Are DTTO and iso‐DTTO Worthwhile Targets for Synthesis?

Theoretical calculations were carried out for the isomeric di‐1,2,3,4‐tetrazine tetraoxides (DTTO and iso‐DTTO). The most important explosion performance parameters, the detonation pressure and detonation velocity, are dominated by the densities and not by the heats of formation of these compounds. Since DTTO and iso‐DTTO are unknown, reliable predictions of their crystal densities are crucial for an evaluation of the potential of these materials as explosives. In this study, the crystal densities were predicted using both Ammon’s Atom/Functional Group and Atom Code Volume Additivity Parameters and Quantum Mechanical molecular Volume methods, resulting in similar densities and explosion parameters. Although the likely uncertainties in our predicted density values are difficult to assess due to a lack of experimental data for closely related known compounds, our results demonstrate that Shechter’s originally proposed densities and performance parameters were grossly overestimated. Furthermore, it is shown that, based on our predicted density value ranges, DTTO and iso‐DTTO could match or substantially outperform the best state of the art explosives, such as CL‐20. Therefore, the synthesis of DTTO and iso‐DTTO should be further pursued.     

Cladosporin,A Highly Potent Antimalaria Drug?

Cladosporin, a unique natural product from the fungus Cladosporium cladosporioides, exhibits nanomolar inhibitory activity against Plasmodium falciparum by targeting its cytosolic lysyl-tRNA synthetase (PfKRS) to inhibit protein biosynthesis. Due to its exquisite selectivity towards pathogenic parasites, cladosporin has become a very promising lead compound for developing antiparasitic drugs to treat drug-resistant malaria and cryptosporidiosis infections. Here we review the recent research progress of cladosporin covering aspects of the chemical synthesis, biosynthesis, bioactivity, cellular target and structure–activity relationship.     

Are short, low-barrier hydrogen bonds unusually strong?

In a symmetric hydrogen bond (H-bond), the hydrogen atom is perfectly centered between the two donor atoms. The energy diagram for hydrogen motion is thus a single-well potential, rather than the double-well potential of a more typical H-bond, in which the hydrogen is covalently bonded to one atom and H-bonded to the other. Examples of symmetric H-bonds are often found in crystal structures, and they exhibit the distinctive feature of unusually short length: for example, the O-O distance in symmetric OHO H-bonds is found to be less than 2.5 ?. In comparison, the O-O distance in a typical asymmetric H-bond, such as ROH···OR(2), ranges from about 2.7 to 3.0 ?. In this Account, we briefly review and update our use of the method of isotopic perturbation to search for a symmetric, centered, or single-well-potential H-bond in solution. Such low-barrier H-bonds are thought to be unusually strong, owing perhaps to the resonance stabilization of two identical resonance forms [A-H···B ? A···H-B]. This presumptive bond strength has been invoked to explain some enzyme-catalyzed reactions. Yet in solution, a wide variety of OHO, OHN, and NHN H-bonds have all been found to be asymmetric, in double-well potentials. Examples include the monoanion of (±)-2,3-di-tert-butylsuccinic acid and a protonated tetramethylnaphthalenediamine, even though these two ions are often considered prototypes of species with strong H-bonds. In fact, all of the purported examples of strong, symmetric H-bonds have been found to exist in solution as pairs of asymmetric tautomers, in contrast to their symmetry in some crystals. The asymmetry can be attributed to the disorder of the local solvation environment, which leads to an equilibrium among solvatomers (that is, isomers that differ in solvation). If the disorder of the local environment is sufficient to break symmetry, then symmetry itself is not sufficient to stabilize the H-bond, and symmetric H-bonds do not have an enhanced stability or an unusual strength. Nor are short H-bonds unusually strong. We discuss previous evidence for "short, strong, low-barrier" H-bonds and show it to be based on ambiguous comparisons. The role of such H-bonds in enzyme-catalyzed reactions is then ascribed not to any unusual strength of the H-bond itself but to relief of "strain."     

Transport in the Brain Extracellular Space: Diffusion,but Which Kind?

The mechanisms of transport of substances in the brain parenchyma have been a hot topic in scientific discussion in the past decade. This discussion was triggered by the proposed glymphatic hypothesis, which assumes a directed flow of cerebral fluid within the parenchyma, in contrast to the previous notion that diffusion is the main mechanism. However, when discussing the issue of “diffusion or non-diffusion”, much less attention was given to the question that diffusion itself can have a different character. In our opinion, some of the recently published results do not fit into the traditional understanding of diffusion. In this regard, we outline the relevant new theoretical approaches on transport processes in complex random media such as concepts of diffusive diffusivity and time-dependent homogenization, which expands the understanding of the forms of transport of substances based on diffusion.     

What Are Reactive Oxygen Species,Free Radicals,and Oxidative Stress in Skin Diseases?

