Non-classical Modes Research Articles

Flight mechanical analysis of a solar-powered high-altitude platform

The German Aerospace Center (DLR) is currently developing an unmanned experimental solar-powered fixed-wing high-altitude platform designed to be stationed in the stratosphere for several days and to carry payload for earth observation missions. This paper deals with a flight mechanical analysis of the aircraft within the preliminary design phase. For this purpose, it briefly describes all disciplines involved in the preliminary design and gives an insight into their methods used. Subsequently, it presents an assessment of the aircraft in terms of stability and control characteristics. Doing so, it first deals with a dynamic stability investigation using a non-linear 6-degrees-of-freedom flight dynamic model with a simple quasi-stationary approach to account for flexibility, in which the aerodynamic derivatives are given for different airspeed-dependent flight shapes. The investigations show that the aircraft is naturally stable over the complete flight envelope. It does not have a typical short period mode. Instead, the corresponding mode involves altitude and airspeed changes to a large extent. At low airspeeds, the Dutch roll and spiral modes couple and form two non-classical modes. Second, it presents a control surface design evaluation process for the aircraft based on a flight mechanical requirement. This requirement addresses the necessary control authority to counteract the aircraft’s responses due to gust encounters to not exceed afore-defined limits and to prevent the aircraft from entering a flight condition that it cannot be recovered from.

Oxygen-boosted biomimetic nanoplatform for synergetic phototherapy/ferroptosis activation and reversal of immune-suppressed tumor microenvironment

Photodynamic therapy (PDT) induces apoptosis of cancer cells by generating cytotoxic reactive oxygen species, the therapeutic effect of which, however, is impeded by intrinsic/inducible apoptosis-resistant mechanisms in cancer cells and hypoxia of tumor microenvironment (TME); also, PDT-induced anti-tumor immunity activation is insufficient. To deal with these obstacles, a novel biomimetic nanoplatform is fabricated for the precise delivery of photosensitizer chlorin e6 (Ce6), hemin and PEP20 (CD47 inhibitory peptide), integrating oxygen-boosted PDT, ferroptosis activation and CD47-SIRPα blockade. Hemin's catalase-mimetic activity alleviates TME hypoxia and enhances PDT. The nanoplatform activates ferroptosis via both classical (down-regulating glutathione peroxidase 4 pathway) and non-classical (inducing Fe2+ overload) modes. Besides the role of hemin in consuming glutathione and up-regulating heme oxygenase-1 expression, interestingly, we observe that Ce6 enhance ferroptosis activation via both classical and non-classical modes. The anti-cancer immunity is reinforced by combining PEP20-mediated CD47-SIRPα blockade and PDT-mediated T cell activation, efficiently suppressing primary tumor growth and metastasis. PEP20 has been revealed for the first time to sensitize ferroptosis by down-regulating system Xc−. This work sheds new light on the mechanisms of PDT-ferroptosis activation interplay and bridges immunotherapy and ferroptosis activation, laying the theoretical foundation for novel combinational modes of cancer treatment.

Vitamin C Sensitizes Pancreatic Cancer Cells to Erastin-Induced Ferroptosis by Activating the AMPK/Nrf2/HMOX1 Pathway.

Ferroptosis is a type of regulated cell death that displays a promising therapeutic pathway for drug-resistant tumor cells. However, some pancreatic cancer (PC) cells are less sensitive to erastin-induced ferroptosis, and normal pancreatic cells are susceptible to this newly discovered cell death. Therefore, there is an urgent need to find drugs to enhance the sensitivity of these PC cells to erastin while limiting side effects. Here, we found that the oxidized form of vitamin C-dehydroascorbic acid (DHA) can be transported into PC cells expressing high levels of GLUT1, resulting in ferroptosis. Moreover, pharmacological vitamin C combined with erastin can synergistically induce ferroptosis of PC cells involving glutathione (GSH) reduction and ferrous iron accumulation while inhibiting the cytotoxicity of normal cells. Mechanistically, as a direct system Xc− inhibitor, erastin can directly suppress the synthesis of GSH, and the recycling of vitamin C and DHA is performed through GSH consumption, which is denoted as the classical mode. Furthermore, oxidative stress induced by erastin and vitamin C could enhance the expression of HMOX1 via the AMP-activated protein kinase (AMPK)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway to increase the labile iron level, which is named the nonclassical mode. In vivo experiments showed that erastin and vitamin C can significantly slow tumor growth in PC xenografts. In summary, the combination of erastin and vitamin C exerts a synergistic effect of classical and nonclassical modes to induce ferroptosis in PC cells, which may provide a promising therapeutic strategy for PC.

