for identification of CD99 ligands by LC-MS/MS.Additional file 2: Figure S1. Validation of the purity and structure of purified CD99HIgG.Additional file 3: Figure S2. Verification the binding activity of purified CD99HIgG.Additional file 4: Figure S3. The expression of CD99 ligands on hematopoietic cells.Additional file 5: Table S1. List of proteins obtained from in-gel digestion of the BSA protein control followed by LC–MS/MS analysis and identified by MASCOT.Additional file 6: Table S2. List of proteins obtained from in-gel digestion of purified CD99HIgG protein control followed by LC–MS/MS analysis and identified by MASCOT.


Idiopathic central precocious puberty (ICPP) is supposed to be non-existent in a context of testicular destruction that is typically present in Klinefelter syndrome (KS). Herein, we describe a rare case of ICPP in a Klinefelter patient  with 2 maternal X chromosomes. Moreover, we highlight the differences in gonadotropin levels in comparison to males with ICPP and a normal karyotype.An 8 years old boy with a history of cryptorchidism was evaluated for precocious puberty (Tanner staging: P2/G3). Both testes measured 25x35mm. His hormonal profile confirmed a central origin of precocious puberty with high serum testosterone (4.3 ng/ml), luteinizing hormone [LH (3.5 UI/l)] and follicle stimulating hormone [FSH (7.7 UI/l)] levels. Luteinizing hormone-releasing hormone (LHRH) test amplified LH and FSH secretion to 24 and 14 UI/l respectively. Brain magnetic resonance imaging (MRI) was normal. No MKRN3 mutation was detected. He was treated for ICPP for two years. During puberty, he suffered from hypergonadotropic hypogonadism leading to the diagnosis of KS . Chromosomal analysis by fluorescent multiplex polymerase chain reaction (PCR) using X chromosome microsatellite markers identified 2 maternal X chromosomes.Analysing 8 cases of KS developing ICPP (our reported case and 7 other published cases) revealed that these KS patients with ICPP have higher LH and FSH levels during ICPP episode than in ICPP patients with a normal karyotype . Furthermore, their response to gonadotropin-releasing hormone (GnRH) stimulation is characterized by excessive LH and FSH secretion .“overrepresentation of ICPP in KS. Thus, karyotype analysis could be considered for boys suffering from ICPP, especially if testicular size is smaller or gonadotropins are significantly elevated.ICPP in boys is extremely rare. The pathophysiology of ICPP in KS is unknown. However, maternal X supplementary chromosome and early testicular destruction may play a significant role in the initiation of ICPP, in part explaining the relative The online version contains supplementary material available at 10.1186/s12610-020-00117-1. Puberty in boys is initiated when gonadotropin-releasing hormone (GnRH) secretion is amplified, inducing the secretion of gonadotropins. Pulsatile secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) is accompanied by enlarged testicular volume, testosterone secretion and initiation of spermatogenesis . The ageWe describe a case of ICPP in a boy who, a few years later, developed hypogonadism in his adulthood secondary to KS . In addition to our patient, we analyze 7 other cases of ICPP in KS patients previously reported in the literature. Among patients with ICPP, those who are also suffering from KS have higher levels of gonadotropins and an exaggerated response to GnRH stimulation compared to those with a normal karyotype. This comparison highlights the possibility of a primitive testicular factor, such as precocious germ cell and Leydig cell dysfunction, participating in the induction of ICPP in KS.A boy, born in 1994, was evaluated for suspicion of precocious puberty. At 8 years old, his height (150 cm) exceeded the mean for age by 3 standard deviations with a growth rate of 10 cm per year. He developed puberty signs (Tanner staging: P2/G3). Both testes measured 25x35mm, the penis was enlarged and increased in length. Bone age was advanced (10 years according to modified Sempé’s method). His past history was marked by cryptorchidism, operated at age of 1 year. No facial dysmorphia, behavioural abnormalities or mental retardation were noticed.His hormonal profile confirmed a central origin of precocious puberty with high serum testosterone (4.3 ng/ml) for age, and detectable LH (3.5 UI/l) and FSH (7.7 UI/l) .Luteinizing hormone-releasing hormone (LHRH) test amplified LH and FSH secretion to 24 and 14 UI/l respectively  to study short tandem repeats polymorphisms .http://projects.tcag.ca/variation). Microsatellite analysis in X chromosome showed two X chromosomes of maternal origin. Furthermore, no mutation was found in the coding regions of MKRN3 gene.Peripheral blood cytogenetic analysis of our patient revealed 47 chromosomes, with an extra X chromosome in all analyzed metaphases, confirming KS. Array-comparative genomic hybridization (CGH) excluded the presence of any other genomic imbalance, except for copy number variations (CNV) previously described