Filling the gaps in video transcoder deployment in the cloud

Cloud-based deployment of content production and broadcast workflows has continued to disrupt the industry after the pandemic. The key tools required for unlocking cloud workflows, e.g., transcoding, metadata parsing, and streaming playback, are increasingly commoditized. However, as video traffic continues to increase there is a need to consider tools which offer opportunities for further bitrate/quality gains as well as those which facilitate cloud deployment. In this paper we consider preprocessing, rate/distortion optimisation and cloud cost prediction tools which are only just emerging from the research community. These tools are posed as part of the per-clip optimisation approach to transcoding which has been adopted by large streaming media processing entities but has yet to be made more widely available for the industry.Comment: Camera-ready version of BEIT Conference at NAB 202

Szerin proteázok az immunrendszerben: szerkezet, funkció, fiziológiai jelentőség = Serine proteases of the immune system: structure, function, physiological significance

A komplement rendszer egy szerin proteázokból álló kaszkádrendszer, amely a természetes immunitás részeként fontos szerepet tölt be a fertőzések elleni védekezésben. Munkánk során tanulmányoztuk a komplement aktiválódás klasszikus és lektin útjában résztvevő szerin proteáz enzimek szerkezetét, működését és fiziológiai jelentőségét. Meghatároztuk a lektin út kulcsenzimének, a MASP-2-nek a térszerkezetét aktív és zimogén formában. Jellemeztük a két forma enzimatikus tulajdonságait is. A szerkezetekből és mérésekből kiindulva modelleztük a MASP-2 szubsztrát-indukálta autoaktiválódási mechanizmusát atomi szinten. Ugyancsak meghatároztuk a C1r, a klasszikus aktiválódási út során autoaktiválódó, szerin proteáz térszerkezetét. A térszekezet és mérési adatok alapján egy új modellt alkottunk a klasszikus út iniciációs lépésére, a C1r autokativálódására a C1 komplexen belül. NMR spektroszkópia segítségével vizsgáltuk, hogy a C1r molekula mely szegmense felelős a funkcióhoz szükséges konformációs flexibilitásért. A komplement proteázok szubsztrátspecificitásának tanulmányozása során megerősítettük, hogy a vérben található két proteolitikus kaszkádrendszer, a véralvadás és a komplement, nem függetlenek egymástól, hanem több ponton is kölcsönhatásban állnak. Sikerült meghatároznunk a korai komplement proteázok közös fiziológiás inhibitorának, a C1-inhibitornak a térszerkezetét. A térszerkezet alapján megmagyaráztuk a heparin inhibitor-moduláló hatását, valamint a betegséget (örökletes angioödéma) okozó mutációk szerkezeti hátterét. | The complement system is a proteolytic cascade system that plays an essential role in the innate immunity. We studied the structure, function and physiological relevance of the serine proteases involved in the classical and lectin activation pathways of complement. We determined the 3D structures of the zymogen and active forms MASP-2 which is the key enzyme of the lectin pathway. We also characterized the enzymatic properties of the two forms. Using the structural and experimental data we built an in silico model for the mechanism of the substrate-induced autoactivation of MASP-2. We also solved the crystal structure of Cr, which is the autoactivating protease of the classical pathway. Based on our data we built a new functional model for the initiation step of the classical pathway: the autoactivation of C1r in the C1 complex. We used NMR to study the conformational flexibility of C1r in solution. Our study concerning the substrate specificity of the complement proteases reinforced our view that the two proteolytic cascade systems that are present in the blood plasma (ie the complement and the coagulation systems) are not independent, but interact with each-other in several ways. We managed to determine the 3D structure of the C1-inhibitor, which is the common inhibitor of the early complement proteases and some other proteases in the blood. The structure revealed the background of the inhibitor function modulating effect of heparin and we could explain the structural basis of some mutation which lead to the development of the disease, hereditary angioedema

Emerging novel porcine parvoviruses in Europe: origin, evolution, phylodynamics and phylogeography