High-Content Phenotypic Screen of a Focused TCAMS Drug Library Identifies Novel Disruptors of the Malaria Parasite Calcium Dynamics.

The search for new antimalarial drugs with unexplored mechanisms of action is currently one of the main objectives to combat the resistance already in the clinic. New drugs should target specific mechanisms that once initiated lead inevitably to the parasite's death and clearance and cause minimal toxicity to the host. One such new mode of action recently characterized is to target the parasite's calcium dynamics. Disruption of the calcium homeostasis is associated with compromised digestive vacuole membrane integrity and release of its contents, leading to programmed cell death-like features characterized by loss of mitochondrial membrane potential and DNA degradation. Intriguingly, chloroquine (CQ)-treated parasites were previously reported to exhibit such cellular features. Using a high-throughput phenotypic screen, we identified 158 physiological disruptors (hits) of parasite calcium distribution from a small subset of approximately 3000 compounds selected from the GSK TCAMS (Tres Cantos Anti-Malarial Set) compound library. These compounds were then extensively profiled for biological activity against various CQ- and artemisinin-resistant Plasmodium falciparum strains and stages. The hits were also examined for cytotoxicity, speed of antimalarial activity, and their possible inhibitory effects on heme crystallization. Overall, we identified three compounds, TCMDC-136230, -125431, and -125457, which were potent in inducing calcium redistribution but minimally inhibited heme crystallization. Molecular superimposition of the molecules by computational methods identified a common pharmacophore, with the best fit assigned to TCMDC-125457. There were low cytotoxicity or CQ cross-resistance issues for these three compounds. IC50 values of these three compounds were in the low micromolar range. In addition, TCMDC-125457 demonstrated high efficacy when pulsed in a single-dose combination with artesunate against tightly synchronized artemisinin-resistant ring-stage parasites. These results should add new drug options to the current armament of antimalarial drugs as well as provide promising starting points for development of drugs with non-classical modes of action.

The Orphan GPCR Receptor, GPR88, Interacts with Nuclear Protein Partners in the Cerebral Cortex.

GPR88 is an orphan G-protein-coupled receptor (GPCR) highly expressed in striatal medium spiny neurons (MSN), also found in cortical neurons at low level. In MSN, GPR88 has a canonical GPCR plasma membrane/cytoplasmic expression, whereas in cortical neurons, we previously reported an atypical intranuclear localization. Molecular size analysis suggests that GPR88, expressed in plasma membrane of MSN or in nuclear compartment of cortical neurons, corresponds to the full-length protein. By transfection of cortical neurons, we showed that GPR88 fluorescent chimeras exhibit a nuclear localization. This localization is contingent on the third intracytoplasmic loop and C-terminus domains, even though these domains do not contain any known nuclear localization signals (NLS). Using yeast two-hybrid screening with these domains, we identified the nuclear proteins ATRX, TOP2B, and BAZ2B, all involved in chromatin remodeling, as potential protein partners of GPR88. We also validated the interaction of GPR88 with these nuclear proteins by proximity ligation assay on cortical neurons in culture and coimmunoprecipitation experiments on cortical extracts from GPR88 wild-type (WT) and knockout (KO) mice. The identification of GPR88 subcellular partners may provide novel functional insights for nonclassical modes of GPCR action that could be relevant in the maturating process of neocortical neurons.

