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Motivated by previous authors' work, where Shannon entropy, box covering and information dimension were applied to quantify pulmonary lesions, this paper extends such a contribution in two fashions: (i) Following the approach to quantify pulmonary lesions with Deng entropy and Deng information dimension obtained through box covering method; (ii) exploiting the Shannon and Deng lesion quantification for pulmonary illnesses classification with a bidirectional Long Short Term Memory (bLSTM). The referred pulmonary illnesses are Common Pneumonia (CP) and COVID-19. Shannon entropy and information dimension are performed here and called the Shannon sequence. Then, Deng entropy and Deng information dimension are computed for chest Computed Tomography (CT) images to obtain and combine two data sequences to quantify the pulmonary lesions. The data sequence resulting from the data combination is called the Deng sequence. Both Shannon and Deng sequences are independently used as input for the bLSTM. CT lung scans of 531 healthy subjects, 497 confirmed COVID-19 diagnoses and 516 with CP were analyzed to obtain the Shannon and Deng sequences. The results demonstrate that Deng entropy and Deng information dimension of CT images can differentiate similar lung lesions between COVID-19 and CP. Besides, a statistical analysis shows that: (a) Classification by the bLSTM is better when using the Deng sequence than the Shannon sequence; (b) Deng sequences plus bLSTM significantly outperform DenseNet-201, GoogLeNet and MobileNet-v2 in classifying COVID-19, CP and Normal CT (healthy subjects) in time and accuracy. Hence, the Deng sequence and bLSTM are fast and accurate tools for helping in diagnosing CP and COVID-19. [ABSTRACT FROM AUTHOR]

In this study, learning pathways are modelled by networks constructed from the log data of student–LMS interactions. These networks capture the sequence of reviewing the learning materials by the students enrolled in a given course. In previous research, the networks of successful students showed a fractal property; meanwhile, the networks of students who failed showed an exponential pattern. This research aims to provide empirical evidence that students' learning pathways have the properties of emergence and non-additivity from a macro level; meanwhile, equifinality (same end of learning process but different learning pathways) is presented at a micro level. Furthermore, the learning pathways of 422 students enrolled in a blended course are classified according to learning performance. These individual learning pathways are modelled by networks from which the relevant learning activities (nodes) are extracted in a sequence by a fractal-based method. The fractal method reduces the number of nodes to be considered relevant. A deep learning network classifies these sequences of each student into passed or failed. The results show that the accuracy of the prediction of the learning performance was 94%, the area under the receiver operating characteristic curve was 97%, and the Matthews correlation was 88%, showing that deep learning networks can model equifinality in complex systems. [ABSTRACT FROM AUTHOR]

Simple Summary: Protein–protein interactions (PPIs) are the basis for understanding cellular events in biological systems. Experimental biochemical, molecular, and genetic methods have been used to identify protein–protein associations. However, they are time-consuming and expensive. Machine learning techniques have been used to characterize PPIs, optimizing time and resources. This study aimed to generate a relevant protein sequence with partial knowledge of interactions by conducting a scale-free and fractal analysis. The outcome of these analyses is then used to fine-tune the fractal method for the vital protein extraction of PPI networks. The results show that several PPI networks are self-similar or fractal, but not both of them. The generated protein sequences by the deep learning network contains an important number of proteins of the original sequence. Moreover, most of the PPIs of generated sequences appear in the original set. This information can help researchers guide experimental design and find key points for new therapeutics. Protein–protein interactions (PPIs) are the basis for understanding most cellular events in biological systems. Several experimental methods, e.g., biochemical, molecular, and genetic methods, have been used to identify protein–protein associations. However, some of them, such as mass spectrometry, are time-consuming and expensive. Machine learning (ML) techniques have been widely used to characterize PPIs, increasing the number of proteins analyzed simultaneously and optimizing time and resources for identifying and predicting protein–protein functional linkages. Previous ML approaches have focused on well-known networks or specific targets but not on identifying relevant proteins with partial or null knowledge of the interaction networks. The proposed approach aims to generate a relevant protein sequence based on bidirectional Long-Short Term Memory (LSTM) with partial knowledge of interactions. The general framework comprises conducting a scale-free and fractal complex network analysis. The outcome of these analyses is then used to fine-tune the fractal method for the vital protein extraction of PPI networks. The results show that several PPI networks are self-similar or fractal, but that both features cannot coexist. The generated protein sequences (by the bidirectional LSTM) also contain an average of 39.5% of proteins in the original sequence. The average length of the generated sequences was 17% of the original one. Finally, 95% of the generated sequences were true. [ABSTRACT FROM AUTHOR]

