Validation of the immersed boundary surface method in computational fluid dynamics

Cilj ovog rada je predstaviti teorijsku i praktičnu pozadinu metode uronjene granice implementirane u foam-extend 4.1, odnosno njene prednosti i nedostatke. Glavni cilj metode uronjene granice je pojednostavljenje izrade mreža u računalnoj dinamici fluida, što može dovesti do značajnog smanjenja količine ljudskog rada koji se mora uložiti pri pripremanju simulacija u računalnoj dinamici fluida, pogotovo kod simulacija sa složenim geometrijama. Također, metoda uronjene granice može donijeti određene prednosti kod simulacija s pomičnim mrežama, u vidu smanjenja računalne zahtjevnosti takvih simulacija. Glavni nedostatak metode uronjene granice je smanjenje točnosti rješenja na uronjenim granicama (površinama simuliranih objekata). Metoda uronjene granice implementirana u foam-extend 4.1 je ovdje validirana na trima slučajevima: unutarnje strujanje u 2-D slučaju u cijevi sa naglim proširenjem, vanjsko strujanje oko Onera M6 krila i strujanje u Francisovoj turbini, što je pogotovo zanimljiv slučaj za metodu uronjene granice. Rezultati simulacija izvedenih uporabom metodom uronjene granice su uspoređeni sa rezultatima simulacija izvedenim konvencionalnim načinom izrade mreže. Rezultati simulacija su zadovoljavajući, odnosno, smanjenje točnosti rješenja na uronjenim granicama je dovoljno maleno da implementaciju metode uronjene granice u foam-extend 4.1 možemo ocjeniti kao dobru.The aim of this thesis is to describe the Immersed Boundary Method version implemented in foam-extend 4.1, both its advantages and shortcomings. The main goal of the Immersed Boundary Method is to simplify the mesh generation process in Computational Fluid Dynamics, which can lead to drastic reductions of human time needed for setting up simulations, especially for simulations with complex geometries. Additionally, it can offer certain advantages in simulations with moving meshes, as it can decrease the computational requirements of such cases. The main shortcoming of the Immersed Boundary Method is loss of solution accuracy on immersed boundaries (surfaces of simulated objects). The foam-extend 4.1 Immersed Boundary Method is here validated on three cases: internal 2-D flow over a backward facing step, external flow around the Onera M6 wing, and the flow in a model Francis turbine, which is an especially interesting case, concerning the Immersed Boundary Method. The results of the Immersed Boundary Method simulations are compared to the results of equivalent body-fitted (conventional) simulations. The simulation results are generally satisfactory, as the loss of accuracy was modest enough to assess the foam-extend 4.1 implementation of the Immersed Boundary Method as successful

Brzo povećanje snage termoenergetskog bloka

U današnjim uvjetima energetske tranzicije, odnosno povećanja udjela obnovljivih izvora energije u proizvodnji električne energije, traže se rješenja koja će postojeće proizvodne kapacitete učiniti fleksibilnijima. Oni moraju omogućiti potporu energetskoj tranziciji prema obnovljivim izvorima energije, odnosno amortizirati problem intermitencije obnovljivih izvora. U radu je stavljen fokus na termoelektrane s parnoturbinskim ciklusom, dan je pregled načina brze promjene njihove snage te je analizirana potencijalna primjena metode ''kondenzat stop'' na primjeru postrojenja nominalne snage 210 MW

Validacija metode uronjene granične površine u numeričkoj mehanici fluida

Cilj ovog rada je predstaviti teorijsku i praktičnu pozadinu metode uronjene granice implementirane u foam-extend 4.1, odnosno njene prednosti i nedostatke. Glavni cilj metode uronjene granice je pojednostavljenje izrade mreža u računalnoj dinamici fluida, što može dovesti do značajnog smanjenja količine ljudskog rada koji se mora uložiti pri pripremanju simulacija u računalnoj dinamici fluida, pogotovo kod simulacija sa složenim geometrijama. Također, metoda uronjene granice može donijeti određene prednosti kod simulacija s pomičnim mrežama, u vidu smanjenja računalne zahtjevnosti takvih simulacija. Glavni nedostatak metode uronjene granice je smanjenje točnosti rješenja na uronjenim granicama (površinama simuliranih objekata). Metoda uronjene granice implementirana u foam-extend 4.1 je ovdje validirana na trima slučajevima: unutarnje strujanje u 2-D slučaju u cijevi sa naglim proširenjem, vanjsko strujanje oko Onera M6 krila i strujanje u Francisovoj turbini, što je pogotovo zanimljiv slučaj za metodu uronjene granice. Rezultati simulacija izvedenih uporabom metodom uronjene granice su uspoređeni sa rezultatima simulacija izvedenim konvencionalnim načinom izrade mreže. Rezultati simulacija su zadovoljavajući, odnosno, smanjenje točnosti rješenja na uronjenim granicama je dovoljno maleno da implementaciju metode uronjene granice u foam-extend 4.1 možemo ocjeniti kao dobru

Structures of monomeric and oligomeric forms of the Toxoplasma gondiiperforin-like protein 1