in the normal population according to the Database of Genomic Variants  and those with a normal karyotype reported in the literature . Comparr et al.  comparedr et al.  or 47,XXIn our patient, despite the precocious puberty, target height was attained. Similarly, in other reported cases of ICPP with KS, the height was attained in all patients, with (3 patients including our case) , 10 or woverrepresentation” of ICPP in Klinefelter patients. The risk is estimated to be 1/370 KS patients by the Health Register of Belgium [Indeed, around 450 boys with ICPP under the age of 9 years have been described in the published cohorts to date, accounting for about 8% of all central precocious puberty cases before the age of 9 year and 10% before the age of 10 years  [MECP2 (responsible for Rett syndrome) [Secondly, in our patient, both X chromosomes were of maternal origin. None of the reported cases studied the origin of the supplementary X chromosome. It is worth noting that the supplementary X chromosome is equally inherited from paternal and maternal origin. When the origin of this supplementary X chromosome is maternal, it is hypothesized that some deleterious genes could escape the natural X chromosome inactivation , 44. Thengenita)  and MECPyndrome) . On the yndrome) . Pubertyyndrome) , and is yndrome) . Indeed,yndrome) . NeverthDespite a number of interesting studies investigating early onset of puberty in patients with KS, the genetic basis of idiopathic central precocious puberty in both sexes remains elusive. Further studies using molecular genetics could help understanding the mechanisms of puberty initiation, timing and progression. Specifically, identifying novel X-linked genes in boys with precocious puberty will be instrumental to shed light on the mechanisms underlying puberty initiation.ICPP is extremely rare in boys. ICPP patients with KS have higher gonadotropin levels than those with a normal karyotype. This suggests a peripheral or “testicular driver” that amplifies gonadotropin secretion through a positive feedback loop, which in turn triggers the initiation of central PP in such patients. Furthermore, maternal supplementary X chromosome in KS might play a role in the timing of puberty initiation. In boys with ICPP, long term endocrinological follow up until definitive puberty and karyotype analysis are important, specially if gonadotropin levels are significantly elevated or testicular volume is reduced.Additional file 1.Additional file 2: Supplementary Table 1. Incidence of central precocious puberty (ICPP) according to sex. ICPP: Idiopathic central precocious puberty. CPP: Central precocious puberty. ICPP in boys accounts for 10% of the aetiologies of CPP. Data represent number of patients or percentage (%).


A methodology based on the concepts that arise from Density Functional Theory named Conceptual Density Functional Theory (CDFT) was chosen for the calculation of some global and local reactivity descriptors of the Discodermins A–H family of marine peptides through the consideration of the KID (Koopmans in DFT) technique that was successfully used in previous studies of this kind of molecular systems. The determination of active sites of the studied molecules for different kinds of reactivities was achieved by resorting to some CDFT-based descriptors like the Fukui functions as well as the Parr functions derived from Molecular Electron Density Theory (MEDT). A few properties identified with their ability to behave as a drug and the bioactivity of the peptides considered in this examination were acquired by depending on a homology model by studying the correlation with the known bioactivity of related molecules in their interaction with various biological receptors. With the further object of analyzing their bioactivity, some parameters of usefulness for future QSAR studies, their predicted biological targets, and the ADME  parameters related to the Discodermins A–H pharmacokinetics are also reported. Several natural resources in the sea may generate molecules which could be a lead toward the design of new medical drugs. It is for this reason that many recent studies have been undertaken towards new products where the knowledge of marine natural products is used as an important source of information . Among tDue to the great potential that these peptides offer as an aid in the treatment of many diseases, they are commonly referred to as therapeutic peptides. As a consequence, there is a lot of current research in this field . By consThe process of drug design is driven by a combination of advanced experimental and computational methods. The use of Computational Chemistry methodologies has a very important role in the practice of modern medicinal chemistry, offering a great potential for the improvement of the different phases of drug research, with special emphasis on time and cost savings. Since the structure of molecules defines the chemical, physical and biological properties of matter, this information is crucial for understanding, explaining