Oxygen in the atmosphere is a crucial component for life-sustaining aerobic respiration in humans. Approximately 95% of oxygen is consumed as energy and ultimately becomes water; however, the remaining 5% produces metabolites called activated oxygen or reactive oxygen species (ROS), which are extremely reactive. Skin, the largest organ in the human body, is exposed to air pollutants, including diesel exhaust fumes, ultraviolet rays, food, xenobiotics, drugs, and cosmetics, which promote the production of ROS. ROS exacerbate skin aging and inflammation, but also function as regulators of homeostasis in the human body, including epidermal keratinocyte proliferation. Although ROS have been implicated in various skin diseases, the underlying mechanisms have not yet been elucidated. Current knowledge on ROS-related and oxidative stress-related skin diseases from basic research to clinical treatment strategies are discussed herein. This information may be applied to the future treatment of skin diseases through the individual targeting of the ROS generated in each case via their inhibition, capture, or regulation.     

Towards the integration of process design,control and scheduling: Are we getting closer?

The integration of design and control, control and scheduling and design, control and scheduling, all have been core PSE challenges. While significant progress has been achieved over the years, it is fair to say that at the moment there is not a generally accepted methodology and/or “protocol” for such an integration – it is also interesting to note that currently, there is not a commercially available software [or even in a prototype form] system to fully support such an activity.Here, we present the foundations for such an integrated framework and especially a software platform that enables such integration based on research developments over the last 25 years. In particular, we describe PAROC, a prototype software system which allows for the representation, modeling and solution of integrated design, scheduling and control problems. Its main features include: (i) a high-fidelity dynamic model representation, also involving global sensitivity analysis, parameter estimation and mixed integer dynamic optimization capabilities; (ii) a suite/toolbox of model approximation methods; (iii) a host of multi-parametric programming solvers for mixed continuous/integer problems; (iv) a state-space modeling representation capability for scheduling and control problems; and (v) an advanced toolkit for multi-parametric/explicit Model Predictive Control and moving horizon reactive scheduling problems. Algorithms that enable the integration capabilities of the systems for design, scheduling and control are presented on a case of a series of cogeneration units.     

Are There Differences in Inflammatory and Fibrotic Pathways between IPAF,CTD-ILDs,and IIPs? A Single-Center Pilot Study

In this pilot study, we aim to determine differences in pathogenetic pathways between interstitial pneumonia with autoimmune features (IPAF), connective-tissue-disease-associated interstitial lung diseases (CTD-ILDs), and idiopathic interstitial pneumonias (IIPs). Forty participants were recruited: 9 with IPAF, 15 with CTD-ILDs, and 16 with IIPs. Concentration of transforming growth factor beta (TGF-β1), surfactant proteins A and D (SP-A, SP-D), interleukin 8 (IL-8), and chemokine 1 (CXCL1) were assessed with ELISA assay in bronchoalveolar lavage (BAL) fluid. We revealed that IL-8 and TGF-β1 concentrations were significantly lower in the IPAF group than in the CTD-ILD group (p = 0.008 and p = 0.019, respectively), but similar to the concentrations in the IIP group. There were significant correlations of IL-8 (rs = 0.46; p = 0.003) and CXCL1 (rs = 0.52; p = 0.001) and BAL total cell count (TCC). A multivariate regression model revealed that IL-8 (β = 0.32; p = 0.037) and CXCL1 (β = 0.45; p = 0.004) are significant predictors of BAL TCC. We revealed that IL-8 and TGF-β1 BAL concentrations vary in patients with different ILDs and found that IL-8 is a predictor of BAL TCC in IPAF. However, this needs to be confirmed in a multicenter cooperative study (ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT03870828","term_id":"NCT03870828"}}NCT03870828).     

Front Cover: Similar but Still Different: Which Amino Acid Residues Are Responsible for Varying Activities in Type-III Copper Enzymes? (7/2021)

Type-III copper enzymes like polyphenol oxidases (PPOs) are ubiquitous among organisms and play a significant role in the formation of pigments. PPOs comprise different enzyme groups, including tyrosinases (TYRs) and catechol oxidases (COs). TYRs catalyze the o-hydroxylation of monophenols and the oxidation of o-diphenols to the corresponding o-quinones (EC 1.14.18.1). In contrast, COs only catalyze the oxidation of o-diphenols to the corresponding o-quinones (EC 1.10.3.1). To date (August 2020), 102 PDB entries encompassing 18 different proteins from 16 organisms and several mutants have been reported, identifying key residues for tyrosinase activity. The structural similarity between TYRs and COs, especially within and around the active center, complicates the elucidation of their modes of action on a structural basis. However, mutagenesis studies illuminate residues that influence the two activities and show that crystallography on its own cannot elucidate the enzymatic activity mode. Several amino acid residues around the dicopper active center have been proposed to play an essential role in the two different activities. Herein, we critically review the role of all residues identified so far that putatively affect the two activities of PPOs.     

