Repositioning Ivermectin for Covid-19 treatment: Molecular mechanisms of action against SARS-CoV-2 replication

Ivermectin (IVM) is an FDA approved macrocyclic lactone compound traditionally used to treat parasitic infestations and has shown to have antiviral potential from previous in-vitro studies. Currently, IVM is commercially available as a veterinary drug but have also been applied in humans to treat onchocerciasis (river blindness - a parasitic worm infection) and strongyloidiasis (a roundworm/nematode infection). In light of the recent pandemic, the repurposing of IVM to combat SARS-CoV-2 has acquired significant attention. Recently, IVM has been proven effective in numerous in-silico and molecular biology experiments against the infection in mammalian cells and human cohort studies. One promising study had reported a marked reduction of 93% of released virion and 99.98% unreleased virion levels upon administration of IVM to Vero-hSLAM cells. IVM's mode of action centres around the inhibition of the cytoplasmic-nuclear shuttling of viral proteins by disrupting the Importin heterodimer complex (IMPα/β1) and downregulating STAT3, thereby effectively reducing the cytokine storm. Furthermore, the ability of IVM to block the active sites of viral 3CLpro and S protein, disrupts important machinery such as viral replication and attachment. This review compiles all the molecular evidence to date, in review of the antiviral characteristics exhibited by IVM. Thereafter, we discuss IVM's mechanism and highlight the clinical advantages that could potentially contribute towards disabling the viral replication of SARS-CoV-2. In summary, the collective review of recent efforts suggests that IVM has a prophylactic effect and would be a strong candidate for clinical trials to treat SARS-CoV-2.     

Phosphorus requirements of the wheat plant in various stages of its life cycle

Summary In pot experiments root growth and P uptake were found to precede shoot growth. The high rate of P uptake in the early stages of the life cycle is not an expression of luxury consumption but reflects a high P requirement in plants. Plants cultivated in nutrient solutions with different P concentrations during various stages of development showed that a high P supply (1 ppm) between Feekes stages 6 and 9 (30 days) caused a higher grain yield than the same P concentration between Feekes stages 11 and 17 (30 days). The early applied P caused a high number of fertile ears per area, a high number of grains per ear, and a high P pool in vegetative parts. The latter could be mobilized during the grain-filling period. Therefore, for high grain yields soil and fertilizers have to meet the high P requirement (about 20 g P/m root · day) in an early stage of plant growth. During the grain filling period the P supply can be much lower.     

Exploring the hidden impact of the Covid-19 pandemic: The role of urbanization

We examine the role of residential environments (urban/rural) in understanding the impact of the COVID-19 pandemic and the restrictions in nationwide movement on several socio-economic attitudes. We conducted large-scale surveys in four European countries (France, Germany, Spain, and the United Kingdom) before and after nationwide lockdowns were implemented. We investigate how the pandemic affected: (i) economic (economic insecurity), (ii) political (trust in domestic and international institutions), and (iii) social attitudes (loneliness), by controlling for the degree of urbanization, obtained from the geocodes of the survey respondents. Our results show that taking the degree of urbanization into account is not only relevant but is also essential. Compared to urban areas, in rural areas lockdowns led to a greater increase of economic insecurity and to a greater decrease in trust in domestic institutions. We also show that these results are particularly valid for women and households with children.     

Differences in the nuclear chromatin among various stages of the life cycle of Trypanosoma cruzi

Trypanosoma cruzi is the etiological agent of Chagas. Although the nuclear chromatin of this parasite is organized in the form of nucleosome filaments, its chromatin is physically and enzymatically fragile, and no condensation into chromosomes occurs during mitosis. All previous investigations have been carried out with epimastigote form in its proliferate stage. It is not known whether these differences in chromatin structure are also found in the non-proliferate stationary epimastigote forms and in tissue derived trypomastigotes. Our results confirm that chromatin of logarithmic epimastigotes presents limited compaction when increasing salt concentrations from 1 to 100 mM NaCl, and no 30-nm fibers were formed. Contrary to these results, non-proliferative forms of the parasites showed a pattern of compactation similar to that observed in rat liver chromatin, where solenoids of 30-nm fibers are formed at 100-mM NaCl. In accordance with these results, digestion of the nuclear chromatin with DNase I revealed that the chromatin of logarithmic phase epimastigotes was more accessible to the enzyme. We conclude from these results that structural differences in the chromatin exist not only between T. cruzi and higher eukaryotes but also among various forms of the parasite. The functional significance of these differences are currently under investigation.     

