Predicting the F(ab)-mediated effect of monoclonal antibodies in vivo by combining cell-level kinetic and pharmacokinetic modelling

Cell-level kinetic models for therapeutically relevant processes increasingly benefit the early stages of drug development. Later stages of the drug development processes, however, rely on pharmacokinetic compartment models while cell-level dynamics are typically neglected. We here present a systematic approach to integrate cell-level kinetic models and pharmacokinetic compartment models. Incorporating target dynamics into pharmacokinetic models is especially useful for the development of therapeutic antibodies because their effect and pharmacokinetics are inherently interdependent. The approach is illustrated by analysing the F(ab)-mediated inhibitory effect of therapeutic antibodies targeting the epidermal growth factor receptor. We build a multi-level model for anti-EGFR antibodies by combining a systems biology model with in vitro determined parameters and a pharmacokinetic model based on in vivo pharmacokinetic data. Using this model, we investigated in silico the impact of biochemical properties of anti-EGFR antibodies on their F(ab)-mediated inhibitory effect. The multi-level model suggests that the F(ab)-mediated inhibitory effect saturates with increasing drug-receptor affinity, thereby limiting the impact of increasing antibody affinity on improving the effect. This indicates that observed differences in the therapeutic effects of high affinity antibodies in the market and in clinical development may result mainly from Fc-mediated indirect mechanisms such as antibody-dependent cell cytotoxicity

PINK1 Defect Causes Mitochondrial Dysfunction, Proteasomal Deficit and α-Synuclein Aggregation in Cell Culture Models of Parkinson's Disease

Mutations in PTEN induced kinase 1 (PINK1), a mitochondrial Ser/Thr kinase, cause an autosomal recessive form of Parkinson's disease (PD), PARK6. Here, we report that PINK1 exists as a dimer in mitochondrial protein complexes that co-migrate with respiratory chain complexes in sucrose gradients. PARK6 related mutations do not affect this dimerization and its associated complexes. Using in vitro cell culture systems, we found that mutant PINK1 or PINK1 knock-down caused deficits in mitochondrial respiration and ATP synthesis. Furthermore, proteasome function is impaired with a loss of PINK1. Importantly, these deficits are accompanied by increased α-synclein aggregation. Our results indicate that it will be important to delineate the relationship between mitochondrial functional deficits, proteasome dysfunction and α-synclein aggregation

The Passive Yet Successful Way of Planktonic Life: Genomic and Experimental Analysis of the Ecology of a Free-Living Polynucleobacter Population

Background: The bacterial taxon Polynucleobacter necessarius subspecies asymbioticus represents a group of planktonic freshwater bacteria with cosmopolitan and ubiquitous distribution in standing freshwater habitats. These bacteria comprise,1 % to 70 % (on average about 20%) of total bacterioplankton cells in various freshwater habitats. The ubiquity of this taxon was recently explained by intra-taxon ecological diversification, i.e. specialization of lineages to specific environmental conditions; however, details on specific adaptations are not known. Here we investigated by means of genomic and experimental analyses the ecological adaptation of a persistent population dwelling in a small acidic pond. Findings: The investigated population (F10 lineage) contributed on average 11 % to total bacterioplankton in the pond during the vegetation periods (ice-free period, usually May to November). Only a low degree of genetic diversification of the population could be revealed. These bacteria are characterized by a small genome size (2.1 Mb), a relatively small number of genes involved in transduction of environmental signals, and the lack of motility and quorum sensing. Experiments indicated that these bacteria live as chemoorganotrophs by mainly utilizing low-molecular-weight substrates derived from photooxidation of humic substances. Conclusions: Evolutionary genome streamlining resulted in a highly passive lifestyle so far only known among free-living bacteria from pelagic marine taxa dwelling in environmentally stable nutrient-poor off-shore systems. Surprisingly, such a lifestyle is also successful in a highly dynamic and nutrient-richer environment such as the water column of the investigate

Changes in gene expression in maize kernel in response to water and salt stress

Increasing pressure on limited water resources for agriculture, together with the global temperature increase, highlight the importance of breeding for drought-tolerant cultivars. A better understanding of the molecular nature of drought stress can be expected through the use of genomics approaches. Here, a macroarray of approximate to 2500 maize cDNAs was used for determining transcript changes during water- and salt-stress treatments of developing kernels at 15 days after pollination. Normalization of relative transcript abundances was carried out using a human nebulin control sequence. The proportions of transcripts that changed significantly in abundance upon treatment (> 2-fold compared to the control) were determined; 1.5% of the sequences examined were up-regulated by high salinity and 1% by water stress. Both stresses induced 0.8% of the sequences. These include genes involved in various stress responses: abiotic, wounding and pathogen attack (abscisic acid response binding factor, glycine and proline-rich proteins, pathogenesis-related proteins, etc.). The proportion of down-regulated genes was higher than that for up-regulated genes for water stress (3.2%) and lower for salt stress (0.7%), although only eight genes, predominantly involved in energy generation, were down-regulated in both stress conditions. Co-expression of genes of unknown function under defined conditions may help in elucidating their roles in coordinating stress responses

The Incentives of a Common Good Based CSR for SDG’s Achievement: the Importance of Mission Statement

According to the entity theory, the !rm is a real person interested in survival and growth quantitatively and qualitatively. However, the literature is often vague and ambiguous for what concern the conditions to achieve for the survival and growth, as well as the modalities through which !nd the right compromise between continuity (or long-term pro!tability) and social function (or sociality) of the !rm. This chapter wants to contribute to the theories that consider the !rm as a real entity, proposing the concept of ‘primary interest of the !rm’, which includes the conditions that allow firms to survive and grow, as well as to serve the common good of their stakeholders and society. The primary interest concept is multidimensional and derives from the intersection of three theories: equilibrium theory, stakeholder theory and common good theory