Furan fatty acids: Occurrence,synthesis, and reactions. Are furan fatty acids responsible for the cardioprotective effects of a fish diet?

Furan FA (F-acids) are tri-or tetrasubstituted furan derivatives characterized by either a propyl or pentyl side chain in one of the α-positions; the other is substituted by a straight long-chain saturated acid with a carboxylic group at its end. F-acids are generated in large amounts in algae, but they are also produced by plants and microorganisms. Fish and other marine organisms as well as mammals consume F-acids in their food and incorporate them into phospholipids and cholesterol esters. F-acids are catabolized to dibasic urofuran acids, which are excreted in the urine. The biogenetic precursor of the most abundant F-acid, F₆, is linoleic acid. Methyl groups in the β-position are derived from adenosylmethionine. Owing to the different alkyl substituents, synthesis of F-acids requires multistep reactions. F-acids react readily with peroxyl radicals to generate dioxoenes. The radical-scavenging ability of F-acids may contribute to the protective properties of fish and fish oil diets against mortality from heart disease.     

Are Nanosilica,Potassium Silicate and New Soluble Sources of Silicon Effective for Silicon Foliar Application to Soybean and Rice Plants?

Silicon - Foliar application of silicon (Si) is an effective way of supplying this beneficial element to plants. The emergence of new potential liquid sources for foliar application requires...     

Are Partial Nutrient Balances Suitable to Evaluate Nutrient Sustainability of Land use Systems? Results from a Case Study in Central Sulawesi,Indonesia

Nutrient input–output balances are often used as indicators for the sustainability of land use systems. In a case study on plot scale in Central Sulawesi, Indonesia, we measured nutrient input–output balances of natural rainforest and two unfertilized land use systems (maize, and coffee/cacao agroforestry). These are the two major land use systems on converted rainforest sites in this part of Sulawesi. We wanted to test if (a) plant nutrient balances are negative, (b) which pathway is most important for losses of plant nutrients, and (c) if partial plant nutrient balances are suitable to evaluate sustainability of the land use systems. We measured nutrient inputs by precipitation and nutrient outputs by harvest export and leaching. We selected two locations, the first was situated on a fertile Cambisol developed on alluvial sediment soil, and the second on a less fertile Cambisol developed on weathered phyllite substrate. Nutrient losses through leaching were higher on sites with higher soil fertility. Nutrient balances in natural forest on fertile soils were negative for N, Ca, K and Mg. Inputs of P by precipitation and outputs by leaching were below detection limit. On less fertile soils, leaching of N and K in natural forest was lower than inputs by precipitation. As net nutrient losses were highest in agroforestry, followed by maize and natural forest stands, forest conversion into agricultural land will result in increased nutrient losses. Main output pathway of N, P and K was harvest, whereas main output pathway for Ca and Mg was through leaching. The annual losses of nutrients we measured were higher than in comparable studies on nutrient poor soils; however losses were only small fractions of available nutrient stocks. Our results showed negative partial nutrient balances in both agricultural systems. Nutrient balances in this study were more influenced by native soil fertility than by land use. Because we found indirect evidence that some nutrient pathways, which were not measured, may have significantly changed the overall balance (biological N fixation, weathering), we conclude that partial nutrient balances are no good indicators for sustainability of land use systems.     

Cardiac Telocytes 16 Years on—What Have We Learned So Far,and How Close Are We to Routine Application of the Knowledge in Cardiovascular Regenerative Medicine?

The regeneration of a diseased heart is one of the principal challenges of modern cardiovascular medicine. There has been ongoing research on stem-cell-based therapeutic approaches. A cell population called telocytes (TCs) described only 16 years ago largely contributed to the research area of cardiovascular regeneration. TCs are cells with small bodies and extremely long cytoplasmic projections called telopodes, described in all layers of the heart wall. Their functions include cell-to-cell signaling, stem-cell nursing, mechanical support, and immunoregulation, to name but a few. The functional derangement or quantitative loss of TCs has been implicated in the pathogenesis of myocardial infarction, heart failure, arrhythmias, and many other conditions. The exact pathomechanisms are still unknown, but the loss of regulative, integrative, and nursing functions of TCs may provide important clues. Therefore, a viable avenue in the future modern management of these conditions is TC-based cell therapy. TCs have been previously transplanted into a mouse model of myocardial infarction with promising results. Tandem transplantation with stem cells may provide additional benefit; however, many underresearched areas need to be addressed in future research before routine application of TC-based cell therapy in human subjects. These include the standardization of protocols for isolation, cultivation, and transplantation, quantitative optimization of TC transplants, cost-effectivity analysis, and many others.