Multinuclear stages of the life cycle ofAcetabularia mediterranea

Summary The reproductive stages of the life cycle ofAcetabularia mediterranea have been studied in Feulgen-stained material. Light-microscopical photographs of secondary nuclei, cyst formation, gamete formation, gamete release, zygote formation and early development of the germlings are presented. The time course of cytological events during gamete formation is described. Mitoses are found between 16 and 24 hours after the induction of cyst germination.The author is indebted to Mrs. S.Artelt who helped with the prepration of the specimens and the photographs.     

新冠病毒抗体药物研发进展及展望分析

抗体药物以其独特的作用机制和靶向性强、特异性好等优点,在恶性肿瘤、自身免疫性疾病、感染类疾病的诊断和治疗中发挥着越来越重要的作用,成为国际创新药物研发的热点。新冠肺炎(COVID-19)疫情发生以来,国内外多家研究机构和企业正在加快推进新冠病毒(SARS-CoV-2)抗体药物的开发。在此情势下,认真分析抗体药物现状和趋势,梳理国内外新冠病毒抗体药物研究进展,明确我国当前抗体药物创新的机遇、挑战和建议,对加快我国药物自主创新研发具有重要意义。     

Three‐dimensional reconstruction of the musculature of various life cycle stages of the cycliophoran Symbion americanus

Cycliophora is a very recently described phylum of acoelomate metazoans with a complex life cycle and a phylogenetic position that has been under debate ever since its discovery in 1995. Symbion americanus, which lives attached to the mouthparts of the American lobster, Homarus americanus, represents the second species described for the phylum. Aiming to increase the morphological knowledge about this cryptic clade, the present study describes the muscle arrangement of the feeding stage, the attached Prometheus larva with the dwarf male inside, the free living male, the Pandora larva, and the chordoid larva of S. americanus using actin staining and confocal laser scanning microscopy. 3D reconstructions of the muscular systems are presented. In the feeding stage, circular muscles compose the buccal funnel aperture. In addition, a pair of muscles runs longitudinally in the buccal funnel. A complex sphincter was found just proximally to the anus, and six longitudinal muscles run from the trunk constriction (“neck”) in basal direction. The musculature of the larval stages and the dwarf male is very complex and includes longitudinal muscles that run dorsally and ventrally. In addition, we found dorso‐ventral muscles. The male has a complex posterior muscle apparatus in the vicinity of the penis. In this stage, X‐ and V‐shaped structures were identified on the dorsal and the ventral side, respectively. Pandora and chordoid larvae possess additional circular muscles. We discuss our findings with respect to muscle elements of other metazoan groups and the chordoid larva of Symbion pandora. J. Morphol., 2009. © 2008 Wiley‐Liss, Inc.     

SARS-CoV-2/COVID-19: a primer for cardiologists

In the late autumn of 2019, a new potentially lethal human coronavirus designated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China. The pandemic spread of this zoonotic virus has created a global health emergency and an unprecedented socioeconomic crisis. The severity of coronavirus disease 2019 (COVID-19), the illness caused by SARS-CoV?2, is highly variable. Most patients (~85%) develop no or mild symptoms, while others become seriously ill, some succumbing to disease-related complications. In this review, the SARS-CoV?2 life cycle, its transmission and the clinical and immunological features of COVID-19 are described. In addition, an overview is presented of the virological assays for detecting ongoing SARS-CoV?2 infections and the serological tests for SARS-CoV-2-specific antibody detection. Also discussed are the different approaches to developing a COVID-19 vaccine and the perspectives of treating COVID-19 with antiviral drugs, immunomodulatory agents and anticoagulants/antithrombotics. Finally, the cardiovascular manifestations of COVID-19 are briefly touched upon. While there is still much to learn about SARS-CoV?2, the tremendous recent advances in biomedical technology and knowledge and the huge amount of research into COVID-19 raise the hope that a remedy for this disease will soon be found. COVID-19 will nonetheless have a lasting impact on human society.