and predicting chemical reactions and biochemical processes, developing new drugs and providing important insights into the nature of the interactions between drug targets and ligands, which allows predictive models that are suitable for lead discovery and optimization to be constructed.For this reason, it is of the utmost importance to study the chemical reactivity of the natural products (in this case of marine origin), because it is likely to help with the development of some medicines with the aid of tools displayed through Computational and Theoretical Chemistry as well as Molecular Modeling. In a special way, Conceptual Density Functional Theory (DFT) ,6,7 is oSince the knowledge of the chemical reactivity is essential for the development of new pharmaceutical drugs, we are now investigating a new family of peptides obtained from marine origin with the hope that this could be a new source for therapeutic peptides . The objKohn–Sham (KS) methodology includes the estimation of the molecular energy and density of a given system, as well as the orbital energies, explicitly connected with the frontier orbitals including the Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccupied Molecular Orbital (LUMO) ,21,22,23nctional ,33,34,35y quoted ,16,17,18Following the methodology considered in our previous studies ,16,17,18http://www.chemspider.com/), which is a website that acts as an online free resource of chemical information related to physical and biological properties, interactive spectra and literature references. In order to get a glimpse of the potential therapeutic properties of the considered peptides, Simplified Molecular Input Line Entry Specification (SMILES) notations for the molecular systems under consideration were fed into the online Molinspiration software from Molinspiration Cheminformatics  allowing for the estimation of several molecular properties that are known to be related to druggability and that could be useful in QSAR studies [The starting molecular structures of the Discodermins A–H peptides to be studied were obtained from ChemSpider  model that is accessible in Gaussian 09 . As it wA graphical display of the tridimensional optimized molecular structures of the Discodermins A–H peptides obtained with the aid of the UCSF Chimera Visualization System  are presIt is usually assumed that the goodness of a given density functional can be estimated by comparing the results that it gives with the experimental values that are trying to be reproduced or with the results that can be obtained through post Hartree–Fock calculations like MP2, MP4 or CCSD. However, this is not always possible due to the lack of experimental results for the molecular systems that are being studied or the large size of the molecules that keep some accurate methodologies to be computationally practical. For this reason, we have developed a protocol named KID (Koopmans in DFT) ,16,17,18ch group ,16,17,18ch group ,16,17,18As can be seen from the results in ElectronegativityGlobal HardnessElectrophilicityElectrodonating PowerElectroaccepting PowerNet Electrophilicitybeing Taking into account the KID methodology considered in the previous research being integrated into the finite difference approximation ,16,17,18nctional .As a complement of these global reactivity descriptors that arise from Conceptual DFT ,7,51,52,By making use of the mentioned CDFT software tool applied to the results of the calculation of the electronic properties of the Discodermins A–H peptides, the values of the defined global reactivity descriptors (including the Nucleophilicity N) could be obtained and they are displayed in The Global Hardness  authors , it can Nucleophilic Fukui FunctionElectrophilic Fukui FunctionDual Descriptorwhich are relationships between the electronic densities of the neutral, positive and negative species as well as between the Nucleophilic and Electrophilic Fukui functions.The presented global descriptors are a representation of the chemical reactivity of a molecule as a whole. However, local reactivity descriptors have been developed that can give an idea of the differences between the reactivity of each of the atoms that form the molecule. One of the most important groups of such reactivity descriptors are the Fukui functions ,6,7 and The Nucleophilic Fukui function, molecule . Thus, aNucleophilic Parr FunctionElectrophilic Parr Functionwhere Another local reactivity descriptors are the Parr functions ,66 that ectively .To perform a comparison between the results that can be obtained from both formulations, the predictions for the specific reactions sites coming from the Electrophilic and Nucleophilic Fukui functions analysis for each peptide have been compiled in a series of tables that are presented as Supplementary Materials in the form of an By looking at the numerical and graphical results presented in The Discodermins A–H family of cyclodepsipeptides of marine origin has been studied by resorting to some techniques of common use in the process of