Structural Analysis of Mitochondrial Dynamics—From Cardiomyocytes to Osteoblasts: A Critical Review

Mitochondria play a crucial role in cell physiology and pathophysiology. In this context, mitochondrial dynamics and, subsequently, mitochondrial ultrastructure have increasingly become hot topics in modern research, with a focus on mitochondrial fission and fusion. Thus, the dynamics of mitochondria in several diseases have been intensively investigated, especially with a view to developing new promising treatment options. However, the majority of recent studies are performed in highly energy-dependent tissues, such as cardiac, hepatic, and neuronal tissues. In contrast, publications on mitochondrial dynamics from the orthopedic or trauma fields are quite rare, even if there are common cellular mechanisms in cardiovascular and bone tissue, especially regarding bone infection. The present report summarizes the spectrum of mitochondrial alterations in the cardiovascular system and compares it to the state of knowledge in the musculoskeletal system. The present paper summarizes recent knowledge regarding mitochondrial dynamics and gives a short, but not exhaustive, overview of its regulation via fission and fusion. Furthermore, the article highlights hypoxia and its accompanying increased mitochondrial fission as a possible link between cardiac ischemia and inflammatory diseases of the bone, such as osteomyelitis. This opens new innovative perspectives not only for the understanding of cellular pathomechanisms in osteomyelitis but also for potential new treatment options.     

Cocaprins, β-Trefoil Fold Inhibitors of Cysteine and Aspartic Proteases from Coprinopsis cinerea

We introduce a new family of fungal protease inhibitors with β-trefoil fold from the mushroom Coprinopsis cinerea, named cocaprins, which inhibit both cysteine and aspartic proteases. Two cocaprin-encoding genes are differentially expressed in fungal tissues. One is highly transcribed in vegetative mycelium and the other in the stipes of mature fruiting bodies. Cocaprins are small proteins (15 kDa) with acidic isoelectric points that form dimers. The three-dimensional structure of cocaprin 1 showed similarity to fungal β-trefoil lectins. Cocaprins inhibit plant C1 family cysteine proteases with K_i in the micromolar range, but do not inhibit the C13 family protease legumain, which distinguishes them from mycocypins. Cocaprins also inhibit the aspartic protease pepsin with K_i in the low micromolar range. Mutagenesis revealed that the β2-β3 loop is involved in the inhibition of cysteine proteases and that the inhibitory reactive sites for aspartic and cysteine proteases are located at different positions on the protein. Their biological function is thought to be the regulation of endogenous proteolytic activities or in defense against fungal antagonists. Cocaprins are the first characterized aspartic protease inhibitors with β-trefoil fold from fungi, and demonstrate the incredible plasticity of loop functionalization in fungal proteins with β-trefoil fold.     

DIELS-ALDER Reaktionen. VI. Weitere Untersuchungen der bei der Homodimerisierung von acyclischen C5-Dienen-(1,3) entstehenden Reaktionsprodukte

DIELS -ALDER -Reactions. VI. Further Studies of the Reaction Products Formed by the Homodimerization of Acyclic 1,3-Diolefines with Five Carbon Atoms The distribution of the products of homodimerization of isoprene, trans-piperylene and cis-piperylene in toluene as solvent was determined as a function of the reaction temperature; the products formed by concurrent reactions were obtained by extrapolating the conversion to zero. From the data obtained the rate constants and the activation parameters were calculated for the six-membered ring dimers formed as the only products of the thermal homodimerization of transpiperylene, and for the four membered, six-membered and eight-membered cyclic compounds formed from isoprene. As was already found in similar studies of 1,3-butadiene, also in the case of homodimerization of isoprene, the activation parameters of the symmetry-allowed six-membered ring formation and of the symmetry-forbidden formation of four-membered and eight-membered cyclic dimers do not differ much from each other.     