Toxoplasma and Plasmodium are the parasitic agents of toxoplasmosis and malaria, respectively, and use perforin-like proteins (PLPs) to invade host organisms and complete their life cycles. The Toxoplasma gondii PLP1 (TgPLP1) is required for efficient exit from parasitophorous vacuoles in which proliferation occurs. We report structures of the membrane attack complex/perforin (MACPF) and Apicomplexan PLP C-terminal β-pleated sheet (APCβ) domains of TgPLP1. The MACPF domain forms hexameric assemblies, with ring and helix geometries, and the APCβ domain has a novel β-prism fold joined to the MACPF domain by a short linker. Molecular dynamics simulations suggest that the helical MACPF oligomer preserves a biologically important interface, whereas the APCβ domain binds preferentially through a hydrophobic loop to membrane phosphatidylethanolamine, enhanced by the additional presence of inositol phosphate lipids. This mode of membrane binding is supported by site-directed mutagenesis data from a liposome-based assay. Together, these structural and biophysical findings provide insights into the molecular mechanism of membrane targeting by TgPLP1

Structure and mechanism of bactericidal mammalian perforin-2, an ancient agent of innate immunity

Perforin-2 (MPEG1) is thought to enable the killing of invading microbes engulfed by macrophages and other phagocytes, forming pores in their membranes. Loss of perforin-2 renders individual phagocytes and whole organisms significantly more susceptible to bacterial pathogens. Here, we reveal the mechanism of perforin-2 activation and activity using atomic structures of pre-pore and pore assemblies, high-speed atomic force microscopy, and functional assays. Perforin-2 forms a pre-pore assembly in which its pore-forming domain points in the opposite direction to its membrane-targeting domain. Acidification then triggers pore formation, via a 180° conformational change. This novel and unexpected mechanism prevents premature bactericidal attack and may have played a key role in the evolution of all perforin family proteins

Emerging glyco-based strategies to steer immune responses

Glycan structures are common posttranslational modifications of proteins, which serve multiple important structural roles (for instance in protein folding), but also are crucial participants in cell-cell communications and in the regulation of immune responses. Through the interaction with glycan-binding receptors, glycans are able to affect the activation status of antigen-presenting cells, leading either to induction of pro-inflammatory responses or to suppression of immunity and instigation of immune tolerance. This unique feature of glycans has attracted the interest and spurred collaborations of glyco-chemists and glyco-immunologists to develop glycan-based tools as potential therapeutic approaches in the fight against diseases such as cancer and autoimmune conditions. In this review, we highlight emerging advances in this field, and in particular, we discuss on how glycan-modified conjugates or glycoengineered cells can be employed as targeting devices to direct tumor antigens to lectin receptors on antigen-presenting cells, like dendritic cells. In addition, we address how glycan-based nanoparticles can act as delivery platforms to enhance immune responses. Finally, we discuss some of the latest developments in glycan-based therapies, including chimeric antigen receptor (CAR)-T cells to achieve targeting of tumor-associated glycan-specific epitopes, as well as the use of glycan moieties to suppress ongoing immune responses, especially in the context of autoimmunity

Perforin Rapidly Induces Plasma Membrane Phospholipid Flip-Flop

The cytotoxic cell granule secretory pathway is essential for host defense. This pathway is fundamentally a form of intracellular protein delivery where granule proteases (granzymes) from cytotoxic lymphocytes are thought to diffuse through barrel stave pores generated in the plasma membrane of the target cell by the pore forming protein perforin (PFN) and mediate apoptotic as well as additional biological effects. While recent electron microscopy and structural analyses indicate that recombinant PFN oligomerizes to form pores containing 20 monomers (20 nm) when applied to liposomal membranes, these pores are not observed by propidium iodide uptake in target cells. Instead, concentrations of human PFN that encourage granzyme-mediated apoptosis are associated with pore structures that unexpectedly favor phosphatidylserine flip-flop measured by Annexin-V and Lactadherin. Efforts that reduce PFN mediated Ca influx in targets did not reduce Annexin-V reactivity. Antigen specific mouse CD8 cells initiate a similar rapid flip-flop in target cells. A lipid that augments plasma membrane curvature as well as cholesterol depletion in target cells enhance flip-flop. Annexin-V staining highly correlated with apoptosis after Granzyme B (GzmB) treatment. We propose the structures that PFN oligomers form in the membrane bilayer may include arcs previously observed by electron microscopy and that these unusual structures represent an incomplete mixture of plasma membrane lipid and PFN oligomers that may act as a flexible gateway for GzmB to translocate across the bilayer to the cytosolic leaflet of target cells

Recent advances on smart glycoconjugate vaccines in infections and cancer

Vaccination is one of the greatest achievements in biomedical research preventing death and morbidity in many infectious diseases through the induction of pathogen-specific humoral and cellular immune responses. Currently, no effective vaccines are available for pathogens with a highly variable antigenic load, such as the human immunodeficiency virus or to induce cellular T-cell immunity in the fight against cancer. The recent SARS-CoV-2 outbreak has reinforced the relevance of designing smart therapeutic vaccine modalities to ensure public health. Indeed, academic and private companies have ongoing joint efforts to develop novel vaccine prototypes for this virus. Many pathogens are covered by a dense glycan-coat, which form an attractive target for vaccine development. Moreover, many tumor types are characterized by altered glycosylation profiles that are known as “tumor-associated carbohydrate antigens”. Unfortunately, glycans do not provoke a vigorous immune response and generally serve as T-cell-independent antigens, not eliciting protective immunoglobulin G responses nor inducing immunological memory. A close and continuous crosstalk between glycochemists and glycoimmunologists is essential for the successful development of efficient immune modulators. It is clear that this is a key point for the discovery of novel approaches, which could significantly improve our understanding of the immune system. In this review, we discuss the latest advancements in development of vaccines against glycan epitopes to gain selective immune responses and to provide an overview on the role of different immunogenic constructs in improving glycovaccine efficacy