drug discovery and development showing that these kind molecules can be regarded as potential therapeutic drugs.With this knowledge in mind, the chemical reactivity of the studied peptides has been exhaustively analyzed through the optimization of their structures using an MN12SX/Def2SVP/H2O model chemistry and the determination of their electronic properties by means of an improved model chemistry, namely MN12SX/Def2TZVP/H20, already used in previous works for the study of peptides, demonstrating their usefulness for this kind of calculations.The chemical reactivity of the considered molecular systems was subject to an analysis based on a particular methodology developed by our research group named Conceptual DFT-based Computational Peptidology being the use of the MN12SX density functional validated once again by resorting to the KID procedure and the in-house software tool CDFT.The analysis of the global and local reactivity descriptors arising from Conceptual DFT together with some proposals like the Nucleophilicity N and the Parr functions allowed for a complete understanding of the chemical reactivity of the studied peptides, by distinguishing the different chemical reactivities through the analysis of the global descriptors and the further identification of the reaction sites or regions within the molecules by resorting to Fukui and Parr functions as well as the Dual Descriptor.Finally, a nice agreement was found between the outcome of the numerical and graphical analysis of the Fukui and Parr functions on each peptide leading to the conclusion that it could be possible to define a new chemical reactivity descriptor analog to the Dual Descriptor on the basis of the difference between the Parr functions which could act as an additional tool for the study of the chemical reactivity of molecular systems.


To the Editor:Virchows Archiv publication, Matias-Guiu et al. [In a recent u et al.  indicateFirst, the authors indicate that molecular results must be interpreted in light of morphology and location of the lesion. However, interpretation of molecular results in relation to tumor genetic concepts and molecular (oncogenic and resistance) pathways is also crucial. This accounts not only for molecular analyses of tissues but also of circulating tumor DNA (ctDNA) from liquid biopsies.Second, as stated, molecular pathology is different from other laboratory specialties because of the oncological pathology specific situation as the use of routine pathology specimens  composed of a mixture of neoplastic and normal cells, and from which often only minute amounts of largely degraded nucleic acids can be retrieved. This pathology-specific molecular biological situation was recognized by the Dutch Pathological Society which implemented since 2014 a 2-year educational program to become a Clinical Scientist in Molecular Pathology (CSMP) [Third, we agree that molecular results should be part of state-of-the-art integrated diagnostics. For securing accredited quality and cost-effective diagnostics, regional centralization of molecular pathology will be inescapable. Ideally, pathologists and CSMPs take the lead in this regionalization and do not leave this to hospitals, insurance companies, or governmental bodies. Within such a regionalized situation, it is important that all pathologists within a region have easy access to the molecular pathology laboratory for consultation and education. In addition, regional molecular tumor boards (MTBs), discussing complex molecular results in the context of clinical and pathological data, should be easy accessible  for all pathologists, CSMPs, and clinicians.deserved by pathology departments. This implies that pathologists need to have broad knowledge of molecular pathology: basic molecular biology including its language and tumor genetic concepts and pathways including targeted treatment resistance mechanisms. In addition, pathologists and CSMPs, in close contact with oncologists, need to keep up with evolving carcinogenesis concepts, implementing new molecular markers, up-to-date molecular technologies, and treatment options.Fourth, the publication is a plea to perform oncological molecular diagnostics within pathology departments. We think indeed that this is crucial for the best patient care. However, solely the plea is not sufficient; this central role in oncology diagnostics has to be As a result of the above, it is clear that the pathologist of the future (and current!) has to be a molecular pathologist. Therefore, we would like to plea for implementation of a substantial part (20–25%) of pathology resident training programs to molecular pathology. These molecular pathologists, together with CSMPs, will play a crucial role in translating morphological and molecular features of tumors to diagnostic and predictive parameters that facilitate optimal personalized treatment. As a result, we expect that the leading role of the discipline Pathology in assessing somatic alterations in cancer will be broadly recognized and assigned.


