Zika Virus Enters Soma of Neuron through NGF/TrkA-Like Endosomal Signaling Pathway

Infection with the Zika virus results in severe neurological disease in adults or congenital Zika syndrome in newborns. We employed the domain search strategy to study the Zika virus glycoprotein E in this work. The results revealed that immature E contains a NGF domain (“MNKCYIQIMDLGHMCDATMSYECPMLDEGVEPDDVDCWCNTTSTWVVYGTCHH”) and is capable of interacting with TrkA. The E/TrkA complex increased E's interaction with receptors such as Axl and facilitated Zika virus endocytosis via clathrin. Rab5 retrograded transmission of Zika virus-containing E/TrkA endosomal signals to neuronal soma. Rab7 helped dissociation of E/TrkA in late acidic endosomes, and then E became mature after the NGF domain was cut. After membrane fusion with the endosome, the Zika virus was released into the neuron cell body. It showed only the immature E protein of Zika had NGF activity. The retrograde trafficking of endosomal signals (E/TrkA) similar to NGF/TrkA enabled Zika virus to infect neuronal cells. E's interference with the TrkA signal impaired neuronal cell growth and results in neuronal cell apoptosis.

Wnt3 Is Lipidated at Conserved Cysteine and Serine Residues in Zebrafish Neural Tissue

Wnt proteins are a family of hydrophobic cysteine-rich secreted glycoproteins that regulate a gamut of physiological processes involved in embryonic development and tissue homeostasis. Wnt ligands are post-translationally lipidated in the endoplasmic reticulum (ER), a step essential for its membrane targeting, association with lipid domains, secretion and interaction with receptors. However, at which residue(s) Wnts are lipidated remains an open question. Initially it was proposed that Wnts are lipid-modified at their conserved cysteine and serine residues (C77 and S209 in mWnt3a), and mutations in either residue impedes its secretion and activity. Conversely, some studies suggested that serine is the only lipidated residue in Wnts, and substitution of serine with alanine leads to retention of Wnts in the ER. In this work, we investigate whether in zebrafish neural tissues Wnt3 is lipidated at one or both conserved residues. To this end, we substitute the homologous cysteine and serine residues of zebrafish Wnt3 with alanine (C80A and S212A) and investigate their influence on Wnt3 membrane organization, secretion, interaction and signaling activity. Collectively, our results indicate that Wnt3 is lipid modified at its C80 and S212 residues. Further, we find that lipid addition at either C80 or S212 is sufficient for its secretion and membrane organization, while the lipid modification at S212 is indispensable for receptor interaction and signaling.

Influence of glucocorticoid hormones on the thyroid gland function

The injection of exogenous analogues of glucocorticoid hormones (cortisone, hydrocortisone, corticosterone, dexamethasone, betamethasone, etc.) leads to a change in thyroid function at all levels (biosynthesis and secretion of hormones by the thyroid gland, the transport, interaction with receptors in target organs, biological action, their metabolism and excretion). Glucocorticoid hormones change regulationof the thyroid function: transhypophysially (glucocorticoids block the secretion of thyroliberin, thyroid stimulating hormone, corticotropin releasing hormone, somatoliberin and the production of somatotropin under the influence of the last one) and parahypophysially (glucocorticoids stimulate formation of insulin in β-cells of the pancreas).

SPECIFICS OF ALCOHOL USE DISORDER IN PRE-HOSPITAL PRACTICES AND EMERGENCY UNIT

Ethanol intoxication is analyzed from the point of ethanol interaction with receptors and enzymes. Ethanol dependence is based on neurochemical misbalance, which is different in acute ethanol intoxication and withdrawal. It is shown that the clinical manifestation of ethanol intoxication and its complications depends on ligand-receptor and enzyme imbalances. Pharmacological approaches to the treatment of acute ethanol intoxication and its complications at the pre-hospital stage and in the emergency, unit are discussed.

The Role of IgA in the Pathogenesis of IgA Nephropathy

Immunoglobulin A (IgA) is the most abundant antibody isotype produced in humans, predominantly present in the mucosal areas where its main functions are the neutralization of toxins, prevention of microbial invasion across the mucosal epithelial barrier, and simultaneous maintenance of a physiologically indispensable symbiotic relationship with commensal bacteria. The process of IgA biosynthesis, interaction with receptors, and clearance can be disrupted in certain pathologies, like IgA nephropathy, which is the most common form of glomerulonephritis worldwide. This review summarizes the latest findings in the complex characteristics of the molecular structure and biological functions of IgA antibodies, offering an in-depth overview of recent advances in the understanding of biochemical, immunologic, and genetic factors important in the pathogenesis of IgA nephropathy.

