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The Schwab Foundation for Social Entrepreneurship provides unparalleled platforms at the regional and global level to highlight and advance leading models of sustainable social innovation. It identifies a select community of social entrepreneurs and engages it in shaping global, regional and industry agendas that improve the state of the world in close collaboration with the other stakeholders of the World Economic Forum.

The pathogenesis of C. diphtheriae involves various steps that lead to invasion of host cells, inhibition of protein synthesis, and ultimately cell death. If the bacteria are able to successfully invade and colonize the host, then diphtheria toxin will be released resulting in illness.

The exact mechanism of adherence by the pili is not known, but many studies have been conducted to formulate a reasonable proposal. It has been discovered that the two minor pili, SpaB and SpaC, are not only found in the pilus, but are also arranged on the bacterial cell wall in monomeric and heterodimeric forms. The binding of SpA- to pharyngeal epithelial cells can be attributed to these two pili. Since these adhesins are found in two forms, as a fiber and intricate proteins on the cell surface, they can mediate both distant and nearby contacts during the initial adherence of the pathogen and its succeeding colonization Adam Lippes tweed mini wrap skirt Discount Cost The Cheapest Cheap Sale Pictures Pay With Visa Outlet Best Seller E7bGVc
. If either minor pili is absent, then adherence to the host cells is greatly diminished. Little is known about the steps that the SpaD- and SpaH- pili take to adhere to the lung and laryngeal epithelial cells, but it is still postulated that they play an imperative role in the process [8] .

When C. diphtheriae enters the body and adheres to a surface, it will begin to secrete DT. However, there are certain conditions that influence the production of this toxin. For example, the extracellular iron levels in the tissues of the respiratory tract determine when and to what extent DT is released. When levels become very low or are depleted, the bacteria will produce its maximal amounts. This is because iron acts as a corepressor, and will repress the toxin gene when it is present in the extracellular space [1] . Also, DT will only be produced when it is lysogenized by a specific beta phage. This is because the phage contains a necessary regulatory gene for the structure of the toxin molecule, and the tox genes are found on the phage chromosome instead of the bacterial chromosome. Therefore, both a beta phage and low extracellular iron levels are important for the release of DT [1] .

DT is initially released as a proenzyme, but is then cleaved by bacterial proteases into two fragments, A and B. Fragment A is catalytically active and is the main source of toxicity, while fragment B is rather unstable and has no enzymatic function. Both fragments are used in different ways to allow for entry of DT into the host cell. First, DT will bind to the extracellular epidermal growth factor, which causes a hydrophobic portion of fragment B to form a channel across the host cell membrane allowing fragment A to pass through and reach the cytoplasm Meme flared trousers Free Shipping Latest Collections OOy0kJ
. Fragment A then acts as a catalyst to inactivate elongation factor-2 (EF-2), which is necessary for the translation process. A covalent bond is formed between the toxin and EF-2, which disables interaction with RNA during translation, thus, all protein synthesis is halted in that ribosome Golden Goose Deluxe Brand palazzo trousers Outlet Pay With Visa dW9q0kg5T
.

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Figure 1.

Progressive engagement of innate immune defenses in an ascending infection. Bacteria enter the urinary tract and ascend against the flow of urine. (1) The microbes initially face an array of constitutively expressed antimicrobial proteins and peptides. (2) As surviving microbes ascend, they stimulate the expression of inducible AMPs such as HBD2 and cathelicidin. (3) Secretion of active AMPs occurs within minutes of microbial exposure, both rapidly killing the threatening bacteria that have adhered as well as attracting nearby phagocytes. (4) Advancing microbes attach to the epithelium and stimulate TLR4-dependent and -independent circuits, leading to the secretion of IL-8 and lipocalin. (5) Microbes now face a barrage of neutrophils, which control the advancing infection through phagocytosis and by their secretion of intracellular AMPs and proteins. (6) When the prior defenses have been overwhelmed, continued neutrophil invasion results in extensive tissue destruction.