Evolutionary functional black-box testing in an industrial setting

During the past years, evolutionary testing research has reported encouraging results for automated functional (i.e. black-box) testing. However, despite promising results, these techniques have hardly been applied to complex, real-world systems and as such, little is known about their scalability, applicability, and acceptability in industry. In this paper, we describe the empirical setup used to study the use of evolutionary functional testing in industry through two case studies, drawn from serial production development environments at Daimler and Berner & Mattner Systemtechnik, respectively. Results of the case studies are presented, and research questions are assessed based on them. In summary, the results indicate that evolutionary functional testing in an industrial setting is both scalable and applicable. However, the creation of fitness functions is time-consuming. Although in some cases, this is compensated by the results, it is still a significant factor preventing functional evolutionary testing from more widespread use in industry.     

Visual simulation by means of a transputer network for a driving simulator

Visual simulation is one of the most important parts of a driving simulator. Unfortunately it is in general the most expensive part too. CGI-manufacturers tend to develop more complex systems because of the demands of the military market. The common systems are strongly hardware-oriented. On the basis of a new type of microprocessor, the transputer, a more software-oriented approach is introduced. Transputers in connection with the new high-level language occam are well suited for pipelining and parallelization owing to their communication concept. The advantages of this approach are reduced costs and development time, and also the capability for fast and cheap changes in algorithms. The achievable performance meets the requirements for a driving simulator very well.     

Pyryliumverbindungen. 45 [1]. 4-Aroyl-fluorene aus 2,4,6-Triaryl-pyryliumsalzen und Indan-1-on via 2-(5-Oxo-pent-2-en-1-yliden)-indan-1-one

Pyrylium Compounds. 45. 4-Aroyl-fluorenes from 2,4,6-Triaryl-pyrylium Salts and Indan-1-one via 2-(5-Oxo-pent-2-en-1-yliden)-indan-1-ones 2,4,6-Triarylpyrylium salts 1 react with indan-1-one in the presence of an appropriate buffer system (e.g. piperidine acetate, triethylamine/acetic acid, triethylamine or sodium acetate) to yield the 2-(1,3,5-triaryl-5-oxo-pent-2-en-1-yliden)-indan-1-ones 2 . For the reaction medium aliphatic alcohols (methanol, ethanol), dipolar aprotic solvents (acetonitrile) or chlorinated hydrocarbons (methylene chloride, chloroform, carbon tetrachloride) can be used. On treating 2 with sodium methanolate in methanol, a cyclization reaction occurs giving rise to the 4-aroyl-1,3-diaryl-fluorenes 3 . As by-products 1,3-diaryl-fluorenes 8 (e.g. 1,3-diphenyl-fluorene) are formed. - I.r., n.m.r. and u.v. spectroscopic data of the novel compounds 2 and 3 are reported.     

Heparin-Functionalized Adsorbents Eliminate Central Effectors of Immunothrombosis,including Platelet Factor 4, High-Mobility Group Box 1 Protein and Histones

Inflammation and thrombosis are closely intertwined in numerous disorders, including ischemic events and sepsis, as well as coronavirus disease 2019 (COVID-19). Thrombotic complications are markers of disease severity in both sepsis and COVID-19 and are associated with multiorgan failure and increased mortality. Immunothrombosis is driven by the complement/tissue factor/neutrophil axis, as well as by activated platelets, which can trigger the release of neutrophil extracellular traps (NETs) and release further effectors of immunothrombosis, including platelet factor 4 (PF4/CXCL4) and high-mobility box 1 protein (HMGB1). Many of the central effectors of deregulated immunothrombosis, including activated platelets and platelet-derived extracellular vesicles (pEVs) expressing PF4, soluble PF4, HMGB1, histones, as well as histone-decorated NETs, are positively charged and thus bind to heparin. Here, we provide evidence that adsorbents functionalized with endpoint-attached heparin efficiently deplete activated platelets, pEVs, PF4, HMGB1 and histones/nucleosomes. We propose that this elimination of central effectors of immunothrombosis, rather than direct binding of pathogens, could be of clinical relevance for mitigating thrombotic complications in sepsis or COVID-19 using heparin-functionalized adsorbents.