Hyaluronic Acid-Coated Nanomedicine for Targeted Cancer Therapy

Hyaluronic acid (HA) has been widely investigated in cancer therapy due to its excellent characteristics. HA, which is a linear anionic polymer, has biocompatibility, biodegradability, non-immunogenicity, non-inflammatory, and non-toxicity properties. Various HA nanomedicines (i.e., micelles, nanogels, and nanoparticles) can be prepared easily using assembly and modification of its functional groups such as carboxy, hydroxy and N-acetyl groups. Nanometer-sized HA nanomedicines can selectively deliver drugs or other molecules into tumor sites via their enhanced permeability and retention (EPR) effect. In addition, HA can interact with overexpressed receptors in cancer cells such as cluster determinant 44 (CD44) and receptor for HA-mediated motility (RHAMM) and be degraded by a family of enzymes called hyaluronidase (HAdase) to release drugs or molecules. By interaction with receptors or degradation by enzymes inside cancer cells, HA nanomedicines allow enhanced targeting cancer therapy. In this article, recent studies about HA nanomedicines in drug delivery systems, photothermal therapy, photodynamic therapy, diagnostics (because of the high biocompatibility), colloidal stability, and cancer targeting are reviewed for strategies using micelles, nanogels, and inorganic nanoparticles.

Participation of Integrinα5β1 in the Fibronectin-Mediated Adherence of EnteroaggregativeEscherichia colito Intestinal Cells

Adherence to the intestinal epithelia is a key feature in enteroaggregativeEscherichia coli(EAEC) infection. The aggregative adherence fimbriae (AAFs) are involved in EAEC interaction with receptors at the surface of intestinal cells. We and others have demonstrated that fibronectin is a receptor for AAF/II fimbriae. Considering that the major cellular receptor of fibronectin is integrinα5β1, in this study we evaluated the participation of this receptor in the fibronectin-mediated adherence of EAEC strain 042 to intestinal cells. We found that EAEC strain 042 has the ability to bind directly and indirectly to integrinα5β1; direct binding was not mediated by AAF/II fimbriae and indirect binding was mediated by AAF/II and fibronectin. Coimmunoprecipitation assays confirmed the formation of the complex AafA/fibronectin/integrinα5β1. To evaluate EAEC adherence to intestinal cells, T84 cells were incubated with fibronectin and an antibody that blocks the interaction region of integrinα5β1to fibronectin, the RGD site. Under these conditions, we found the number of adherent bacteria to epithelial cells significantly reduced. Additionally, fibronectin-mediated adherence of EAEC strain 042 was abolished in HEp-2 cells transfected with integrinα5shRNA. Altogether, our data support the involvement of integrinα5β1in the fibronectin-mediated EAEC binding to intestinal cells.

What are extreme environmental conditions and how do organisms cope with them?

Severe environmental conditions affect organisms in two major ways. The environment may be predictably severe such as in deserts, polar and alpine regions, or individuals may be exposed to temporarily extreme conditions through weather, presence of predators, lack of food, social status etc. Existence in an extreme environment may be possible, but then to breed or molt in addition can present major bottlenecks that have resulted in the evolution of hormone-behavior adaptations to cope with unpredictable events. Examples of hormone-behavior adaptations in extreme conditions include attenuated testosterone secretion because territoriality and excess courtship may be too costly when there is one opportunity to reproduce. The individual may even become insensitive to testosterone when target areas of the brain regulating reproductive behavior no longer respond to the hormone. A second example is reduced sensitivity to glucocorticoids following acute stress during the breeding season or molt that allows successful reproduction and/or a vital renewal of the integument to endure extreme conditions during the rest of the year. Reduced sensitivity could involve: (a) modulated response of the hypothalamo-pituitary-adrenal axis, (b) reduced sensitivity to high glucocorticoid levels, or (c) a combination of (a) and (b). Moreover, corticosteroid binding proteins (CBP) buffer responses to stress by reducing the movement of glucocorticoids into target cells. Finally, intracellular enzymes (11β-hydroxysteroid dehydrogenase and variants) can deactivate glucocorticoids entering cells thus reducing interaction with receptors. These mechanisms have important implications for climate change and increasing extremes of weather.