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.     

Natural and human forcing in recent geomorphic change; case studies in the Rio de la Plata basin

An analysis of geomorphic system's response to change in human and natural drivers in some areas within the Río de la Plata basin is presented. The aim is to determine whether an acceleration of geomorphic processes has taken place in recent years and, if so, to what extent it is due to natural (climate) or human (land-use) drivers. Study areas of different size, socio-economic and geomorphic conditions have been selected: the Río de la Plata estuary and three sub-basins within its watershed. Sediment cores were extracted and dated (²¹⁰Pb) to determine sedimentation rates since the end of the 19th century. Rates were compared with time series on rainfall as well as human drivers such as population, GDP, livestock load, crop area, energy consumption or cement consumption, all of them related to human capacity to disturb land surface. Data on river discharge were also gathered. Results obtained indicate that sedimentation rates during the last century have remained essentially constant in a remote Andean basin, whereas they show important increases in the other two, particularly one located by the São Paulo metropolitan area. Rates in the estuary are somewhere in between. It appears that there is an intensification of denudation/sedimentation processes within the basin.Rainfall remained stable or varied very slightly during the period analysed and does not seem to explain increases of sedimentation rates observed. Human drivers, particularly those more directly related to capacity to disturb land surface (GDP, energy or cement consumption) show variations that suggest human forcing is a more likely explanation for the observed change in geomorphic processes. It appears that a marked increase in denudation, of a “technological” nature, is taking place in this basin and leading to an acceleration of sediment supply. This is coherent with similar increases observed in other regions.     

Understanding the detrimental effect of nitrate presence on EBPR systems: effect of the plant configuration

The interaction between enhanced biological phosphorus removal (EPBR) and biological nitrogen removal may result in EBPR failure in full‐scale wastewater treatment plants (WWTPs). This work studies one of the common causes of this failure: the presence of nitrate in the anaerobic phase, which may act as an inhibitor for polyphosphate accumulating organisms (PAO) activity or may activate the competition between PAO and denitrifying bacteria for the carbon source. Several batch experiments were performed with different carbon sources (acetic acid, propionic acid and sucrose) at different nitrate concentrations using PAO‐enriched sludge from two different pilot plants: an anaerobic/aerobic sequential batch reactor (SBR) and an anaerobic/anoxic/aerobic (A²/O) continuous plant. The results imply that the operational conditions of the A²/O pilot plant selected a PAO population capable of i) coexisting with nitrate without an inhibitory effect and ii) outcompeting denitrifying bacteria for the carbon source, in contrast to the SBR pilot plant where nitrate had an inhibitory effect on EBPR. Copyright © 2012 Society of Chemical Industry     

Conformational properties of poly(diallyldimethyl ammonium chloride) (PDDA) determined by combination of molecular dynamics, rotational isomeric states and Monte Carlo procedures

A theoretical model describing the conformational properties of poly(diallyldimethyl ammonium chloride) (PDDA) is developed with the following strategy: molecular dynamics simulations are performed on model molecules representing dimers of PDDA. The results are employed to formulate a rotational isomeric state model for these molecules in terms of short-range interactions. Furthermore, the MD trajectories permit the evaluation of conformational energies and probabilities for the 27 conformations allowed to the three bonds sequence contained in the dimers. These probabilities are then employed to generate single chains of PDDA in vacuo according to standard Monte Carlo procedures and their main squared end to end distance 〈r²〉 are computed. The procedure (MD simulations, evaluation of energies and probabilities and MC calculations) is then repeated for two more realistic systems obtained by fitting into a cubic box, having side length L and periodic boundary conditions, a forty repeating units oligomer of PDDA together with 40 Cl⁻ as counterions and 500 water molecules (referred to as water system, ) or the oligomer with its counterions, 500 water molecules and 20 NaCl molecules (referred to as salt system, ). The behavior of the three systems is noticeably different and the value of unperturbed dimensions computed for the realistic systems are in good agreement with preliminary results of experimental measurements being carried out in our laboratory.     

Dose due to mushroom ingestion in Spain

The dose due to ingestion of mushrooms depends on their radioactive content. However, not all the mass of the mushroom ingested is digested and assimilated completely by man. To analyse the degree of assimilation of the radioactive content of mushrooms, we have carried out culture under controlled laboratory conditions for Pleurotus eryngii mushrooms to which we added known activities of 134Cs, 85Sr and 239Pu. We then applied the Van Soest method to the fruiting bodies, which were obtained in order to determine the fraction of these radionuclides associated with the major components of the cell that are assimilable by man. Finally, on the basis of the results, we determined the dose due to 137Cs, 90Sr and (239+240)Pu for several mushroom species collected in different natural and semi-natural ecosystems in Spain.     

Using implicit equations of parametric curves and surfaces without computing them: Polynomial algebra by values

The availability of the implicit equation of a plane curve or of a 3D surface can be very useful in order to solve many geometric problems involving the considered curve or surface: for example, when dealing with the point position problem or answering intersection questions. On the other hand, it is well known that in most cases, even for moderate degrees, the implicit equation is either difficult to compute or, if computed, the high degree and the big size of the coefficients makes extremely difficult its use in practice.We will show that, for several problems involving plane curves, 3D surfaces and some of their constructions (for example, offsets), it is possible to use the implicit equation (or, more precisely, its properties) without needing to explicitly determine it. We replace the computation of the implicit equation with the evaluation of the considered parameterizations in a set of points. We then translate the geometric problem in hand, into one or several generalized eigenvalue problems on matrix pencils (depending again on several evaluations of the considered parameterizations).This is the so-called “polynomial algebra by values” approach where the huge polynomial equations coming from Elimination Theory (e.g., using resultants) are replaced by big structured and sparse numerical matrices. For these matrices there are well-known numerical techniques allowing to provide the results we need to answer the geometric questions on the considered curves and surfaces.     

On-line titrimetric monitoring of anaerobic-anoxic EBPR processes.

Denitrifying phosphorus accumulating organisms (DPAO) are able to remove nitrogen and phosphorus simultaneously. The use of DPAO in EBPR systems results in a substantial saving on aeration cost and a lower sludge production when compared to anaerobic-aerobic EBPR systems. This process is usually studied in sequencing batch reactors (SBR) and monitored with off-line measurements. However, off-line monitoring implies low frequency data sampling and delay between sampling and obtainment of the results. For this reason, an online measurement such as titrimetry is strongly recommended to improve the daily management of the lab-scale SBR. This paper shows different applications of titrimetric measurements for on-line monitoring of DPAO lab-scale SBR cycles. The results demonstrate that titrimetry is a suitable tool for detecting the end of phosphorus release and carbon substrate depletion point in the anaerobic phase. Moreover, this paper proposes the indirect measurement of nitrate/nitrite uptake rate with titrimetric measurements, which allows the on-line estimation of its concentration during the anoxic phase. Therefore, titrimetry is an on-line measurement with a high potential to implement new control strategies in DPAO lab-scale SBR systems.