To elucidate the spatiotemporal phylodynamics, dispersion and evolutionary processes underlying the emergence of novel porcine parvovirus 2 (PPV2), PPV3 and PPV4 species, we analysed all available complete capsid genes, together with ours, obtained in Europe. Bayesian phylogeography indicates that Romania (PPV2 and PPV4) and Croatia (PPV3) are the most likely ancestral areas from which PPVs have subsequently spread to other European countries and regions. The timescale of our reconstruction supported a relatively recent history of the currently circulating novel PPV species (1920s to 1980s) in the domestic or sylvatic host. While PPV2 strains exhibited a large genetic exchange characterized by significant recombination and gene flow between distinct regions and hosts, PPV3 and PPV4 showed a diversification reflected by the accumulation of geographically structured polymorphisms. The RNA-like evolutionary rates detected inter- and intrahost recombination and the positive selection sites provided evidence that the PPV2-4 capsid gene plays a prominent role in host adaptation

Fehérjék konformációs dinamikája mint a biomolekuláris felismerés és jelátvitel meghatározó eleme = Protein conformational dynamics as a key determinant in biomolecular recognition and signal transmission

A térszerkezet alapján, a konformációs dinamika figyelembevételével kíséreltük meg az intramolekuláris és molekulák közötti jelátvitel megértését atomi felbontással. Kísérleti objektumok: a komplement rendszer, azon belül is a nemrég felfedezett lektin út fehérjekomplexei, a flagelláris exportrendszer valamint moduláris monomer, dimer és oligomer felépítésű enzimek álltak. Megállapítottuk, hogy FliI ATPáz, amely képes az exportálandó fehérjéje kitekerésére, a FliJ, FliH és FliS komponensekkel együtt képez olyan szupramolekuláris komplexet, amely képes az export szubsztrátumok felismerésére. Leírtuk a foszfoglicerát kináz enzim alloszterikus működési mechanizmusát, atomi felbontással. Feltártuk az izopropilmalát dehidrogenáz molekuláris csuklóinak működését és szerepét az alegységek kölcsönhatásaiban. Szelektív inhibitorokkal a tankönyvi tézissel ellentétes felismerésre jutottunk, miszerint a komplement rendszer lektin útjának meghatározó aktivátora a MASP-1 szerin proteáz. Így a komplement aktiválással összefüggő betegségek új gyógyszercélpont molekuláját azonosítottuk. Felfedeztük, hogy a MASP-1 képes a kininogén hasítása útján, bradikinint felszabadítva, komplement függő gyulladást keltésére. Felfedeztük, hogy a trombinhoz hasonlóan a MASP-1, PAR-4 receptoron keresztül endotél sejteket aktivál. Bizonyítékot találtunk arra, hogy a fehérjék konformációs dinamikája meghatározza a szerkezet evolúciójának lehetséges irányait, több milliárd éves időskálán is. | The CUB2 domain of C1r without calcium has disordered structure. This flexibility, necessary for autocativation of C1r inside the C1 complex, is regulated by calcium. Using MASP-selective inhibitors we proved that, in contrast to the previous textbook picture, MASP-1 is the exclusive activator of MASP-2. Blocking the proteolytic activity of MASP-1 prevents activation of the lectin pathway, therefore MASP-1 is a new target in treating complement related diseases. We solved the structure of the catalytic region of MASP-1. The structure explains the special enzymatic characteristics of this complement protease. We discovered a new, inflammation related function of the complement system: MASP-1 is able to directly activate endothelial cells through cleaving protease activated receptor-4. We discovered that MASP-1 is able to cleave kininogen and liberates bradykinin. In this way MASP-1 can contribute to the local inflammatory reaction triggered by complement activation. The allosteric mechanismnof human PGK has been explored at atomic details. In the dimeric enzyme IPMDH structural and site-directed mutagenesis studies revealed the operation of the two main molecular hinges and their relationship with the subunit interactions. We have shown that conformational motions are linked to protein evolution by producing structural variants that can be evolutionarily stabilized. This process is exemplified by segment-swapped proteins, a new group of proteins discovered by us

Single DermaVir Immunization: Dose-Dependent Expansion of Precursor/Memory T Cells against All HIV Antigens in HIV-1 Infected Individuals

