Increasing evidence suggests that gut dysbiosis is associated with coronavirus disease 2019 (COVID-19) infection and may persist long after disease resolution. The excessive use of antimicrobials in ...patients with COVID-19 can lead to additional destruction of the microbiota, as well as to the growth and spread of antimicrobial resistance. The problem of bacterial resistance to antibiotics encourages the search for alternative methods of limiting bacterial growth and restoring the normal balance of the microbiota in the human body. Bacteriophages are promising candidates as potential regulators of the microbiota. In the present study, two complex phage cocktails targeting multiple bacterial species were used in the rehabilitation of thirty patients after COVID-19, and the effectiveness of the bacteriophages against the clinical strain of
was evaluated for the first time using real-time visualization on a 3D Cell Explorer microscope. Application of phage cocktails for two weeks showed safety and the absence of adverse effects. An almost threefold statistically significant decrease in the anaerobic imbalance ratio, together with an erythrocyte sedimentation rate (ESR), was detected. This work will serve as a starting point for a broader and more detailed study of the use of phages and their effects on the microbiome.
Abstract
The small intestinal villus tip is the first point of contact for lumen-derived substances including nutrients and microbial products. Electron microscopy studies from the early 1970s ...uncovered unusual spatial organization of small intestinal villus tip blood vessels: their exterior, epithelial-facing side is fenestrated, while the side facing the villus stroma is non-fenestrated, covered by pericytes and harbors endothelial nuclei. Such organization optimizes the absorption process, however the molecular mechanisms maintaining this highly specialized structure remain unclear. Here we report that perivascular LGR5
+
villus tip telocytes (VTTs) are necessary for maintenance of villus tip endothelial cell polarization and fenestration by sequestering VEGFA signaling. Mechanistically, unique VTT expression of the protease ADAMTS18 is necessary for VEGFA signaling sequestration through limiting fibronectin accumulation. Therefore, we propose a model in which LGR5
+
ADAMTS18
+
telocytes are necessary to maintain a “just-right” level and location of VEGFA signaling in intestinal villus blood vasculature to ensure on one hand the presence of sufficient endothelial fenestrae, while avoiding excessive leakiness of the vessels and destabilization of villus tip epithelial structures.
RATIONALE:Cardiac lymphangiogenesis contributes to the reparative process post-myocardial infarction, but the factors and mechanisms regulating it are not well understood.
OBJECTIVE:To determine if ...epicardial-secreted factor AM (adrenomedullin; Adm=gene) improves cardiac lymphangiogenesis post-myocardial infarction via lateralization of Cx43 (connexin 43) in cardiac lymphatic vasculature.
METHODS AND RESULTS:Firstly, we identified sex-dependent differences in cardiac lymphatic numbers in uninjured mice using light-sheet microscopy. Using a mouse model of Adm (Adm overexpression) and permanent left anterior descending ligation to induce myocardial infarction, we investigated cardiac lymphatic structure, growth, and function in injured murine hearts. Overexpression of Adm increased lymphangiogenesis and cardiac function post-myocardial infarction while suppressing cardiac edema and correlated with changes in Cx43 localization. Lymphatic function in response to AM treatment was attenuated in mice with a lymphatic-specific Cx43 deletion. In vitro experiments in cultured human lymphatic endothelial cells identified a novel mechanism to improve gap junction coupling by pharmaceutically targeting Cx43 with verapamil. Finally, we show that connexin protein expression in cardiac lymphatics is conserved between mouse and human.
CONCLUSIONS:AM is an endogenous, epicardial-derived factor that drives reparative cardiac lymphangiogenesis and function via Cx43, and this represents a new therapeutic pathway for improving myocardial edema after injury.
Antipsychotics (AP) induced prolongation of the QT interval in patients with schizophrenia (Sch) is an actual interdisciplinary problem as it increases the risk of sudden death syndrome. Long QT ...syndrome (LQTS) as a cardiac adverse drug reaction is a multifactorial symptomatic disorder, the development of which is influenced by modifying factors (APs' dose, duration of APs therapy, APs polytherapy, and monotherapy, etc.) and non-modifying factors (genetic predisposition, gender, age, etc.). The genetic predisposition to AP-induced LQTS may be due to several causes, including causal mutations in the genes responsible for monoheme forms of LQTS, single nucleotide variants (SNVs) of the candidate genes encoding voltage-dependent ion channels expressed both in the brain and in the heart, and SNVs of candidate genes encoding key enzymes of APs metabolism. This narrative review summarizes the results of genetic studies on AP-induced LQTS and proposes a new personalized approach to assessing the risk of its development (low, moderate, high). We recommend implementation in protocols of primary diagnosis of AP-induced LQTS and medication dispensary additional observations of the risk category of patients receiving APs, deoxyribonucleic acid profiling, regular electrocardiogram monitoring, and regular therapeutic drug monitoring of the blood APs levels.
Many modern applications of description logics (DLs, for short), such as biomedical ontologies and semantic web policies, provide fresh motivations for extending DLs with nonmonotonic inferences—a ...topic that has attracted a significant amount of attention along the years. Despite this, nonmonotonic inferences are not yet supported by DL technology due to a number of issues related to expressiveness, computational complexity, and optimizations. This paper contributes to the practical support of nonmonotonic inferences in description logics by introducing a new semantics expressly designed to address knowledge engineering needs. This formalism has appealing expressiveness, enjoys nice computational properties, and constitutes an interesting solution to an ample class of application needs. The formalism is validated through extensive comparison with the other nonmonotonic DLs, and systematic scalability tests. The test case generator and its novel validation methodology constitute a further contribution of this paper.