The computed tomography (CT) chest is a tool for diagnostic tests and the early evaluation of lung infections, pulmonary interstitial damage, and complications caused by common pneumonia and COVID-19. Additionally, computer-aided diagnostic systems and methods based on entropy, fractality, and deep learning have been implemented to analyse lung CT images. This article aims to introduce an Entropy-based Measure of Complexity (EMC). In addition, derived from EMC, a Lung Damage Measure (LDM) is introduced to show a medical application. CT scans of 486 healthy subjects, 263 diagnosed with COVID-19, and 329 with pneumonia were analysed using the LDM. The statistical analysis shows a significant difference in LDM between healthy subjects and those suffering from COVID-19 and common pneumonia. The LDM of common pneumonia was the highest, followed by COVID-19 and healthy subjects. Furthermore, LDM increased as much as clinical classification and CO-RADS scores. Thus, LDM is a measure that could be used to determine or confirm the scored severity. On the other hand, the d-summable information model best fits the information obtained by the covering of the CT; thus, it can be the cornerstone for formulating a fractional LDM. [ABSTRACT FROM AUTHOR]

Objectives The main aim of this work was to analyse the potential tumour growth inhibition effects of (−)-epicatechin (EC). Triple-negative breast cancer (TNBC) is an invasive form of cancer characterized by the absence of progesterone receptor, estrogen receptor and human epidermal growth factor receptor 2. Doxorubicin (DOX) is widely used for its anti-tumour activity. EC belongs to the flavanol subfamily and is a candidate molecule for the adjuvant treatment of cancer due to its antiproliferative activities. Methods Evaluation of EC effects and pathways involved in a model of TNBC. Key findings EC inhibited tumour growth as efficiently as DOX (inhibition rates of 74% and 79% for EC and DOX, respectively). The evaluation of adenosine monophosphate-activated protein kinase (AMPK) and Akt phosphorylation and mTOR expression indicates that EC modulates these pathways, resulting in the inhibition of cell proliferation. Additionally, we found an increase in the survival of EC-treated animals compared with control-treated animals. This effect was similar to the effects induced by DOX (survival rates of 44% and 30% for EC and DOX, respectively). Conclusion EC has antiproliferative properties and increases survival in a model of TNBC. These effects may occur through the modulation of deregulated AMPK and Akt/mTOR signalling pathways. [ABSTRACT FROM AUTHOR]

The current COVID-19 pandemic mainly affects the upper respiratory tract. People with COVID-19 report a wide range of symptoms, some of which are similar to those of common flu, such as sore throat and rhinorrhea. Additionally, COVID-19 shares many clinical symptoms with severe pneumonia, including fever, fatigue, dry cough, and respiratory distress. Several diagnostic strategies, such as the real-time polymerase chain reaction technique and computed tomography imaging, which are more costly than chest radiography, are employed as diagnostic tools. The purpose of this paper is to describe the role of the d-summable information dimension of X-ray images in differentiating several lesions and lung illnesses better than both fractal and information dimensions. The statistical analysis shows that the d-summable information dimension model better describes the information obtained from the X-ray images. Therefore, it is a more precise measure of complexity than the information and box-counting dimension. The results also show that the X-ray images of COVID-19 pneumonia reveal greater damage than those of tuberculosis, pneumonia, and various lung lesions, where the damage is minor or much focused. Because the d-summable information dimension increases as the image complexity decreases, it could pave the way to formulate a new measure to quantify the lung damage and assist the clinical diagnosis based on the area under the d-summable information model. In addition, the physical meaning of the ν parameter in the d-summable information dimension is given. [ABSTRACT FROM AUTHOR]

The production of nitric oxide (NO) by nitric oxide synthases (NOS) depends on the bioavailability of L -arginine as NOS competes with arginase for this common substrate. As arginase activity increases, less NO is produced and adverse cardiovascular consequences can emerge. (-)-Epicatechin (EPI), the most abundant flavonoid in cacao, has been reported to stimulate endothelial and neuronal NOS expression and function leading to enhanced vascular function and cardioprotective effects. However, little is known about the effects of EPI on myocardial arginase activity. The aim of the present study was to determine if EPI is able to interact and modulate myocardial arginase and NOS expression and activity. For this purpose, in silico modeling, in vitro activity assays and a rat model of ischemia/reperfusion injury were used. In silico and in vitro results demonstrate that EPI can interact with arginase and significantly decrease its activity. In vivo , 10 days of EPI pretreatment reduces ischemic myocardium arginase expression while increasing NOS expression and phosphorylation levels. Altogether, these results may partially account for the cardioprotective effects of EPI. [ABSTRACT FROM AUTHOR]