BACKGROUND: The GIHU004 study was designed to evaluate the safety and immunogenicity of three doses of DermaVir immunization in HIV-infected subjects on fully suppressive combination antiretroviral therapy (cART). METHODOLOGY/PRINCIPAL FINDINGS: This first-in-human dose escalation study was conducted with three topical DermaVir doses targeted to epidermal Langerhans cells to express fifteen HIV antigens in draining lymph nodes: 0.1 mg DNA targeted to two, 0.4 mg and 0.8 mg DNA targeted to four lymph nodes. Particularly, in the medium dose cohort 0.1 mg DNA was targeted per draining lymph node via ∼8 million Langerhans cells located in 80 cm(2) epidermis area. The 28-days study with 48-week safety follow-up evaluated HIV-specific T cell responses against Gag p17, Gag p24 and Gag p15, Tat and Rev antigens. DermaVir-associated side effects were mild, transient and not dose-dependent. Boosting of HIV-specific effector CD4(+) and CD8(+) T cells expressing IFN-gamma and IL-2 was detected against several antigens in every subject of the medium dose cohort. The striking result was the dose-dependent expansion of HIV-specific precursor/memory T cells with high proliferation capacity. In low, medium and high dose cohorts this HIV-specific T cell population increased by 325-, 136,202 and 50,759 counts after 4 weeks, and by 3,899, 9,878 and 18,382 counts after one year, respectively, compared to baseline. CONCLUSIONS/SIGNIFICANCE: Single immunization with the DermaVir candidate therapeutic vaccine was safe and immunogenic in HIV-infected individuals. Based on the potent induction of Gag, Tat and Rev-specific memory T cells, especially in the medium dose cohort, we speculate that DermaVir boost T cell responses specific to all the 15 HIV antigens expressed from the single DNA. For durable immune reactivity repeated DermaVir immunization might be required since the frequency of DermaVir-boosted HIV-specific memory T cells decreased during the 48-week follow up. TRIAL REGISTRATION: ClinicalTrial.gov NCT00712530

Analysis of Tp53 Codon 72 Polymorphisms, Tp53 Mutations, and HPV Infection in Cutaneous Squamous Cell Carcinomas

Non-melanoma skin cancers are one of the most common human malignancies accounting for 2-3% of tumors in the US and represent a significant health burden. Epidemiology studies have implicated Tp53 mutations triggered by UV exposure, and human papilloma virus (HPV) infection to be significant causes of non-melanoma skin cancer. However, the relationship between Tp53 and cutaneous HPV infection is not well understood in skin cancers. In this study we assessed the association of HPV infection and Tp53 polymorphisms and mutations in lesional specimens with squamous cell carcinomas.We studied 55 cases of histologically confirmed cutaneous squamous cell carcinoma and 41 controls for the presence of HPV infection and Tp53 genotype (mutations and polymorphism).We found an increased number of Tp53 mutations in the squamous cell carcinoma samples compared with perilesional or control samples. There was increased frequency of homozygous Tp53-72R polymorphism in cases with squamous cell carcinomas, while the Tp53-72P allele (Tp53-72R/P and Tp53-72P/P) was more frequent in normal control samples. Carcinoma samples positive for HPV showed a decreased frequency of Tp53 mutations compared to those without HPV infection. In addition, carcinoma samples with a Tp53-72P allele showed an increased incidence of Tp53 mutations in comparison carcinomas samples homozygous for Tp53-72R.These studies suggest there are two separate pathways (HPV infection and Tp53 mutation) leading to cutaneous squamous cell carcinomas stratified by the Tp53 codon-72 polymorphism. The presence of a Tp53-72P allele is protective against cutaneous squamous cell carcinoma, and carcinoma specimens with Tp53-72P are more likely to have Tp53 mutations. In contrast Tp53-72R is a significant risk factor for cutaneous squamous cell carcinoma and is frequently associated with HPV infection instead of Tp53 mutations. Heterozygosity for Tp53-72R/P is protective against squamous cell carcinomas, possibly reflecting a requirement for both HPV infection and Tp53 mutations