Methuosis Nonapoptotic Cell Death Associated with Vacuolization of Macropinosome and Endosome Compartments

Apoptosis is the most widely recognized form of physiological programmed cell death. During the past three decades, various nonapoptotic forms of cell death have gained increasing attention, largely because of their potential importance in pathological processes, toxicology, and cancer therapy. A recent addition to the panoply of cell death phenotypes is methuosis. The neologism is derived from the Greek methuo (to drink to intoxication) because the hallmark of this form of cell death is displacement of the cytoplasm by large fluid-filled vacuoles derived from macropinosomes. The demise of the cell resembles many forms of necrosis, insofar as there is a loss of metabolic capacity and plasma membrane integrity, without the cell shrinkage and nuclear fragmentation associated with apoptosis. Methuosis was initially defined in glioblastoma cells after ectopic expression of activated Ras, but recent reports have described small molecules that can induce the features of methuosis in a broad spectrum of cancer cells, including those that are resistant to conventional apoptosis-inducing drugs. This review summarizes the available information about the distinguishing morphological characteristics and underlying mechanisms of methuosis. We compare and contrast methuosis with other cytopathological conditions in which accumulation of clear cytoplasmic vacuoles is a prominent feature. Finally, we highlight key questions that need to be answered to determine whether methuosis truly represents a unique form of regulated cell death

A chalcone-related small molecule that induces methuosis, a novel form of non-apoptotic cell death, in glioblastoma cells

<p>Abstract</p> <p>Background</p> <p>Methuosis is a unique form of non-apoptotic cell death triggered by alterations in the trafficking of clathrin-independent endosomes, ultimately leading to extreme vacuolization and rupture of the cell.</p> <p>Results</p> <p>Here we describe a novel chalcone-like molecule, 3-(2-<b>m</b>ethyl-1H- <b>i</b>ndol-3-yl)-1-(4-<b>p</b>yridinyl)-2-<b>p</b>ropen-1-one (MIPP) that induces cell death with the hallmarks of methuosis. MIPP causes rapid accumulation of vacuoles derived from macropinosomes, based on time-lapse microscopy and labeling with extracellular fluid phase tracers. Vacuolization can be blocked by the cholesterol-interacting compound, filipin, consistent with the origin of the vacuoles from non-clathrin endocytic compartments. Although the vacuoles rapidly acquire some characteristics of late endosomes (Rab7, LAMP1), they remain distinct from lysosomal and autophagosomal compartments, suggestive of a block at the late endosome/lysosome boundary. MIPP appears to target steps in the endosomal trafficking pathway involving Rab5 and Rab7, as evidenced by changes in the activation states of these GTPases. These effects are specific, as other GTPases (Rac1, Arf6) are unaffected by the compound. Cells treated with MIPP lose viability within 2-3 days, but their nuclei show no evidence of apoptotic changes. Inhibition of caspase activity does not protect the cells, consistent with a non-apoptotic death mechanism. U251 glioblastoma cells selected for temozolomide resistance showed sensitivity to MIPP-induced methuosis that was comparable to the parental cell line.</p> <p>Conclusions</p> <p>MIPP might serve as a prototype for new drugs that could be used to induce non-apoptotic death in cancers that have become refractory to agents that work through DNA damage and apoptotic mechanisms.</p

Ablation and functionalization of flexographic printing forms using femtosecond lasers for additively manufactured polymer-optical waveguides

An efficient and low-cost approach to manufacture Opto-Mechatronic Interconnect Devices will be obligatory to handle the strongly increasing amount of data. The presented approach is based on a flexographic printing process. To adjust the transferred material the printing form is functionalized by means of laser-induced structures using an ultrashort-pulsed laser. The long-term goal is to adjust the printing result through microstructures in the printing form in order to create spatially resolved material transfer. In this work, first the ablation parameters are investigated at different repetition rates using a femtosecond laser. Further, a line structure is inserted in the material transferring areas of the printing form, which is consequently widened. Its influence on the printing result is presented. © 2020 The Authors. Published by Elsevier B.V

Thermoforming of planar polymer optical waveguides for integrated optics in smart packaging materials

The innovations in smart packaging will open up a wide range of opportunities in the future. This work describes the processing of additive manufactured and planar integrated polymer optical waveguides for use in smart packaging products. The previously published combination of flexographic and Aerosol Jet printing is complemented by thermoforming and thus creates three-dimensional integrated multimode waveguides with optical attenuation of 1.9 dB/cm ± 0.1 dB/cm @ 638 nm. These properties will be the basis to develop smart applications in packaging materials

