DICE

The conventional view of CD95 (Fas/APO-1) is that it is a dedicated apoptosis-inducing receptor with important functions in immune cell homeostasis and in viral and tumor defense. There is an emerging recognition, however, that CD95 also has multiple non-apoptotic activities. In the context of cancer, CD95 was shown to have tumor-promoting activities, and the concept of this new function of CD95 in cancer is gaining traction. Recently, we showed that not only is CD95 a growth promoter for cancer cells, but, paradoxically, when either CD95 or CD95 ligand (CD95L) is removed, that virtually all cancer cells die through a process we have named DICE (death induced by CD95R/L elimination). In this perspective, I outline a hypothesis regarding the physiological function of DICE, and why it may be possible to use induction of DICE to treat many, if not most, cancers.     

Extracellular ATP Hydrolysis Inhibits Synaptic Transmission by Increasing pH Buffering in the Synaptic Cleft

Neuronal computations strongly depend on inhibitory interactions. One such example occurs at the first retinal synapse, where horizontal cells inhibit photoreceptors. This interaction generates the center/surround organization of bipolar cell receptive fields and is crucial for contrast enhancement. Despite its essential role in vision, the underlying synaptic mechanism has puzzled the neuroscience community for decades. Two competing hypotheses are currently considered: an ephaptic and a proton-mediated mechanism. Here we show that horizontal cells feed back to photoreceptors via an unexpected synthesis of the two. The first one is a very fast ephaptic mechanism that has no synaptic delay, making it one of the fastest inhibitory synapses known. The second one is a relatively slow (τ≈200 ms), highly intriguing mechanism. It depends on ATP release via Pannexin 1 channels located on horizontal cell dendrites invaginating the cone synaptic terminal. The ecto-ATPase NTPDase1 hydrolyses extracellular ATP to AMP, phosphate groups, and protons. The phosphate groups and protons form a pH buffer with a pKa of 7.2, which keeps the pH in the synaptic cleft relatively acidic. This inhibits the cone Ca²⁺ channels and consequently reduces the glutamate release by the cones. When horizontal cells hyperpolarize, the pannexin 1 channels decrease their conductance, the ATP release decreases, and the formation of the pH buffer reduces. The resulting alkalization in the synaptic cleft consequently increases cone glutamate release. Surprisingly, the hydrolysis of ATP instead of ATP itself mediates the synaptic modulation. Our results not only solve longstanding issues regarding horizontal cell to photoreceptor feedback, they also demonstrate a new form of synaptic modulation. Because pannexin 1 channels and ecto-ATPases are strongly expressed in the nervous system and pannexin 1 function is implicated in synaptic plasticity, we anticipate that this novel form of synaptic modulation may be a widespread phenomenon.     

Epidermal Growth Factor Signalling Controls Myosin II Planar Polarity to Orchestrate Convergent Extension Movements during Drosophila Tubulogenesis

Most epithelial tubes arise as small buds and elongate by regulated morphogenetic processes including oriented cell division, cell rearrangements, and changes in cell shape. Through live analysis of Drosophila renal tubule morphogenesis we show that tissue elongation results from polarised cell intercalations around the tubule circumference, producing convergent-extension tissue movements. Using genetic techniques, we demonstrate that the vector of cell movement is regulated by localised epidermal growth factor (EGF) signalling from the distally placed tip cell lineage, which sets up a distal-to-proximal gradient of pathway activation to planar polarise cells, without the involvement for PCP gene activity. Time-lapse imaging at subcellular resolution shows that the acquisition of planar polarity leads to asymmetric pulsatile Myosin II accumulation in the basal, proximal cortex of tubule cells, resulting in repeated, transient shortening of their circumferential length. This repeated bias in the polarity of cell contraction allows cells to move relative to each other, leading to a reduction in cell number around the lumen and an increase in tubule length. Physiological analysis demonstrates that animals whose tubules fail to elongate exhibit abnormal excretory function, defective osmoregulation, and lethality.     