If microbial organisms succeed in breaching these early defenses, uroepithelia may be susceptible to attachment and damage. Through TLR-mediated pathways (and receptors still uncharacterized), bacterial attachment, propagation, and invasion, as well as cellular injury, stimulates the production and secretion of cytokines such as IL-8 and antimicrobial proteins such as lipocalin. The presence of IL-8 will lead to the rapid recruitment of more neutrophils, providing both anti-infective relief as well as local epithelial damage. Lipocalin, induced by cellular injury, provides antimicrobial defense through sequestration of microbial siderophores. Should these layers of defense fail, the neutrophil influx grows increasingly more aggressive and results in destruction of the normal microanatomy. If this cellular response is overwhelmed systemic infection ensues.

Enhancing Expression of Endogenous AMPs to Protect against Urinary Tract Infections: Might It Be Possible?

How might we use this information to protect the health of our patients? Perhaps one of the most intriguing possibilities is that we could prevent or treat infections by pharmacologically inducing AMPs. Recent studies demonstrate that expression of AMP genes in various epithelial cells can be induced by a variety of nutrients and vitamins. For example, cathelicidin can be induced by vitamin D and short-chain fatty acids. In the distal colon, fecal bacteria convert complex carbohydrates into short chain fatty acids; these fatty acids are used as a source of energy by the enterocytes. Perhaps it is not surprising that these microbially engendered substances also stimulate expression of cathelicidin by colonocytes. In human dysentery, cathelicidin expression in the rectosigmoid colon is dramatically depressed during the active stage of the disease, but it recovers as the infection clears. Treatment with oral sodium butyrate during early phases of an experimental infection results in the induction of colonic expression of cathelicidin, reduction in the numbers of fecal , and accelerated recovery.

The expression of the gene encoding human cathelicidin is vitamin D–dependent and has a vitamin D receptor site. This is not the case for mice and other fur-covered mammals, where expression of cathelicidin is independent of vitamin D regulation. Through a series of steps, cholecalciferol is hydroxylated at positions 25 and 1 to become fully active. While the liver converts cholecalciferol generated in the skin to calcidiol, the final hydroxylation takes place within specific cells through the enzymatic action of 1-α-hydroxylase (CYP27B1). In both keratinocytes and macrophages, microbes cause the induction of CYP27B1 and the vitamin D receptor by stimulating TLR2 receptors. The local synthesis of calcitriol, in turn, leads to induction of vitamin D–dependent genes, including cathelicidin.

In the case of the human macrophage, the vitamin D–dependent synthesis of cathelicidin is required for optimal killing of ingested . The plasma concentrations of calcidiol from dark-skinned people who live in the Northern Hemisphere appear to be below that required to support maximal microbe-stimulated calcitriol/cathelicidin synthesis; the possibility that the high prevalence of tuberculosis in some human populations might be attributable to inadequate levels of vitamin D has been suggested. Clinical studies suggest that vitamin D supplementation can have significant benefit in the treatment of tuberculosis in individuals with suboptimal plasma concentrations of calcidiol.

Vitamin D is known to exert suppressive effects on the inflammatory arm of the adaptive immune response. Indeed, vitamin D attenuates the production of the proinflammatory cytokines IFN-γ and TNFα in macrophages exposed to ; at the same time it stimulates their production of cathelicidin. In a sense, calcitriol can be thought of as activating the AMP arm of innate immunity while suppressing the proinflammatory arm of adaptive immunity. In an organ like the kidney, where inflammation can result in irreversible damage, a noninflammatory antimicrobial defense seems prudent.