The Ambiguous Functions of the Precursors That Enable Nonclassical Modes of Olanzapine Nucleation and Growth

One of the most consequential assumptions of the classical theories of crystal nucleation and growth is the Szilard postulate, which states that molecules from a supersaturated phase join a nucleus or a growing crystal individually. In the last 20 years, observations in complex biological, geological, and engineered environments have brought to light violations of the Szilard rule, whereby molecules assemble into ordered or disordered precursors that then host and promote nucleation or contribute to fast crystal growth. Nonclassical crystallization has risen to a default mode presumed to operate in the majority of the inspected crystallizing systems. In some cases, the existence of precursors in the growth media is admitted as proof for their role in nucleation and growth. With the example of olanzapine, a marketed drug for schizophrenia and bipolar disorder, we demonstrate that molecular assemblies in the solution selectively participate in crystal nucleation and growth. In aqueous and organic solutions, olanzapine assembles into both mesoscopic solute-rich clusters and dimers. The clusters facilitate nucleation of crystals and crystal form transformations. During growth, however, the clusters land on the crystal surface and transform into defects, but do not support step growth. The dimers are present at low concentrations in the supersaturated solution, yet the crystals grow by the association of dimers, and not of the majority monomers. The observations with olanzapine emphasize that detailed studies of the crystal and solution structures and the dynamics of molecular association may empower classical and nonclassical models that advance the understanding of natural crystallization, and support the design and manufacture of promising functional materials.

Fluorescent pyrene moiety in fluorinated C6F5-corroles increases the interaction with HSA and CT-DNA

Two fluorinated meso-C6F5-corroles (5,15-bis(pentafluorophenyl)-10-(phenyl)corrole and 5,15-bis(pentafluorophenyl)-10-(1-pyrenyl)corrole) were biologically evaluated in terms of binding affinity to human serum albumin (HSA) and calf-thymus DNA (CT-DNA) via multiple spectroscopic techniques under physiological conditions combined with molecular docking calculations. The HSA:corrole interaction is spontaneous and moderate via static binding, disturbing both secondary and tertiary albumin structures at high fluorinated corrole concentrations. The competitive binding studies indicated positive cooperativity or allosteric activation, while molecular docking calculations suggested that both fluorinated corroles bind preferentially inside subdomains IIA and IB (sites I and III, respectively). The experimental CT-DNA binding assays indicated that fluorinated corroles interact spontaneously by non-classical modes in the minor groove of the CT-DNA strands via static fluorescence quenching mechanism. Molecular docking results also showed the minor groove as the main binding site for CT-DNA. Overall, the pyrene moiety increased the interaction with HSA and CT-DNA, which is probably due to the planarity and volume that favors the pyrene unit to be buried inside the biomacromolecule pockets.

Quasidistribution of phases in Raman process with weak and strong pumps

Nonclassicality is quantified using a quasidistribution of phases for the Raman process under both weak and strong pump conditions. In the former case, the solution is applicable to both resonant and off-resonant Raman processes, while strong classical pump is assumed at resonance. Under weak pump conditions (i.e. in a complete quantum treatment), the phase difference of phases described by single nonclassical modes is required to be filtered to describe a regular distribution function, which is not the case with strong pump. Compound Stokes-phonon mode shows nonclassical features of phases in both weak and strong pumping, which effect is similar to that for compound pump-phonon (Stokes–anti-Stokes) mode with weak (strong) pump. While anti-Stokes-phonon mode is observed to be classical and coherence conserving in strong pump case, pump-Stokes mode shows similar behavior in a special case in quantum treatment.

Drosophila melanogaster Responses against Entomopathogenic Nematodes: Focus on Hemolymph Clots.

Several insect innate immune mechanisms are activated in response to infection by entomopathogenic nematodes (EPNs). In this review, we focus on the coagulation of hemolymph, which acts to stop bleeding after injury and prevent access of pathogens to the body cavity. After providing a general overview of invertebrate coagulation systems, we discuss recent findings in Drosophila melanogaster which demonstrate that clots protect against EPN infections. Detailed analysis at the cellular level provided insight into the kinetics of the secretion of Drosophila coagulation factors, including non-classical modes of secretion. Roughly, clot formation can be divided into a primary phase in which crosslinking of clot components depends on the activity of Drosophila transglutaminase and a secondary, phenoloxidase (PO)-dependent phase, characterized by further hardening and melanization of the clot matrix. These two phases appear to play distinct roles in two commonly used EPN infection models, namely Heterorhabditis bacteriophora and Steinernema carpocapsae. Finally, we discuss the implications of the coevolution between parasites such as EPNs and their hosts for the dynamics of coagulation factor evolution.