The glycated hemoglobin (HbA1c) test is a useful, economic, and practical clinical tool for long-term glycemic control in patients with diabetes mellitus (DM). Historically, since 1955, the HbA1c was described for the first time by Kunkel and Wallenius as a minor fraction of human hemoglobin. However, until the 70s, the molecule was recognized as a glycemic control marker. The HbA1c is a conjugated protein (heteroprotein, hemoglobin-glucose) formed through the non-enzymatic and post-translational process called glycation (Maillard reaction) as a stable Amadori product. If the reaction continues, the final results are irreversible products called advanced glycation end products (AGEs). AGEs are responsible for modifying proteins of the whole tissues and contribute to inflammatory reactions mediated by the AGE receptor and complications of DM. Additionally, HbA1c levels of less than 7% have been associated with reducing microvascular and macrovascular lesions. An adequate evaluation and monitoring routinely of HbA1c levels would allow adequa te glycemic control and help to reduce the risk of future complications. [ABSTRACT FROM AUTHOR]

(-)-Epicatechin (EPI) is cardioprotective in the setting of ischemia/reperfusion (IR) injury and doxycycline (DOX) is known to preserve cardiac structure/function after myocardial infarction (MI). The main objective of this study was to examine the effects of EPI and DOX co-administration on MI size after IR injury and to determine if cardioprotection may involve the mitigation of mitochondrial swelling. For this purpose, a rat model of IR was used. Animals were subjected to a temporary 45 min occlusion of the left anterior descending coronary artery. Treatment consisted of a single or double dose of EPI (10 mg/kg) combined with DOX (5 mg/kg). The first dose was given 15 min prior to reperfusion and the second 12 h post-MI. The effects of EPI +/− DOX on mitochondrial swelling (i.e. mPTP opening) were determined using isolated mitochondria exposed to calcium overload and data examined using isobolographic analysis. To ascertain for the specificity of EPI effects on mitochondrial swelling other flavonoids were also evaluated. Single dose treatment reduced MI size by ~46% at 48 h and 44% at three weeks. Double dosing evidenced a synergistic, 82% reduction at 3 weeks. EPI plus DOX also inhibited mitochondrial swelling in a synergic manner thus, possibly accounting for the cardioprotective effects whereas limited efficacy was observed with the other flavonoids. Given the apparent lack of toxicity in humans, the combination of EPI and DOX may have clinical potential for the treatment of myocardial IR injury. [ABSTRACT FROM AUTHOR]

Abstract: Overweight and obesity have been associated with increase in cardiometabolic risk. Therapeutics include lifestyle changes and/or pharmacologic agents. However, such interventions are often limited by poor compliance and/or significant side effects. The consumption of certain dietary products, such as cocoa, exerts positive effects on cardiometabolic risk factors. (−)-Epicatechin (EPI), the most abundant flavonoid in cacao has been reported to replicate such effects. However its mechanisms of action have not been fully elucidated.In a rat model of high-fat diet-induced obesity and its associated crdiometabolic risk factors, we administered 1mg/kg of EPI, by gavage, for 2 weeks. Endpoints included weight-gain, glycemia, triglyceridemia, and systolic blood pressure. We also assessed food intake and fecal excretion. Mitochondrial function and structure related proteins were measured by Westerns.Obesity, hyperglycemia, hypertriglyceridemia, and systolic hypertension were developed after the administration of the high-fat diet for five weeks. EPI significantly decreased the rate of weight gain, glycemia and hypertriglyceridemia. The ratio between energy intake and excretion was not significantly modified by treatment. EPI restored the obesity-induced decreases in the levels of skeletal muscle and abdominal tissue sirtuins (SIRTs), peroxisome proliferator-activated receptor coactivator (PGC-1α), mitofilin, transcription factor A mitochondrial (TFAM), uncoupling protein 1 (UCP1), and deiodinase.EPI treatment yielded beneficial effects on high fat diet-induced endpoints thus may be considered as a potential agent for the treatment of obesity and its cardiometabolic associated abnormalities. Mechanism of action may be attributed to the modulation of cellular/mitochondrial function, thus improving overall metabolism. [Copyright &y& Elsevier]