The 1-α-hydroxylation of calcidiol in the proximal tubule is required for calcium metabolism and bone health. However, 1-α-hydroxylase is present in other sites within the kidney, such as the distal tubules and collecting ducts. Perhaps most curious is the observation that 1-α-hydroxylase is induced by LPS in the distal nephron, as studied in cell culture. This leads to the possibility that, as in other settings, calcitriol might be utilized to regulate innate immune defenses in the kidney. Because it appears that vitamin D–deficient humans have lower innate immune function, might an association exist between the prevalence of urinary tract infections or asymptomatic bacteriuria and vitamin D stores? Asymptomatic bacteriuria is said to occur in 2% to 10% of pregnant women and in up to 20% of women 80 years of age or older; might this condition be linked to vitamin D deficiency, which has recently been reported to be widespread in both pregnant women and the elderly? Might it be possible to treat certain forms of urinary tract infection with vitamin D supplementation rather than conventional antibiotics? Should we be concerned about compromising defenses of the urinary tract when treating patients with the antifungal itraconazole, ketoconazole, or the HIV-protease inhibitor ritonavir, drugs that are known to pharmacologically inhibit 1-α-hydroxylase? I suspect that as our understanding of the innate antimicrobial mechanisms operating in the kidney becomes more complete, new insights into the treatment and management of urinary tract infections will enter clinical practice.

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I wish to acknowledge the many discussions relating to the role of AMPs in the health of the urinary tract with my Scandinavian colleagues, Annelie Brauner, Brigitta Agerberth, Gudmundur Gudmundsson, and Catharina Svanborg, who shared their valuable insights over the years. I also wish to acknowledge Dr. Aaron Nelson for his very insightful thoughts on the biologic importance of lipocalin in innate immune defense.

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The development and refinement of high-speed live-cell imaging techniques has fuelled the investigation of the dynamics of synapse formation and CTL-mediated killing. Over the course of the past 10 years, the order and timing of some key steps in the attack have been unravelled, although some of the details vary somewhat depending on the technique and cell system used.

In vitro , when placed on a glass surface, CTLs migrate with a lamellipodium at the front and a uropod at the rear (see poster). As soon as a target cell is recognised, CTLs stop migrating and accumulate F-actin at the contact site. This is followed by a reduction in F-actin at the centre of the contact site within one minute after initial contact ( Ritter et al., 2015 ). As a consequence, an F-actin ring appears at the edge of the interface, known as the dSMAC. At the same time, TCR microclusters gather at the centre of the interface to form the cSMAC.

During CTL migration, the centrosome (MTOC) is located away from the leading edge, behind the nucleus, in the uropod. When a target encounter triggers TCR signalling, the centrosome starts moving towards the immune synapse ( Kuhn and Poenie, 2002 ). It is thought that ‘pioneer’ microtubules link the centrosome to the synapse interface, and their shortening and the motor protein dynein act together to reel the centrosome to the synapse ( Combs et al., 2006 ; Philosophy Di Lorenzo Serafini Ruffle dress with pearl embellished ribbons Cheap Sale Fake Explore Cheap Online gawbdotY5N
). The centrosome finally docks at the plasma membrane next to the cSMAC, in a region where F-actin is depleted. It takes about six minutes from the cell–cell contact to centrosome docking at the synapse ( Ritter et al., 2015 ) (see poster).

As cytolytic granules cluster around the centrosome, they move together with the centrosome towards the synapse where they release perforin and granzymes into the space between the CTL and the target ( Ritter et al., 2015 ). Following the release of granule contents, perforin facilitates transport of granzymes into the target, which trigger rapid target cell death. Finally, the CTL detaches from the dying target cell and moves on to find the next target. A new lamellipodium is formed distant from the immune synapse. The centrosome detaches from the synapse membrane and a new uropod is formed as the CTL moves away ( Ritter et al., 2015 ). Intriguingly, the signal to detach appears to be dependent upon the demise of the target cell through caspase activity ( Jenkins et al., 2015 ).

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Precise targeting of cytolytic granules towards exocytic sites opposite the target is mediated by an unusual mechanism that involves centrosome positioning to the immune synapse membrane. On CTL activation, the centrosome moves from the back of the cell around the nucleus and docks with the plasma membrane within the immune synapse, at the boundary between the cSMAC and secretory domain ( Ritter et al., 2015 ; Stinchcombe et al., 2006 ; Yi et al., 2013 ).

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