Copper is an essential cofactor for all organisms, and yet it becomes toxic if concentrations exceed a threshold maintained by evolutionarily conserved homeostatic mechanisms. How excess copper ...induces cell death, however, is unknown. Here, we show in human cells that copper-dependent, regulated cell death is distinct from known death mechanisms and is dependent on mitochondrial respiration. We show that copper-dependent death occurs by means of direct binding of copper to lipoylated components of the tricarboxylic acid (TCA) cycle. This results in lipoylated protein aggregation and subsequent iron-sulfur cluster protein loss, which leads to proteotoxic stress and ultimately cell death. These findings may explain the need for ancient copper homeostatic mechanisms.
Midlatitude anthropogenic mercury (Hg) emissions and discharge reach the Arctic Ocean (AO) by atmospheric and oceanic transport. Recent studies suggest that Arctic river Hg inputs have been a ...potentially overlooked source of Hg to the AO. Observations on Hg in Eurasian rivers, which represent 80% of freshwater inputs to the AO, are quasi-inexistent, however, putting firm understanding of the Arctic Hg cycle on hold. Here, we present comprehensive seasonal observations on dissolved Hg (DHg) and particulate Hg (PHg) concentrations and fluxes for two large Eurasian rivers, the Yenisei and the Severnaya Dvina. We find large DHg and PHg fluxes during the spring flood, followed by a second pulse during the fall flood. We observe well-defined water vs. Hg runoff relationships for Eurasian and North American Hg fluxes to the AO and for Canadian Hg fluxes into the larger Hudson Bay area. Extrapolation to pan-Arctic rivers and watersheds gives a total Hg river flux to the AO of 44 ± 4 Mg per year (1σ), in agreement with the recent model-based estimates of 16 to 46 Mg per year and Hg/dissolved organic carbon (DOC) observation-based estimate of 50 Mg per year. The river Hg budget, together with recent observations on tundra Hg uptake and AO Hg dynamics, provide a consistent view of the Arctic Hg cycle in which continental ecosystems traffic anthropogenic Hg emissions to the AO via rivers, and the AO exports Hg to the atmosphere, to the Atlantic Ocean, and to AO marine sediments.
This study examines private homebuilding as a specific conflict-laden form of urbanization in post-Second World War Soviet Central Asia, based on the example of Samarkand. It elucidates the neglected ...role of private initiatives in Soviet urban planning and housing policy, which it describes as a tension-filled realm of conflicting interests, urban development tasks, and pressures.
Nah am Boden Petrova, Mariya
2020, 2020-11-23
eBook
Die Nachkriegsgeschichte des sowjetischen Zentralasiens und deren Stadte ist bisher nur wenig erforscht. Gerade in jener Zeit veranderten Industrialisierung und Wohnungsbauprogramme nachhaltig die ...urbanen Raume der Region. Doch die Vorstellung einer radikalen Modernisierung sowjetischer Stadte greift zu kurz, denn lokale Prozesse, private Interessen und Handlungsspielraume fur unterschiedliche Akteure waren ebenso Teil des stadtebaulichen Geschehens.Am Beispiel des privaten Hausbaus in Samarkand der 50er- und 60er-Jahre und mit Hilfe von Zeitzeugenerinnerungen und Archivdokumenten untersucht die Arbeit die legalen wie illegalen Formen dieser Baupraxis, ihre Bedeutung bei der Bewaltigung der Wohnungskrise sowie ihre weitreichenden Folgen fur die Struktur der Stadt. Sowjetische Stadtplanung erscheint hier als Spannungsfeld von Interessenskonflikten, Aushandlungsprozessen und Kompromissen zwischen Burokratie, Politik und einzelnen Akteuren.Die Arbeit zeigt die Grenzen des sowjetischen Modernisierungsprojektes und eroffnet damit neue Perspektiven fur die historische Stadtforschung der ehemaligen Sowjetunion und speziell fur Zentralasien.
Heterozygous germline mutations in the zinc finger transcription factor GATA2 have recently been shown to underlie a range of clinical phenotypes, including Emberger syndrome, a disorder ...characterized by lymphedema and predisposition to myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). Despite well-defined roles in hematopoiesis, the functions of GATA2 in the lymphatic vasculature and the mechanisms by which GATA2 mutations result in lymphedema have not been characterized. Here, we have provided a molecular explanation for lymphedema predisposition in a subset of patients with germline GATA2 mutations. Specifically, we demonstrated that Emberger-associated GATA2 missense mutations result in complete loss of GATA2 function, with respect to the capacity to regulate the transcription of genes that are important for lymphatic vessel valve development. We identified a putative enhancer element upstream of the key lymphatic transcriptional regulator PROX1 that is bound by GATA2, and the transcription factors FOXC2 and NFATC1. Emberger GATA2 missense mutants had a profoundly reduced capacity to bind this element. Conditional Gata2 deletion in mice revealed that GATA2 is required for both development and maintenance of lymphovenous and lymphatic vessel valves. Together, our data unveil essential roles for GATA2 in the lymphatic vasculature and explain why a select catalogue of human GATA2 mutations results in lymphedema.
PDF
