Theophylline: Old Drug in a New Light,Application in COVID-19 through Computational Studies

Theophylline (3-methyxanthine) is a historically prominent drug used to treat respiratory diseases, alone or in combination with other drugs. The rapid onset of the COVID-19 pandemic urged the development of effective pharmacological treatments to directly attack the development of new variants of the SARS-CoV-2 virus and possess a therapeutical battery of compounds that could improve the current management of the disease worldwide. In this context, theophylline, through bronchodilatory, immunomodulatory, and potentially antiviral mechanisms, is an interesting proposal as an adjuvant in the treatment of COVID-19 patients. Nevertheless, it is essential to understand how this compound could behave against such a disease, not only at a pharmacodynamic but also at a pharmacokinetic level. In this sense, the quickest approach in drug discovery is through different computational methods, either from network pharmacology or from quantitative systems pharmacology approaches. In the present review, we explore the possibility of using theophylline in the treatment of COVID-19 patients since it seems to be a relevant candidate by aiming at several immunological targets involved in the pathophysiology of the disease. Theophylline down-regulates the inflammatory processes activated by SARS-CoV-2 through various mechanisms, and herein, they are discussed by reviewing computational simulation studies and their different applications and effects.     

Biofabrication of Collagen Tissue-Engineered Blood Vessels with Direct Co-Axial Extrusion

Cardiovascular diseases are considered one of the worldwide causes of death, with atherosclerosis being the most predominant. Nowadays, the gold standard treatment is blood vessel replacement by bypass surgery; however, autologous source is not always possible. Thereby, tissue-engineered blood vessels (TEBVs) are emerging as a potential alternative source. In terms of composition, collagen has been selected in many occasions to develop TEBVs as it is one of the main extracellular matrix components of arteries. However, it requires specific support or additional processing to maintain the tubular structure and appropriate mechanical properties. Here, we present a method to develop support-free collagen TEBVs with co-axial extrusion in a one-step procedure with high concentrated collagen. The highest concentration of collagen of 20 mg/mL presented a burst pressure of 619.55 ± 48.77 mmHg, being able to withstand perfusion of 10 dynes/cm². Viability results showed a high percentage of viability (86.1 and 85.8% with 10 and 20 mg/mL, respectively) of human aortic smooth muscle cells (HASMCs) and human umbilical vein endothelial cells (HUVEC) after 24 h extrusion. Additionally, HUVEC and HASMCs were mainly localized in their respective layers, mimicking the native distribution. All in all, this approach allows the direct extrusion of collagen TEBVs in a one-step procedure with enough mechanical properties to be perfused.     

Exciton storage by Mn(2+) in colloidal Mn(2+)-doped CdSe quantum dots

Colloidal Mn (2+)-doped CdSe quantum dots showing long excitonic photoluminescence decay times of up to tau exc = 15 mus at temperatures over 100 K are described. These decay times exceed those of undoped CdSe quantum dots by approximately 10 (3) and are shown to arise from the creation of excitons by back energy transfer from excited Mn (2+) dopant ions. A kinetic model describing thermal equilibrium between Mn (2+ 4)T 1 and CdSe excitonic excited states reproduces the experimental observations and reveals that, for some quantum dots, excitons can emit with near unity probability despite being approximately 100 meV above the Mn (2+ 4)T 1 state. The effect of Mn (2+) doping on CdSe quantum dot luminescence at high temperatures is thus completely opposite from that at low temperatures described previously.     

Development and Characterization of a Factor V-Deficient CRISPR Cell Model for the Correction of Mutations

Factor V deficiency, an ultra-rare congenital coagulopathy, is characterized by bleeding episodes that may be more or less intense as a function of the levels of coagulation factor activity present in plasma. Fresh-frozen plasma, often used to treat patients with factor V deficiency, is a scarcely effective palliative therapy with no specificity to the disease. CRISPR/Cas9-mediated gene editing, following precise deletion by non-homologous end-joining, has proven to be highly effective for modeling on a HepG2 cell line a mutation similar to the one detected in the factor V-deficient patient analyzed in this study, thus simulating the pathological phenotype. Additional CRISPR/Cas9-driven non-homologous end-joining precision deletion steps allowed correction of 41% of the factor V gene mutated cells, giving rise to a newly developed functional protein. Taking into account the plasma concentrations corresponding to the different levels of severity of factor V deficiency, it may be argued that the correction achieved in this study could, in ideal conditions, be sufficient to turn a severe phenotype into a mild or asymptomatic one.     

NMDA and P2X7 Receptors Require Pannexin 1 Activation to Initiate and Maintain Nociceptive Signaling in the Spinal Cord of Neuropathic Rats

Pannexin 1 (Panx1) is involved in the spinal central sensitization process in rats with neuropathic pain, but its interaction with well-known, pain-related, ligand-dependent receptors, such as NMDA receptors (NMDAR) and P2X7 purinoceptors (P2X7R), remains largely unexplored. Here, we studied whether NMDAR- and P2X7R-dependent nociceptive signaling in neuropathic rats require the activation of Panx1 channels to generate spinal central sensitization, as assessed by behavioral (mechanical hyperalgesia) and electrophysiological (C-reflex wind-up potentiation) indexes. Administration of either a selective NMDAR agonist i.t. (NMDA, 2 mM) or a P2X7R agonist (BzATP, 150 μM) significantly increased both the mechanical hyperalgesia and the C-reflex wind-up potentiation, effects that were rapidly reversed (minutes) by i.t. administration of a selective pannexin 1 antagonist (10panx peptide, 300 μM), with the scores even reaching values of rats without neuropathy. Accordingly, 300 μM 10panx completely prevented the effects of NMDA and BzATP administered 1 h later, on mechanical hyperalgesia and C-reflex wind-up potentiation. Confocal immunofluorescence imaging revealed coexpression of Panx1 with NeuN protein in intrinsic dorsal horn neurons of neuropathic rats. The results indicate that both NMDAR- and P2X7R-mediated increases in mechanical hyperalgesia and C-reflex wind-up potentiation require neuronal Panx1 channel activation to initiate and maintain nociceptive signaling in neuropathic rats.     