     

Cystic fibrosis improves COVID-19 survival and provides clues for treatment of SARS-CoV-2

Systemic pools of ATP are elevated in individuals homozygous for cystic fibrosis (CF) as evidenced by elevated blood and plasma ATP levels. This elevated ATP level seems to provide benefit in the presence of advanced solid tumors (Abraham et al., Nature Medicine 2(5):593–596, 1996). We published in this journal a paper showing that IV ATP can elevate the depleted ATP pools of advanced cancer patients up to levels found in CF patients with subsequent clinical, biochemical, and quality of life (QOL) improvements (Rapaport et al., Purinergic Signalling 11(2): 251–262, 2015). We hypothesize that the elevated ATP levels seen in CF patients may be benefiting CF patients in another way: by improving their survival after contracting COVID-19. We discuss here the reasoning behind this hypothesis and suggest how these findings might be applied clinically in the general population.     

Computational framework to understand the clinical stages of COVID-19 and visualization of time course for various treatment strategies

Coronavirus disease 2019 is known to be regulated by multiple factors such as delayed immune response, impaired T cell activation, and elevated levels of proinflammatory cytokines. Clinical management of the disease remains challenging due to interplay of various factors as drug candidates may elicit different responses depending on the staging of the disease. In this context, we propose a computational framework which provides insights into the interaction between viral infection and immune response in lung epithelial cells, with an aim of predicting optimal treatment strategies based on infection severity. First, we formulate the model for visualizing the nonlinear dynamics during the disease progression considering the role of T cells, macrophages and proinflammatory cytokines. Here, we show that the model is capable of emulating the dynamic and static data trends of viral load, T cell, macrophage levels, interleukin (IL)-6 and TNF-α levels. Second, we demonstrate the ability of the framework to capture the dynamics corresponding to mild, moderate, severe, and critical condition. Our result shows that, at late phase (>15 days), severity of disease is directly proportional to pro-inflammatory cytokine IL6 and tumor necrosis factor (TNF)-α levels and inversely proportional to the number of T cells. Finally, the simulation framework was used to assess the effect of drug administration time as well as efficacy of single or multiple drugs on patients. The major contribution of the proposed framework is to utilize the infection progression model for clinical management and administration of drugs inhibiting virus replication and cytokine levels as well as immunosuppressant drugs at various stages of the disease.     

Cytochemical study of various stages of life cycle of Toxoplasma gondii. 10. Phosphatases in the parasites during developmental stages in cat's intestines]

Several methods of acid and alkaline phosphatese and ATPase detection using both natural and artificial substrates were applied to the intestinal stages of Toxoplasma gondii with negative results to reveal enzymatic activity in all the stages except the microgametocyte. Possible explanation of this unexpected phenomenon is discussed taking into account host-parasite relationships with intestinal stages of Toxoplasma and with coccidia in general.     

Genome ploidy in different stages of the Giardia lamblia life cycle

The early diverging eukaryotic parasite Giardia lamblia is unusual in that it contains two apparently identical nuclei in the vegetative trophozoite stage. We have determined the nuclear and cellular genome ploidy of G. lamblia cells during all stages of the life cycle. During vegetative growth, the nuclei cycle between a diploid (2N) and tetraploid (4N) genome content and the cell, consequently, cycles between 4N and 8N. Stationary phase trophozoites arrest in the G₂ phase with a ploidy of 8N (two nuclei, each with a 4N ploidy). On its way to cyst formation, a G₁ trophozoite goes through two successive rounds of chromosome replication without an intervening cell division event. Fully differentiated cysts contain four nuclei, each with a ploidy of 4N, resulting in a cyst ploidy of 16N. The newly excysted cell, for which we suggest the term 'excyzoite', contains four nuclei (cellular ploidy 16N). In a reversal of the events occurring during encystation, the excyzoite divides twice to form four trophozoites containing two diploid nuclei each. The formation of multiple cells from a single cyst is likely to be one of the main reasons for the low infectious doses of G. lamblia .