Background Targeting the mitochondria during ischemia/reperfusion (IR) can confer cardioprotection leading to improved clinical outcomes. The cardioprotective potential of (-)-epicatechin (EPI) during IR via modulation of mitochondrial function was evaluated. Methods and results Ischemia was induced in rats via a 45min occlusion of the left anterior descending coronary artery followed by 1h, 48h, or 3week reperfusion. EPI (10mg/kg) was administered IV 15min prior to reperfusion for the single dose group and again 12h later for the double dose group. Controls received water. Experiments also utilized cultured neonatal rat ventricular myocytes (NRVM) and myoblasts. A single dose of EPI reduced infarct size by 27% at 48h and 28% at 3week. Double dose treatment further decreased infarct size by 80% at 48h, and 52% by 3weeks. The protective effect of EPI on mitochondrial function was evident after 1h of reperfusion when mitochondria demonstrated less respiratory inhibition, lower mitochondrial Ca2+ load, and a preserved pool of NADH that correlated with higher tissue ATP levels. Mechanistic studies in NRVM revealed that EPI acutely stimulated maximal rates of respiration, an effect that was blocked by inhibitors of the mitochondrial pyruvate carrier, nitric oxide synthase, or soluble guanylyl cyclase. In myoblasts, knockdown of components of the mitochondrial pyruvate carrier blocked EPI-induced respiratory stimulation. Conclusions IV EPI confers cardioprotection via preservation of mitochondrial function potentially through enhanced substrate provision. These provocative results document a novel mechanism of a natural product with potential clinical utility. [ABSTRACT FROM AUTHOR]

Endothelial dysfunction (EnD) occurs with aging and endothelial nitric oxide (NO) production by NO synthase (NOS) can be impaired. Low NO levels have been linked to increased arginase (Ar) activity as Ar competes with NOS for L-arginine. The inhibition of Ar activity can reverse EnD and (−)-epicatechin (Epi) inhibits myocardial Ar activity. In this study, through in silico modeling we demonstrate that Epi interacts with Ar similarly to its inhibitor Norvaline (Norv). Using in vitro and in vivo models of aging, we examined Epi and Norv-inhibition of Ar activity and its endothelium-protective effects. Bovine coronary artery endothelial cells (BCAEC) were treated with Norv (10 μM), Epi (1 μM) or the combination (Epi + Norv) for 48 h. Ar activity increased in aged BCAEC, with decreased NO generation. Treatment decreased Ar activity to levels seen in young cells. Epi and Epi + Norv decreased nitrosylated Ar levels by ~25% in aged cells with lower oxidative stress (~25%) (dihydroethidium) levels. In aged cells, Epi and Epi + Norv restored the eNOS monomer/dimer ratio, protein expression levels and NO production to those of young cells. Furthermore, using 18 month old rats 15 days of treatment with either Epi (1 mg/kg), Norv (10 mg/kg) or combo, decreased hypertension and improved aorta vasorelaxation to acetylcholine, blood NO levels and tetra/dihydribiopterin ratios in cultured rat aortic endothelial cells. In conclusion, results provide evidence that inhibiting Ar with Epi reverses aged-related loss of eNOS function and improves vascular function through the modulation of Ar and eNOS protein levels and activity. • In aged endothelium, arginase (Ar) activity is increased, leading to a reduction in NO production. • (−)-Epicatechin (Epi) inhibits Ar activity and modulates L-arginine availability. • Inhibition of Ar with Epi reverses aged-related loss of eNOS function. • Epi and Epi plus Norvaline improves endothelial and vascular function in aged endothelium. [ABSTRACT FROM AUTHOR]

Abstract: The role of testosterone in cardiovascular (CV) homeostasis is in controversy, and the exact effects of testosterone on the cardiovascular system remain poorly understood. Testosterone is metabolized by aromatase into 17β-estradiol and by 5α-reductase into dihydrotestosterone (DHT). Thus, identification of these metabolites in the heart may help to explain the controversy regarding the cardiovascular effects of testosterone. We analyzed the expression patterns of these testosterone-metabolizing enzymes and assessed the effect of its enzymatic activity inhibition on ischemia (40min)/reperfusion (4h, I/R) via the left anterior descendent coronary artery in intact and gonadectomized male rats. Myocardial damage was measured as percentage of infarcted area vs. area at risk. Aromatase and 5α-reductase protein expression was found in the left ventricle of intact and orchidectomized rats. Exogenous testosterone had no effect on I/R induced myocardial damage in intact male rats, meanwhile exogenous testosterone protects against I/R injury in orchidectomized rats. However, enzymatic inhibition of aromatase increased myocardial damage in the presence of testosterone, while enzymatic inhibition of 5α-reductase significantly decreased the level of myocardial damage. Our results also showed that sub-chronic inhibition of 5α-reductase resulted in myocardial protection in both groups. Furthermore, in orchidectomized and intact male rats IV treatment with DHT induces a significant increase in the myocardial damage induced by I/R. Thus, the effect of testosterone on cardiovascular pathophysiology could be related, at least in part to changes in the balance of testosterone 5α-reduction and aromatization. [Copyright &y& Elsevier]