The genomes of nucleocytoplasmic large DNA viruses: viral evolution writ large

The nucleocytoplasmic large DNA viruses (NCLDVs) are a diverse group that currently contain the largest known virions and genomes, also called giant viruses. The first giant virus was isolated and described nearly 20 years ago. Their genome sizes were larger than for any other known virus at the time and it contained a number of genes that had not been previously described in any virus. The origin and evolution of these unusually complex viruses has been puzzling, and various mechanisms have been put forward to explain how some NCLDVs could have reached genome sizes and coding capacity overlapping with those of cellular microbes. Here we critically discuss the evidence and arguments on this topic. We have also updated and systematically reanalysed protein families of the NCLDVs to further study their origin and evolution. Our analyses further highlight the small number of widely shared genes and extreme genomic plasticity among NCLDVs that are shaped via combinations of gene duplications, deletions, lateral gene transfers and de novo creation of protein-coding genes. The dramatic expansions of the genome size and protein-coding gene capacity characteristic of some NCLDVs is now increasingly understood to be driven by environmental factors rather than reflecting relationships to an ancient common ancestor among a hypothetical cellular lineage. Thus, the evolution of NCLDVs is writ large viral, and their origin, like all other viral lineages, remains unknown.

The thymic microenvironment gradually modulates the phenotype of thymus-homing peripheral conventional dendritic cells

Thymic conventional dendritic cells (t-DCs) are crucial for the development of T cells. A substantial fraction of t-DCs originates extrathymically and migrates to the thymus. Here, these cells contribute to key processes of central tolerance like the clonal deletion of self-reactive thymocytes and the generation of regulatory T (Treg) cells. So far, it is only incompletely understood which impact the thymic microenvironment has on thymus-homing conventional DCs (cDCs), which phenotypic changes occur after the entry of peripheral cDCs into the thymus and which functional properties these modulated cells acquire. In the present study, we mimicked the thymus-homing of peripheral cDCs by introducing ex vivo isolated splenic cDCs (sp-DCs) into re-aggregated thymic organ cultures (RTOCs). Already after two days of culture, the transcriptomic profile of sp-DCs was modulated and had acquired certain key signatures of t-DCs. The regulated genes included immunomodulatory cytokines and chemokines as well as co-stimulatory molecules. After four days of culture, sp-DCs appeared to have at least partially acquired the peculiar Treg cell-inducing capacity characteristic of t-DCs. Taken together, our findings indicate that peripheral cDCs possess a high degree of plasticity enabling them to quickly adapt to the thymus-specific microenvironment. We further provide indirect evidence that thymus-specific properties such as the efficient induction of Treg cells under homeostatic conditions can be partially transferred to thymus-homing peripheral cDC subsets.

NAD+ enhances ribitol and ribose rescue of α-dystroglycan functional glycosylation in human FKRP-mutant myotubes

Mutations in the fukutin-related protein (FKRP) cause Walker-Warburg Syndrome (WWS), a severe form of congenital muscular dystrophy. Here we established a WWS human induced pluripotent stem cell-derived myogenic model that recapitulates hallmarks of WWS pathology. We used this model to investigate the therapeutic effect of metabolites of the pentose phosphate pathway in human WWS. We show that functional recovery of WWS myotubes is promoted not only by ribitol but also its precursor ribose. Moreover, we found that the combination of each of these metabolites with NAD+ results in a synergistic effect, as demonstrated by rescue of α-dystroglycan glycosylation and laminin binding capacity. Mechanistically, we find that FKRP residual enzymatic capacity, characteristic of many recessive FKRP mutations, is required for rescue as supported by functional and structural mutational analysis. These findings provide the rationale for testing ribose/ribitol in combination with NAD+ to treat WWS and other diseases associated with FKRP mutations.

IMMU-37. DIRECT REPROGRAMMING OF GLIOBLASTOMA TO ANTIGEN PRESENTING-LIKE CELLS BY MASTER REGULATORS PREDICTED FROM AN ARTIFICIAL INTELLIGENCE PLATFORM

Glioblastoma (GBM) is the most common and lethal malignant brain cancer in adults. Immunotherapy has emerged as a potentially powerful approach to achieve long-term survival in patients with GBM. Antigen presenting cells (APCs) play a central role in priming cancer-specific immune responses due to their ability to sample and present tumor neoantigens to the immune system. We hypothesis that antigen presenting cells could be induced by transdifferentiated from GBM in-situ so that these locally created APC will find themselves pre-planted in the tumor microenvironment (TME) with full access to tumor neoantigens. Top ten ranked candidate fate determinants for the GBM-DC transdifferentiation were predicted by NETZEN, an integrated deep-learning and gene network-based ranking artificial intelligence (AI) platform for precision medicine. We successfully transdifferentiated the murine GBM cell line GL261 into CD45+ immune cells accompanying morphological changes to less adhering cells by a combination of four factors (PU.1, IRF8, BATF3, ID2). Of these induced CD45 positive cells, a significant fraction also expresses high levels of the myeloid marker CD11b and antigen presenting molecules MHCII and MHCI by flow cytometry, suggesting these induced CD45+ cells are myeloid lineage APCs (iAPC).These iAPC exhibit phagocytic property, tested by incubating pHrodo Red bioparticles conjugated with Zymosan, an antigen found on the surface of fungi. More importantly, these induced iAPC appear to have lost their proliferative capacity characteristic of the parental GBM cells. Total live cell numbers were significantly reduced in 4F-induced culture compared to the EV control. In conclusion, we successfully transdifferentiated mouse GBM cells into APC-like cells based on NETZEN prediction and our work can potentially provide a novel therapeutic approach for developing an in-situ APC vaccine immunotherapy for GBM, and for other cancers.