The final hybrid products were characterized by X-ray diffraction, Fourier transform infrared and X-ray photoelectron spectroscopies, thermogravimetric analysis, scanning electron microscopy and porosity measurements. As proof of principle, the porous heterostructure with the maximum surface area was chosen for investigating its CO2 adsorption properties.In this work, we report on a facile and rapid synthetic procedure to create highly porous heterostructures with tailored properties through the silylation of organically modified graphene oxide. Three silica precursors with various structural characteristics  were employed to create high-yield silica networks as pillars between the organo-modified graphene oxide layers. The removal of organic molecules through the thermal decomposition generates porous heterostructures with very high surface areas (≥ 500 m Approximately 35 billion metric tons of CO2 separation technologies that are currently being developed and used  to the sorbent's surface  and Potassium chlorate  were purchased from Fluka Inc. Dodecylamine , 1,4-bis(triethoxysilyl)-benzene (BTB 99%), tetraethylorthosilicate (TEOS 98+%) and (3-aminopropyl)triethoxysilane (APTEOS ≥ 98%) were acquired from Sigma-Aldrich, and sulfuric acid , n-butanol and sodium hydroxide (NaOH) were obtained from Merck. All reagents were of analytical grade and used without further purification. Distilled deionized water was used for all the experiments.Graphite , Nitric acid , and finally air-dried at room temperature after being spread on a glass plate.Graphene oxide, denoted as GO in the following, was synthesized using a modified Staudenmaier's method  under vigorous stirring (dodecylamine/GO 3:1 w/w). The mixture was stirred for 24 h, centrifuged, washed three times with ethanol/ water: 1/1, and air-dried after being spread on a glass plate. The organo-modified GO is denoted as org-GO.2O/n-butanol: 1/4/54. The sol-gel reactions were performed at 50°C while stirring, and the obtained gel was placed in the oven at 50°C overnight. The silica–GO organo-heterostructures are denoted as GO-BTB, GO-APTEOS and GO-TEOS, depending on which of the three organosilica precursors was employed. The final porous structures were collected after calcination in air at 370°C for 120 min. The calcinated samples are denoted as G-BTB, G-APTEOS, and G-TEOS.Before silylation, GO was dried a second time under vacuum at room temperature overnight. 100 mg of org-GO were dispersed in n-butanol (5 mL), sonicated for 30 min and left under stirring overnight. The silica precursor  and a secondary beam graphite monochromator. The patterns were recorded in a 2θ range from 2 to 40°, in steps of 0.02° and with a counting time of 2 s per step. Fourier transform infrared (FTIR) spectra in the range 400–4000 cm−1 were measured with a Shimadzu FT-IR 8400 spectrometer equipped with a deuterated triglycine sulfate (DTGS) detector. Each spectrum was the average of 64 scans collected at 2 cm−1 resolution. Samples were in the form of KBr pellets containing ca. 2 wt% sample. X-ray Photoelectron Spectroscopy (XPS) analysis was performed using a Surface Science SSX-100 ESCA instrument with a monochromatic Al Kα X-ray source (hν = 1486.6 eV). The pressure in the measurement chamber was maintained at 1 × 10−9 mbar during data acquisition. The electron take-off angle with respect to the surface normal was 37°. The XPS data were acquired by using a spot size of 1,000 μm in diameter and the energy resolution was 1.3 eV for both the survey spectra and the detailed spectra of the C1s, O1s, and Si2p core level regions. Binding energies are reported ±0.1 eV and referenced to the C1s photoemission peak centered at a binding energy of 284.8 eV . Before exposure to CO2 the samples were outgassed overnight in 250 °C under high vacuum (10−8 mbar) until the mass was observed to remain constant.The powder X-ray diffraction (XRD) patterns were collected on a D8 Advanced Bruker diffractometer with a Cu K001 spacing of GO and hence to the successful insertion of the guest molecules in the interlayer galleries. More specifically, the basal spacing, d001, of the org-GO shifts to 18.4 Å corresponding to an interlayer separation of Δ= 18.4–6.1 = 12.3 Å, where 6.1 Å is the thickness of the GO monolayer , the d spacing was calculated to amount to ~24.5 Å and even larger d values (26–27 Å) were achieved for APTEOS and BTB. The diffraction peak in this case is broader as a result of a distribution of different conformations. These larger values may be attributed to steric effects from the amino-terminated alkyl chains or phenylene ring anchored/bridged by silane centers of APTEOS and BTB, respectively.