The one-dimensional Stefan problem with non-Fourier heat conduction

We investigate the one-dimensional growth of a solid into a liquid bath, starting from a small crystal, using the Guyer-Krumhansl and Maxwell-Cattaneo models of heat conduction. By breaking the solidification process into the relevant time regimes we are able to reduce the problem to a system of two coupled ordinary differential equations describing the evolution of the solid-liquid interface and the heat flux. The reduced formulation is in good agreement with numerical simulations. In the case of silicon, differences between classical and non-classical solidification kinetics are relatively small, but larger deviations can be observed in the evolution in time of the heat flux through the growing solid. From this study we conclude that the heat flux provides more information about the presence of non-classical modes of heat transport during phase-change processes.

Computational Complexity Theory and the Philosophy of Mathematics†

AbstractComputational complexity theory is a subfield of computer science originating in computability theory and the study of algorithms for solving practical mathematical problems. Amongst its aims is classifying problems by their degree of difficulty — i.e., how hard they are to solve computationally. This paper highlights the significance of complexity theory relative to questions traditionally asked by philosophers of mathematics while also attempting to isolate some new ones — e.g., about the notion of feasibility in mathematics, the $\mathbf{P} \neq \mathbf{NP}$ problem and why it has proven hard to resolve, and the role of non-classical modes of computation and proof.

On the unification of classical, intuitionistic and affine logics

This article presents aunified logicthat combines classical logic, intuitionistic logic and affine linear logic (restricting contraction but not weakening). We show that this unification can be achieved semantically, syntactically and in the computational interpretation of proofs. It extends our previous work in combining classical and intuitionistic logics. Compared to linear logic, classical fragments of proofs are better isolated from non-classical fragments. We define a phase semantics for this logic that naturally extends the Kripke semantics of intuitionistic logic. We present a sequent calculus with novel structural rules, which entail a more elaborate procedure for cut elimination. Computationally, this system allows affine-linear interpretations of proofs to be combined with classical interpretations, such as the λμ calculus. We show how cut elimination must respect the boundaries between classical and non-classical modes of proof that correspond to delimited control effects.

Anticancer metallodrugs: where is the next cisplatin?

Despite the severe side effects and the emergence of drug resistance, the use of DNA-targeting platinum drugs remains strong either alone or in a combination chemotherapy regimen. New strategies and formulations are being explored in the design of anticancer metal complexes that exhibit nonclassical modes of action, selectively hit precise biomolecular targets or are even able to induce immunogenic anticancer activity. These developments will ameliorate the systemic toxicity of metal-based drugs and widen the range of treatable cancers.

Synaptic plasticity by antidromic firing during hippocampal network oscillations

Learning and other cognitive tasks require integrating new experiences into context. In contrast to sensory-evoked synaptic plasticity, comparatively little is known of how synaptic plasticity may be regulated by intrinsic activity in the brain, much of which can involve nonclassical modes of neuronal firing and integration. Coherent high-frequency oscillations of electrical activity in CA1 hippocampal neurons [sharp-wave ripple complexes (SPW-Rs)] functionally couple neurons into transient ensembles. These oscillations occur during slow-wave sleep or at rest. Neurons that participate in SPW-Rs are distinguished from adjacent nonparticipating neurons by firing action potentials that are initiated ectopically in the distal region of axons and propagate antidromically to the cell body. This activity is facilitated by GABA(A)-mediated depolarization of axons and electrotonic coupling. The possible effects of antidromic firing on synaptic strength are unknown. We find that facilitation of spontaneous SPW-Rs in hippocampal slices by increasing gap-junction coupling or by GABA(A)-mediated axon depolarization resulted in a reduction of synaptic strength, and electrical stimulation of axons evoked a widespread, long-lasting synaptic depression. Unlike other forms of synaptic plasticity, this synaptic depression is not dependent upon synaptic input or glutamate receptor activation, but rather requires L-type calcium channel activation and functional gap junctions. Synaptic stimulation delivered after antidromic firing, which was otherwise too weak to induce synaptic potentiation, triggered a long-lasting increase in synaptic strength. Rescaling synaptic weights in subsets of neurons firing antidromically during SPW-Rs might contribute to memory consolidation by sharpening specificity of subsequent synaptic input and promoting incorporation of novel information.

