Modeling the TNFα-Induced Apoptosis Pathway in Hepatocytes

The proinflammatory cytokine TNFα fails to provoke cell death in isolated hepatocytes but has been implicated in hepatocyte apoptosis during liver diseases associated with chronic inflammation. Recently, we showed that TNFα is able to sensitize primary murine hepatocytes cultured on collagen to Fas ligand-induced apoptosis and presented a mathematical model of the sensitizing effect. Here, we analyze how TNFα induces apoptosis in combination with the transcriptional inhibitor actinomycin D (ActD). Accumulation of reactive oxygen species (ROS) in response to TNFR activation turns out to be critical for sustained activation of JNK which then triggers mitochondrial pathway-dependent apoptosis. In addition, the amount of JNK is strongly upregulated in a ROS-dependent way. In contrast to TNFα plus cycloheximide no cFLIP degradation is observed suggesting a different apoptosis pathway in which the Itch-mediated cFLIP degradation and predominantly caspase-8 activation is not involved. Time-resolved data of the respective pro- and antiapoptotic factors are obtained and subjected to mathematical modeling. On the basis of these data we developed a mathematical model which reproduces the complex interplay regulating the phosphorylation status of JNK and generation of ROS. This model was fully integrated with our model of TNFα/Fas ligand sensitizing as well as with a published NF-κB-model. The resulting comprehensive model delivers insight in the dynamical interplay between the TNFα and FasL pathways, NF-κB and ROS and gives an example for successful model integration

Systematic comparison of incomplete-supervision approaches for biomedical image classification.

Deep learning based classification of biomedical images requires expensive manual annotation by experts. Incomplete-supervision approaches including active learning, pre-training, and semi-supervised learning have thus been developed to increase classification performance with a limited number of annotated images. In practice, a combination of these approaches is often used to reach the desired performance for biomedical images. Most of these approaches are designed for natural images, which differ fundamentally from biomedical images in terms of color, contrast, image complexity, and class imbalance. In addition, it is not always clear which combination to use in practical cases. We, therefore, analyzed the performance of combining seven active learning, three pre-training, and two semi-supervised methods on four exemplary biomedical image datasets covering various imaging modalities and resolutions. The results showed that the ImageNet (pre-training) in combination with pseudo-labeling (semi-supervised learning) dominates the best performing combinations, while no particular active learning algorithm prevailed. For three out of four datasets, this combination reached over 90% of the fully supervised results by only adding 25% of labeled data. An ablation study also showed that pre-training and semi-supervised learning contributed up to 25% increase in F1-score in each cycle. In contrast, active learning contributed less than 5% increase in each cycle. Based on these results, we suggest employing the correct combination of pre-training and semi-supervised learning can be more efficient than active learning for biomedical image classification with limited annotated images. We believe that our study is an important step towards annotation-efficient model training for biomedical classification challenges

Reverse Development in Cnidaria

Cnidarians have long been considered simple animals in spite of the variety of their complex life cycles and developmental patterns. Several cases of developmental conversion are known, leading to the formation of resting stages or to offspring proliferation. Besides their high regenerative and asexual-reproduction potential, a number of cnidarians can undergo ontogeny reversal, or reverse development: one or more stages in the life cycle can reactivate genetic programs specific to earlier stages, leading to back-transformation and morph rejuvenation. The switch is achieved by a variable combination of cellular processes, such as transdifferentiation, programmed cell death, and proliferation of interstitial cells. The potential for ontogeny reversal has limited ecological meaning and is probably just an extreme example of a more general strategy for withstanding unfavourable periods and allowing temporal persistence of species in the environment

Evidence of reverse development in Leptomedusae (Cnidaria, Hydrozoa): the case of <i>Laodicea undulata</i> (Forbes and Goodsir 1851)

Laboratory rearing and reconstruction of Laodicea undulata (Hydrozoa) life cycle led to the discovery for the first time in Leptomedusae of the potential for ontogeny reversal, i.e. the medusa stage can asexually transform back into the polyp stage. In turn, each rejuvenated polyp stage can newly activate the standard developmental programme towards colony morphogenesis and budding of secondary medusae. These can be considered as clonemates of the initial medusa batch, since they originate by asexual processes. In combination with the ordinary medusa budding process, the potential for reverse development might represent a tool to increase jellyfish population growth rate during the favourable season, but eventually it does not avoid jellyfish to die. Comparably to polyembryony, reverse development leads to offspring multiplication from a single fertilization event, with a wider dispersal of each single genotype; eventually, it favours the enhancement of the overall genetic diversity at small spatial scale. The life cycle of L. undulata from the Mediterranean Sea is re-described, linking previously uncoupled descriptions of either the polyp or the early medusa stages. Taxonomic considerations of the genus Laodicea and a comparison among the known Mediterranean species are also provided

Self-healing processes in plants: A treasure trove for biomimetic self-repairing materials

After an artificial injury in succulent leaves of Delosperma cooperi and Delosperma ecklonis rapid wound sealing by deformation of the entire leaf takes place within approximately 90 minutes. On the basis of comparative anatomical and biomechanical analyses of the closely related species conclusions can be drawn on necessary boundary conditions allowing self-sealing by leaf deformation and movement. An analytical model of the underlying principle found in D. cooperi has been developed as basis for the transfer into bio-inspired self-repairing materials

Evidence of reverse development in Leptomedusae (Cnidaria, Hydrozoa): the case of Laodicea undulata(Forbes and Goodsir 1851)

Laboratory rearing and reconstruction of Laodicea undulata (Hydrozoa) life cycle led to the discovery for the first time in Leptomedusae of the potential for ontogeny reversal, i.e. the medusa stage can asexually transform back into the polyp stage. In turn, each rejuvenated polyp stage can newly activate the standard developmental programme towards colony morphogenesis and budding of secondary medusae. These can be considered as clonemates of the initial medusa batch, since they originate by asexual processes. In combination with the ordinary medusa budding process, the potential for reverse development might represent a tool to increase jellyfish population growth rate during the favourable season, but eventually it does not avoid jellyfish to die. Comparably to polyembryony, reverse development leads to offspring multiplication from a single fertilization event, with a wider dispersal of each single genotype; eventually, it favours the enhancement of the overall genetic diversity at small spatial scale. The life cycle of L. undulata from the Mediterranean Sea is re-described, linking previously uncoupled descriptions of either the polyp or the early medusa stages. Taxonomic considerations of the genus Laodicea and a comparison among the known Mediterranean species are also provided

Induction of reverse development in two marine hydrozoans

Cnidarians are unique organisms in the animal kingdom because of their unequalled potential to undergo reverse development (RD). The life cycle of some species can temporarily shift ordinary, downstream development from zygote to adult into the opposite ontogenetic direction by back-transformation of some life stages. The potential for RD in cnidarians offers the possibility to investigate how integrative signalling networks operate to control directionality of ontogeny (reverse vs. normal development). Striking examples are found in some hydrozoans, where RD of medusa bud or liberated medusa stages leads to rejuvenation of the post-larval polyp stage. Artificial stress may determine ontogeny reversal. We describe here the results of experimental assays on artificial induction of RD by different chemical and physical inducers on two marine hydrozoans, Turritopsis dohrnii and Hydractinia carnea, showing a different potential for RD. A cascade of morphogenetic events occurs during RD by molecular mechanisms and cellular patterns recalling larval metamorphosis. For the first time, we show here that exposure to cesium chloride (CsCl), an inducer of larval metamorphosis, may also induce RD, highlighting similarities and differences between these two master ontogenetic processes in cnidarian