−1 associated with the asymmetric and symmetric stretching vibrations of CH2 groups as well as a band at 1450 cm−1 due to the vibrations of the N-H bond of the amino group molecules. These spectral signatures clearly serve as evidence for the presence of dodecylamine in org-GO and thereby testify to the success of the organo-modification.FTIR and XPS spectroscopies can provide additional information on the elemental composition and the type of chemical bonds present in the final hybrid heterostructures. −1, 1065 and 1151 cm−1 are due to Si-O-Si vibrations, while the ones at 690 cm−1 and 950 cm−1 are assigned to the vibrations of O-Si-O. Similar spectral signatures were also found for the other heterostructures  are absent from the spectrum of G-BTB, pointing to the successful removal of the surfactant molecules and hence give a first hint that porous silica-GO heterostructures developed during calcination.The spectra of the heterostructure obtained by reaction with the silica precursor BTB exhibit a set of new peaks before (GO-BTB) and after calcination (G-BTB), which can be attributed to vibrations of the silicate matrix: the peaks at 520 cmThe relative amount of silicon oxide in the three porous structures can be deduced by TGA; 2 adsorption and desorption at 77 K. 0 < 0.01), the G-BTB heterostructure shows the highest N2 adsorption, which indicates that a significant amount of micropores is accessible after the creation of the silica network. For this system the BET surface area was calculated to be 576 m2/g, or more than twice that of G-APTEOS (227 m2/g) and more than 20 times that of G-TEOS (27 m2/g). Note that for all three heterostructures the final increase of the N2 uptake at relative pressures above 0.95 is attributed to adsorption on the external surface and/or the surface of macropores.To determine the surface area of the heterostructures after calcination , we monitored NHence, we followed all modification steps leading to the G-BTB sample by X-ray photoelectron spectroscopy. XPS survey scan of the G-BTB is shown in s spectrum of org-GO in s line in the cases of GO-BTB  contains a higher amount of Si than GO-APTEOS (C:Si=65.3±0.9), and GO-TEOS (C:Si=101.4±4.1) ranks lowest in Si content, in agreement with the TGA results discussed above.From the areas of C1Representative scanning electron micrographs of G-BTB are shown in 2 capture performance of G-BTB was studied at three different temperatures  and for different pressures. The results are presented in 2 adsorption capacities of 3.5 mmol/g at 5 bar and of 4.5 mmol/g at 17 bar and 0 °C. At higher temperatures the capacity is slightly lower, which is probably because the kinetic energy of the CO2 gas molecules is higher and hence the molecules desorb more easily (lower sticking coefficient). Such high values agree with the high BET surface area and the presence of microporosity. Furthermore, the CO2 adsorption capacity is comparable with that of other graphene-based porous materials with higher surface areas, measured under the same conditions -benzene due to steric effects. FTIR and XPS spectroscopies gave evidence for the reduction of graphene oxide to graphene after calcination of the heterostructures and confirmed the presence of silica oxide. Thermogravimetric analysis allowed to evaluate the degree of silylation for each silica precursor, and to identify 1,4-Bis(triethoxysilyl)-benzene (with the bridged phenyl group) as the one giving the highest yield. Thermal treatment is necessary to obtain highly porous materials with sponge-like structures, characterized by a BET surface area of 550 mThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.2 measurements. All authors contributed to manuscript revision, read, and approved the submitted version.AE, DG, and PR designed the experiments and finalized the manuscript. ET and ED performed the synthesis, characterization, and data analysis. EM and EMA participated in the synthesis of the materials. KS and ODL conducted the XPS measurements and analyzed the data. ET, ED, and KS wrote the manuscript. LB performed the SEM measurements. AS performed the COThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Mw/Mn ≈ 1.2), which indicated a living nature of copolymerization at room temperature. The random copolymerization results indicated the possibility of precise branched structure control, depending on the polymerization temperature and time.Homo- and copolymers of propylene and 1-decene were synthesized by controlled chain-walking (co)polymerization using phenyl substituted α-diimine nickel complexes activated with modified methylaluminoxane (MMAO). This catalytic system was found to polymerize propylene in a living fashion to furnish high molecular weight ethylene-propylene (EP) copolymers. The copolymerizations proceeded to give high molecular weight P/1-decene copolymers with narrow molecular weight distribution ( Cationic late-transition metal catalyzed homo- and copolymerization of alkenes such as ethylene and propylene have received substantial attention in polymer science and materials chemistry ,2,3,4,5.ortho-substituent groups of the catalysts and the polymerization temperature NiBr2 (5)}  and N2−C31 [1.264(8) Å] have typical imine double bonds character, respectively. In the solid state, the Ni1−N1 and Ni1−N2 bond distances of 2.036(6) and 2.017(6) Å in 3 are slightly narrower than the value of 2.041(5) Å for analogue 2 . In addition, the N1–Ni1–Br3 