Vibration of nonclassical shear beams with Winkler-Pasternak-type restraint

Transverse vibration of the shear beams containing rotary inertia and with a two-parameter elastic foundation is studied. Using asymptotic analysis of Timoshenko beam theory, we derive explicit characteristic equations of the nonclassical shear beams with Winkler-Pasternak elastic restraint and with both ends linked to translational and rotational springs. The condition of the nonclassical shear beams reducing to the classical ones is found. Natural frequencies of the nonclassical modes are evaluated for free- and pinned-elastically restrained shear beams with or without bracing. The influences of elastic restraint stiffness and rotary inertia on the natural frequencies are discussed. Some extreme cases can be recovered from the present. The obtained results are helpful in the design of a tall frame building.

Comparative Kinetic Study and Microwaves Non-Thermal Effects on the Formation of Poly(amic acid) 4,4′-(Hexafluoroisopropylidene)diphthalic Anhydride (6FDA) and 4,4′-(Hexafluoroisopropylidene)bis(p-phenyleneoxy)dianiline (BAPHF). Reaction Activated by Microwave, Ultrasound and Conventional Heating

Green chemistry is the design of chemical processes that reduce or eliminate negative environmental impacts. The use and production of chemicals involve the reduction of waste products, non-toxic components, and improved efficiency. Green chemistry applies innovative scientific solutions in the use of new reagents, catalysts and non-classical modes of activation such as ultrasounds or microwaves. Kinetic behavior and non-thermal effect of poly(amic acid) synthesized from (6FDA) dianhydride and (BAPHF) diamine in a low microwave absorbing p-dioxane solvent at low temperature of 30, 50, 70 °C were studied, under conventional heating (CH), microwave (MW) and ultrasound irradiation (US). Results show that the polycondensation rate decreases (MW > US > CH) and that the increased rates observed with US and MW are due to decreased activation energies of the Arrhenius equation. Rate constant for a chemical process activated by conventional heating declines proportionally as the induction time increases, however, this behavior is not observed under microwave and ultrasound activation. We can say that in addition to the thermal microwave effect, a non-thermal microwave effect is present in the system.

Discovering New Bioactive Neuropeptides in the Striatum Secretome Using in Vivo Microdialysis and Versatile Proteomics

The striatum, a major component of the brain basal nuclei, is central for planning and executing voluntary movements and undergoes lesions in neurodegenerative disorders such as Huntington disease. To perform highly integrated tasks, the striatum relies on a complex network of communication within and between brain regions with a key role devoted to secreted molecules. To characterize the rat striatum secretome, we combined in vivo microdialysis together with proteomics analysis of trypsin digests and peptidomics studies of native fragments. This versatile approach, carried out using different microdialysis probes and mass spectrometer devices, allowed evidencing with high confidence the expression of 88 proteins and 100 processed peptides. Their secretory pathways were predicted by in silico analysis. Whereas high molecular weight proteins were mainly secreted by the classical mode (94%), low molecular weight proteins equally used classical and non-classical modes (53 and 47%, respectively). In addition, our results suggested alternative secretion mechanisms not predicted by bioinformatics tools. Based on spectrum counting, we performed a relative quantification of secreted proteins and peptides in both basal and neuronal depolarization conditions. This allowed detecting a series of neuropeptide precursors and a 6-fold increase for neurosecretory protein VGF and proenkephalin (PENK) levels. A focused investigation and a long peptide experiment led to the identification of new secreted non-opioid PENK peptides, referred to as PENK 114-133, PENK 239-260, and PENK 143-185. Moreover we showed that injecting synthetic PENK 114-133 and PENK 239-260 into the striatum robustly increased glutamate release in this region. Thus, the combination of microdialysis and versatile proteomics methods shed new light on the secreted protein repertoire and evidenced novel neuropeptide transmitters.