Effective Natural Killer Cell Degranulation Is an Essential Key in COVID-19 Evolution

NK degranulation plays an important role in the cytotoxic activity of innate immunity in the clearance of intracellular infections and is an important factor in the outcome of the disease. This work has studied NK degranulation and innate immunological profiles and functionalities in COVID-19 patients and its association with the severity of the disease. A prospective observational study with 99 COVID-19 patients was conducted. Patients were grouped according to hospital requirements and severity. Innate immune cell subpopulations and functionalities were analyzed. The profile and functionality of innate immune cells differ between healthy controls and severe patients; CD56dim NK cells increased and MAIT cells and NK degranulation rates decreased in the COVID-19 subjects. Higher degranulation rates were observed in the non-severe patients and in the healthy controls compared to the severe patients. Benign forms of the disease had a higher granzymeA/granzymeB ratio than complex forms. In a multivariate analysis, the degranulation capacity resulted in a protective factor against severe forms of the disease (OR: 0.86), whereas the permanent expression of NKG2D in NKT cells was an independent risk factor (OR: 3.81; AUC: 0.84). In conclusion, a prompt and efficient degranulation functionality in the early stages of infection could be used as a tool to identify patients who will have a better evolution.     

Learning Structure from Data and Its Application to Ozone Prediction

In this paper we propose an algorithm for structure learning in predictive expert systems based on a probabilistic network representation. The idea is to have the simplest structure (minimum number of links) with acceptable predictive capability. The algorithm starts by building a tree structure based on measuring mutual information between pairs of variables, and then it adds links as necessary to obtain certain predictive performance. We have applied this method for ozone prediction in México City, where the ozone level is used as a global indicator for the air quality in different parts of the city. It is important to predict the ozone level a day, or at least several hours in advance, to reduce the health hazards and industrial losses that occur when the ozone reaches emergency levels. We obtained as a first approximation a tree-structured dependency model for predicting ozone in one part of the city. We observe that even with only three parameters, its estimations are acceptable.A causal network representation and the structure learning techniques produced some very interesting results for the ozone prediction problem. Firstly, we got some insight into the dependence structure of the phenomena. Secondly, we got an indication of which are the important and not so important variables for ozone forecasting. Taking this into account, the measurement and computational costs for ozone prediction could be reduced. And thirdly, we have obtained satisfactory short term ozone predictions based on a small set of the most important parameters.     

Analyzing the problem of unsustainable health information systems in less-developed economies: Case studies from Tanzania and Mozambique

Most of donor-supported information technology (IT)–based projects developed or implemented in less-developed economies (LDEs) end up as complete or partial failures or unsustainable. Notably, a number of intra-organizational and external factors are associated with this problem, including inadequate infrastructure and human resource capacity, fragmented donor policy, and lack of policies to manage the sustainability problem. Accordingly, IT initiatives are often donor-driven, top-down, and hijacked by top managers who (normally) do not have adequate skills, but have enormous power to enforce such initiatives across organizational hierarchies.

In analyzing the concepts from sustainability and institutionalization, key insights towards a better understanding of the problem of unsustainability are developed. It is argued that health information systems (HISs) become sustainable if they are institutionalized in the sense of being integrated into the everyday routine of the user organization. However, a sustainable HIS should also be flexible enough to allow changes as the user needs change. Moreover, introduction of a new HIS is not only a technical change, but requires the cultivation and institutionalization of a new kind of culture.

Through a comparative case analysis of the HIS development and implementation processes in Tanzania and Mozambique, we have identified two sets of relationships, between the Ministry of Health (MoH) and donor agencies and between the MoH and software development agencies as critical and contributing factors to the unsustainability of a HIS. Given this setting, we highlight three key strategies for dealing with the problem of unsustainability in LDEs: (a) integration of a HIS, (b) local shaping of new cultures, and (c) cultivation approach to systems development. © 2005 Wiley Periodicals, Inc.     

Various phases in surface movements linked to deep coal longwall mining:from start-up till the period after closure

This paper covers the entire lifetime of an underground coal mine,including the start-up of the mining oper-ations and the period after the closure and sealing ...     

Probing the electromagnetic field distribution within a metallic nanodisk

A Co nanolayer is used as a local probe to evaluate the vertical inhomogeneous distribution of the electromagnetic (EM) field within a resonant metallic nanodisk. Taking advantage of the direct relation between the magneto-optical activity and the electromagnetic field intensity in the Co layer, it is shown that the nonuniform EM distribution within the nanodisk under plasmon resonant conditions has maximum values close to the upper and lower flat faces, and a minimum value in the middle.