angles of 117.99(7)° for 3 is also approximate to those for complex 2 (112.96°). The conjugation effect of phenyl substituents in the para- and ortho-aryl position of α-diimine ligand can be clearly observed in these molecular structures, expected to improve the catalyst performance for propylene (co)polymerization.Single-crystal of fraction . Crystalfraction . The geo1–5 with the [Al]/[Ni] ratio of 300 at 1.2 bar of propene for 30 min, and the results are listed in 4 g mol−1 were observed with 2-MMAO at 25 °C  × 104 g mol−1 and narrow molecular weight distribution . Complex 2 produced higher molecular weight PP in highest yield than those of one methyl or phenyl groups , the produced PPs had low Tg of approximately −29.4~−24.1 °C and no Tm  was catalyzed by 2-MMAO at 25 °C showed narrow molecular weight distribution of 1.14  constant. This result verified that the P/1-decene copolymerization with 2-MMAO proceeded in a living/controlled manner at 25 °C within a certain period of time. To the best of our knowledge, this is the first example of late transition metal catalyzed living copolymerization of propylene and 1-decene at room temperature.The P/1-decene copolymer obtained with  of 1.14 , entry 1Tg of approximately −49 °C no Tm  branch separately in 1,2-insertion. For example, the 13C NMR spectra of the copolymers obtained by 2-MMAO, and showed that the poly(P-co-D) produced at 25 °C possessed 170 branches/1000 carbons including 133 methyl and 37 longer chains (C8)  produced at 0 °C possessed 186 branches/1000 carbons including 146 methyl and 40 longer chains  , whereasequences . The brar chains b.α-diimine nickel catalysts in combination with MMAO to generate high molecular weights amorphous “ethylene-propylene (EP) copolymers” at room temperature. Copolymerization of propylene and 1-decene was successfully achieved using 2-MMAO, produced highly branched P/1-decene copolymers with high molecular weight and narrow molecular weight distribution. At room temperature, living copolymerization of propylene and 1-decene was observed. The 13C NMR spectra of the P/1-decene copolymers obtained showed a microstructure almost exclusively composed of methyl and octyl (C8) branches.In summary, we conducted the living chain-walking polymerization of propylene using phenyl substituted


The main goal of this thematic issue was to bring both original research papers and reviews together to provide an insight into the rather broad topic of molecular biology of retinal ganglion cells (RGCs). The objective for such a collection of articles is given by the fact that RGCs are the output neurons of the vertebrate retina and, in addition to integrating information and passing it to target neurons in retinorecipient brain centers, they also perform a significant computation to encode signals into action potential trains. Since this mechanism requires the coordinated expression, activation, modulation, deactivation, and disintegration of molecules that partake in RGC signaling, the molecular constituents of the RGC intracellular molecular milieu play a functionally relevant role in terms of visual signaling and vision. In a review article, May  summarizBesides normal functioning, changes in the expression levels of certain molecules may induce pathological alterations in the retina, or their down- and upregulation is simply the consequence of a chain of molecular changes that occur during the development of a disease. One of the most common vision deficits is myopia, which is a substantial public health problem worldwide. It has been known that defocused images alter eye growth and refraction. In this issue, Feng Pan  shows thMechanical impacts or chemical changes may deteriorate the retinal tissue, even with no clear sign of any progressive retinal disease, thereby inducing disruptive changes in the retinal tissue and RGC function. One of the great challenges of modern neuroscience is to prevent such alterations via neuroprotective mechanisms and even to induce regenerative processes in the nervous tissue. Dulz and colleagues report that the combined administration of glial cell line-derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF) conferred lifelong protection to injured RGCs . Interes++- binding proteins (CaBPs) in the mouse RGC population was described by Kovács-Öller and colleagues [Besides their functional or pathological relevance, some of the expressed molecules or their combination can also be utilized as neurochemical marker fingerprints to detect specific subtypes of the 20–30 morphologically identified RGCs. In this issue, the spatial expression pattern of Calleagues . The autTaken together, the Special Issue “Molecular Biology of Retinal Ganglion Cells” collects a set of articles that further expand our view regarding the intracellular molecular mechanisms that may occur during normal functioning or induced when pathological changes set on in RGCs. Therefore, this present article collection will open new perspectives for both basic research and clinically relevant investigations in the future.