Functional coatings of sol-gel on glass substrate using CO2 laser irradiation

Often Glass products achieve their component functionality only by a specific surface finishing, such as coating or patterning. Compared to vacuum based CVD and PVD coating techniques, the equipment for wet-chemical deposition of sol-gels is less expensive. Heat is needed for a chemical reaction to cure gels and form solid functional layers. In this study, sols with titanium and zirconium were applied on glass substrates by dip coating. The investigated layer thicknesses were in the range between 320 nm and 650 nm. The gel layers were annealed with CO2 laser radiation. Different scanning speeds and laser powers were investigated. Microscope images were used to compare the laser-annealed layers with oven-annealed layers. To conclude, the oven-process can be substituted by laser annealing and additionally enables local patterning. This allows gradient coating solutions for architecture applications

Juxtaposition of Spin Freezing and Long Range Order in a Series of Geometrically Frustrated Antiferromagnetic Gadolinium Garnets

Specific heat measurements in zero magnetic field are presented on a homologous series of geometrically frustrated, antiferromagnetic, Heisenberg garnet systems. Measurements of Gd3Ga5O12, grown with isotopically pure Gd, agree well with previous results on samples with naturally abundant Gd, showing no ordering features. In contrast, samples of Gd3Te2Li3O12 and Gd3Al5O12 are found to exhibit clear ordering transitions at 243 mK and 175 mK respectively. The effects of low level disorder are studied through dilution of Gd3+ with non-magnetic Y3+ in Gd3Te2Li3O12. A thorough structural characterization, using X-ray diffraction, is performed on all of the samples studied. We discuss possible explanations for such diverse behavior in very similar systems.Comment: Accepted for publication in Physical Review

Combination of Cladding Processes with Subsequent Hot Forming as a New Approach for the Production of Hybrid Components

A new process chain for the manufacturing of load-adapted hybrid components is presented. The "Tailored Forming” process chain consists of a deposition welding process, hot forming, machining and an optional heat treatment. This paper focuses on the combination of laser hot-wire cladding with subsequent hot forming to produce hybrid components. The applicability is investigated for different material combinations and component geometries, e.g. a shaft with a bearing seat or a bevel gear. Austenitic stainless steel AISI 316L and martensitic valve steel AISI HNV3 are used as cladding materials, mild steel AISI 1022M and case hardening steel AISI 5120 are used as base materials. The resulting component properties after laser hot-wire cladding and hot forming such as hardness, microstructure and residual stress state are presented. In the cladding and the heat-affected zone, the hot forming process causes a transformation from a welding microstructure to a fine-grained forming microstructure. Hot forming significantly affects the residual stress state in the cladding the resulting residual stress state depends on the material combination.Mechanical Engineerin

The Influence of Coastal Access on Isotope Variation in Icelandic Arctic Foxes

To quantify the ecological effects of predator populations, it is important to evaluate how population-level specializations are dictated by intra- versus inter-individual dietary variation. Coastal habitats contain prey from the terrestrial biome, the marine biome and prey confined to the coastal region. Such habitats have therefore been suggested to better support predator populations compared to habitats without coastal access. We used stable isotope data on a small generalist predator, the arctic fox, to infer dietary strategies between adult and juvenile individuals with and without coastal access on Iceland. Our results suggest that foxes in coastal habitats exhibited a broader isotope niche breadth compared to foxes in inland habitats. This broader niche was related to a greater diversity of individual strategies rather than to a uniform increase in individual niche breadth or by individuals retaining their specialization but increasing their niche differentiation. Juveniles in coastal habitats exhibited a narrower isotope niche breadth compared to both adults and juveniles in inland habitats, and juveniles in inland habitats inhabited a lower proportion of their total isotope niche compared to adults and juveniles from coastal habitats. Juveniles in both habitats exhibited lower intra-individual variation compared to adults. Based on these results, we suggest that foxes in both habitats were highly selective with respect to the resources they used to feed offspring, but that foxes in coastal habitats preferentially utilized marine resources for this purpose. We stress that coastal habitats should be regarded as high priority areas for conservation of generalist predators as they appear to offer a wide variety of dietary options that allow for greater flexibility in dietary strategies

Non-hexagonal neural dynamics in vowel space

Are the grid cells discovered in rodents relevant to human cognition? Following up on two seminal studies by others, we aimed to check whether an approximate 6-fold, grid-like symmetry shows up in the cortical activity of humans who "navigate" between vowels, given that vowel space can be approximated with a continuous trapezoidal 2D manifold, spanned by the first and second formant frequencies. We created 30 vowel trajectories in the assumedly flat central portion of the trapezoid. Each of these trajectories had a duration of 240 milliseconds, with a steady start and end point on the perimeter of a "wheel". We hypothesized that if the neural representation of this "box" is similar to that of rodent grid units, there should be an at least partial hexagonal (6-fold) symmetry in the EEG response of participants who navigate it. We have not found any dominant n-fold symmetry, however, but instead, using PCAs, we find indications that the vowel representation may reflect phonetic features, as positioned on the vowel manifold. The suggestion, therefore, is that vowels are encoded in relation to their salient sensory-perceptual variables, and are not assigned to arbitrary gridlike abstract maps. Finally, we explored the relationship between the first PCA eigenvector and putative vowel attractors for native Italian speakers, who served as the subjects in our study