Gamma irradiation preserves immunosuppressive potential and inhibits clonogenic capacity of human bone marrow‐derived mesenchymal stromal cells

Mesenchymal stromal cells (MSCs) are promising candidates for the treatment of graft‐versus‐host and autoimmune diseases. Here, by virtue of their immunosuppressive effects, they are discussed to exhibit inhibitory actions on various immune effector cells, including T lymphocytes that promote the underlying pathology. While it becomes apparent that MSCs exhibit their therapeutic effect in a transient manner, they are usually transplanted from third party donors into heavily immunocompromised patients. However, little is known about potential late complications of persisting third party MSCs in these patients. We therefore analysed the effect of gamma irradiation on the potency and proliferation of MSCs to elucidate an irradiation dose, which would allow inhibition of MSC proliferation while at the same time preserving their immunosuppressive function. Bone marrow‐derived MSCs (BM‐MSCs) were gamma‐irradiated at increasing doses of 5, 10 and 30 Gy and subsequently assessed by colony formation unit (CFU)‐assay, Annexin V‐staining and in a mixed lymphocyte reaction, to assess colony growth, apoptosis and the immunosuppressive capacity, respectively. Complete loss of proliferative capacity measured by colony formation was observed after irradiation with a dose equal to or greater than 10 Gy. No significant decrease of viable cells was detected, as compared to non‐irradiated BM‐MSCs. Notably, irradiated BM‐MSCs remained highly immunosuppressive in vitro for at least 5 days after irradiation. Gamma irradiation does not impair the immunosuppressive capacity of BM‐MSCs in vitro and thus might increase the safety of MSC‐based cell products in clinical applications.     

Model-based design and integration of a two-step biopharmaceutical production process

This paper presents the design of a two-step process in which the first step is PEGylation of a protein, and the second step is chromatographic purification of the target mono-PEGylated protein from the unreacted and the di-PEGylated impurities. The difference between optimizing each process step separately and optimizing them simultaneously is studied. It was found that by optimizing the steps simultaneously up to a 100 % increase in productivity could be obtained without reduction in yield. Optimizing both steps at the same time makes it possible for the optimization method to take into account that the di-PEGylated protein is much easier to separate than the non-PEGylated protein. The easier separation makes it possible to get a higher yield and productivity at the same time. The effect of recycling was also studied and the yield could be increased by 30 % by recycling the unreacted protein. However, if maximum productivity is required, batch mode is preferable.     

The Influence of Nanocrystal Aggregates on Photovoltaic Performance in Nanocrystal–Polymer Bulk Heterojunction Solar Cells

CdSe nanocrystals (NCs) can be used as an electron acceptor in solar cells, employing organic ligands to passivate their surface and make them processable from solution. The nature and abundance of impurities present after NC ligand exchange from oleic acid to n‐butylamine are identified. A further purification step using hexane as a selective solvent is described, which excludes NC aggregates from solution. The influence of NC aggregates on photovoltaic device performance is studied in a CdSe:poly[2‐methoxy‐5‐(3′,7′‐dimethyloctyloxy)‐1,4‐phenylene vinylene] (MDMO‐PPV) bulk heterojunction solar cell. The exclusion of NC aggregates leads to a four‐fold increase in device power conversion efficiency (PCE) in optimized devices. A superior blend morphology leading to improved charge generation and a better NC percolation network is identified as the main causes of this increased solar cell performance.     

Can we use plant traits and soil characteristics to predict leaf damage in savanna woody species?

Although several hypotheses aim to explain insect herbivory on plants, the relative importance of plant traits, environment, and organizational scale (i.e., individual or community) to herbivory damage level is not well understood. We used an approach based on a local scale, divided into individual and community levels, to test if plant traits, soil characteristics, and plant density explain leaf damage. We sampled 983 individuals in 49 plots distributed over dense and open savanna formations in Emas National Park. In order to explain plant damage, we performed a multi-model inference analysis of four plant traits associated with plant damage, five soil characteristics, and plant density. We did not find any support to plant vigor or plant stress hypotheses at individual plant level. However, the resource concentration hypothesis and plant stress hypothesis explained leaf damage at the community level. We found that increased availability of calcium (Ca) in soils reduced plant damage at the community level. Because soil Ca concentration is a major constraint to plant development in the Brazilian savanna, we postulated that its increasing availability permits plants to invest more in defense strategies. We demonstrate that plant density, Ca soil concentration, and leaf size can be used to predict the plant damage suffered by woody species in savannas at community level.