The P2X7 receptor for extracellular ATP is a well-established mediator of tumoral development and progression both in solid cancers and hematological malignancies. The human P2X7 gene is highly polymorphic, and several splice variants of the receptor have been identified in time. P2X7 single-nucleotide polymorphisms (SNPs) have been broadly analyzed by studies relating them to pathologies as different as infectious, inflammatory, nervous, and bone diseases, among which cancer is included. Moreover, in the last years, an increasing number of reports concentrated on P2X7 splice variants’ different roles and their implications in pathological conditions, including oncogenesis. Here, we give an overview of established and recent literature demonstrating a role for human P2X7 gene products in oncological conditions, mainly focusing on current data emerging on P2X7 isoform B and nfP2X7. We explored the role of these and other genetic variants of P2X7 in cancer insurgence, dissemination, and progression, as well as the effect of chemotherapy on isoforms expression. The described literature strongly suggests that P2X7 variants are potential new biomarkers and therapeutical targets in oncological conditions and that their study in carcinogenesis deserves to be further pursued. P2X receptors are ATP gated ion channels permeable to Naunits P2X-7 [1]. T(P2X1-7) . Among t(P2X1-7) ,5,6. Mor(P2X1-7) . The mac(P2X1-7) . Whether(P2X1-7) ,11. Howe(P2X1-7) . While t(P2X1-7) ,14,15, t(P2X1-7) . The aut(P2X1-7) . Therefo(P2X1-7) . Many ce(P2X1-7) ,20. Inde(P2X1-7) . The P2X(P2X1-7) ,23,24. T(P2X1-7) ,30,31,32The human P2X7 receptor gene is located on chromosome 12 and consists of 13 exons ; it is hMore than 13,000 single-nucleotide polymorphisms (SNPs) of the P2X7 receptor were identified in the human gene. Among those SNPs, 10 were demonstrated to give rise to loss-of-function variants, and three were demonstrated to give rise to gain-of-function variants ,36,46. TAmong the three gain-of-function polymorphisms known, the most recurrent P2X7 SNP in humans is the 489 C > T (rs208294), which carries a tyrosine instead of a histidine at position 155 in the extracellular domain (H155Y)  Figure . This SNThe P2X7 receptor and its ligand ATP recently emerged as important players in regulating solid cancer and leukemic growth as well as immune system/cancer cross-talk . Indeed,de novo), relapsing patients with a pathology return after chemotherapy, and remitting patients with no evident AML appearance. We observed that both P2X7A and P2X7B mRNA levels were strongly increased in de novo AML as compared to MDS, supporting the hypothesis that both receptor variants positively correlate with disease progression . P2. P235]. nfP2X7 was the object of numerous tumor-related studies due to its widespread expression in cancer specimens ,90,91,92Finally, an intriguing splice variant of human P2X7 is P2X7-V3, which was attributed a role as long non-coding RNA promoting uveal melanoma transformation  Table 1Table 1. A defined number of studies also analyzed the association between P2X7 SNPs and cancer occurrence or prognosis . Most ofAn increasing body of literature correlating P2X7 variants with tumoral insurgence and progression has emerged in recent years, testifying to the central role of these proteins and mRNAs in oncology. Recent evidence that appeared on P2X7B and nfP2X7 isoforms strongly suggest that variants lacking the pore-forming cytotoxic activity are central in oncologic progression and response to current anti-tumoral therapies and offer fascinating insights for the development of new therapeutic strategies. Although further efforts are required to understand better the interplay among P2X7 variants in cancer evolution and in the tumor–host interplay, we firmly believe that this investigation field will be fertile in the years to come and pave the way for the testing of P2X7 targeting drugs in oncology.