Neurocomputational mechanisms underlying emotional awareness: insights afforded by deep active inference and their potential clinical relevance

Emotional awareness (EA) is recognized as clinically relevant to the vulnerability to, and maintenance of, psychiatric disorders. However, the neurocomputational processes that underwrite individual variations remain unclear. In this paper, we describe a deep (active) inference model that reproduces the cognitive-emotional processes and self-report behaviors associated with EA. We then present simulations to illustrate (seven) distinct mechanisms that (either alone or in combination) can produce phenomena – such as somatic misattribution, coarse-grained emotion conceptualization, and constrained reflective capacity – characteristic of low EA. Our simulations suggest that the clinical phenotype of impoverished EA can be reproduced by dissociable computational processes. The possibility that different processes are at work in different individuals suggests that they may benefit from distinct clinical interventions. As active inference makes particular predictions about the underlying neurobiology of such aberrant inference, we also discuss how this type of modelling could be used to design neuroimaging tasks to test predictions and identify which processes operate in different individuals – and provide a principled basis for personalized precision medicine.

Informational-theoretical approach to the evaluation of supercomputers

Предложен теоретико-информационный подход к оценке производительности суперкомпьютеров. Этот подход основан на характеристике “вычислительная способность”, которую можно определить теоретически, опираясь исключительно на описание архитектуры исследуемой системы. Предложен метод определения вычислительной способности суперкомпьютеров с учетом влияния межпроцессорного взаимодействия. Метод применяется в работе для оценки производительности пяти суперкомпьютеров среди первых 50 позиций в списке TOP500 (ноябрь 2016). Полученные результаты сравниваются с аналогичными значениями бенчмарка LINPACK и характеристиками Theoretical peak, используемыми для формирования рейтинга TOP500. По результатам сравнения делаются выводы относительно применимости указанного подхода для оценки производительности суперкомпьютеров на этапе разработки. In this paper we present the informational-theoretical approach to the evaluation of performance for supercomputers. This approach is based on the computer capacity characteristic which can be estimated theoretically (without any experiments over the working model of the investigated computer) relying on the description of the architecture of the system under study. We describe the method for estimation of the supercomputers Computer capacity which takes into account the influence of the interprocess communication. The described method is used in this paper to estimate the performance of the five supercomputers among the first fifty positions in TOP500 list (according to November 2016 data). The obtained results are compared with the values of LINPACK benchmark and Theoretical peak characteristic which are used to form the TOP500 rating. Based on the comparison we draw conclusions about the applicability of the presented approach to the evaluation of supercomputers performance at the design stage.

Bearing capacity characteristic of subgrade layer quicklime treated laterite soil

This study aimed to analyze bearing capacity characteristics of laterite soil with quicklime stabilization as road subgrade layer. The laterite soil obtained from three different locations with three different ferrous (FeO) content. Soil samples were conduct by mixing laterite soil with 3%, 5%, 7%, and 10% lime content on Proctor initial condition, then cured for 3, 14, and 28 days before tested for soil bearing capacity using CBR laboratory test. Result showed that the lime treated laterite soil increases the bearing capacity for all types of laterite soil significantly in line with incrasing of lime content on 28 days curing time (11,67% to 51,67%, 14% to 53,33%, and 14,17% to 71,67%, respectively for LH1, LH2 and LH3). The increasing of soil bearing capacity due to pozzolanic strength gain. Based on these results, the laterite soil has potentially to be used as road subgrade layer.

Microgravity Simulator Based on Air Levitation for Astronauts EVA Operation Training

Because of the microgravity environment of the space and mobility restriction by pressurized spacesuit, astronaut extravehicular operation is quite different from that in the ground. For ensuring high reliability of extravehicular operations, the astronauts need to do a great deal of training in simulated environments. A 3-dof of micro-gravity operation training system is designed in the paper, and the kinematics and dynamics of the interaction between the space station system and spacesuit system were simulated. Pressure and flow velocity distributions in the air orifice and air cavity were calculated by FLUENT. Experiments on the bearing capacity characteristic were carried out. The carrying capacities of the air bearing in different air pressures were achieved. Experiments validated the simulation analysis. The research provides the basis for the development of multi-degree of freedom space microgravity ground simulation technology, provides a basis for further development and application of flotation technology as well.