Discussion of “On the Comparison of Timoshenko and Shear Models in Beam Dynamics” by Noël Challamel

This technical note questions the validity of a general approach developed by Aristizabal-Ochoa 2004 for the dynamic analysis of a Timoshenko beam-column with generalized boundary conditions and the nonclassical modes of vibration of shear beams, in particular the theoretical relationship between both models for large values of bending to shear stiffness parameter. A simply supported beam is analytically studied for both models by the author of the discussed paper, and asymptotic solutions are obtained for large values of bending to shear stiffness parameter. Using the particular case of a simply supported beam with zero rotational inertia i.e., r =0 , the author claims that, “In the general case, it is proven that the shear beam model cannot be deduced from the Timoshenko model, by considering large values of bending to shear stiffness parameter. This is only achieved for specific geometrical parameter in the present example.” Finally, the author concludes based on his asymptotic solutions of the simply supported beam with zero rotational inertia that “the capability of the shear model to approximate Timoshenko model for large values of bending to shear stiffness parameter is firmly dependent on the material and geometrical characteristics of the beam section and on the boundary conditions.” The author is congratulated for studying the free vibration of beams. However, it is unfortunate that the author uses a degenerate beam model to prove that the general approach developed by Aristizabal-Ochoa 2004 for the dynamic analysis of a Timoshenko beam-column with generalized boundary conditions and the nonclassical modes of vibration of shear beams is in some way incorrect. The main objective of this discussion is to show that 1 it is incorrect to assume a Timoshenko beam with r = 0 and still expect that it is capable of predicting the free vibration of the Timoshenko shear model for large values of bending to shear stiffness parameter; and 2 the conclusions based on the asymptotic solutions presented by the author are not correct because they are based on a free-vibration analysis of a degenerate Timoshenko beam. What follows is the proof that it is incorrect to assume that the rotational inertia can be simply ignored in the free-vibration analysis of shear beams and to expect that the natural frequencies and modal shapes are correct. Kausel 2002 elegantly proved this point in shear beams with unrestrained or partially restrained ends against rotation of the cross sections, showing that the classical solutions which are based on r =0 violate the principle of angular moment.

Quantum dots provide an optical signal specific to full collapse fusion of synaptic vesicles

Synaptic vesicles are responsible for releasing neurotransmitters and are thus essential to brain function. The classical mode of vesicle recycling includes full collapse of the vesicle into the plasma membrane and clathrin-mediated regeneration of a new vesicle. In contrast, a nonclassical mode known as "kiss-and-run" features fusion by a transient fusion pore without complete loss of vesicle identity and offers possible advantages for increasing the throughput of neurotransmission. Studies of vesicular traffic have benefited greatly from fluorescent probes like FM dyes and synaptopHluorin. However, intrinsic properties of these probes limit their ability to provide a simple and precise distinction between classical and nonclassical modes. Here we report a novel optical probe specific to full collapse fusion, capitalizing on the size and superior photo-properties of photoluminescent quantum dots (Qdots). Qdots with exposed carboxyl groups were readily taken up by synaptic vesicles in an activity-, Ca(2+)-, and clathrin-dependent manner. Electron microscopy showed that Qdots were harbored within individual vesicles in a 1:1 ratio. The release of Qdots was activity- and Ca(2+)-dependent, similar to FM dyes. As artificial cargo, approximately 15 nm in diameter, Qdots will not escape vesicles during kiss-and-run but only with full collapse fusion. Strikingly, Qdots unloaded with kinetics substantially slower than destaining of FM dye, indicating that full-collapse fusion contributed only a fraction of all fusion events. As a full-collapse-fusion-responsive reporter, Qdots will likely promote better understanding of vesicle recycling at small CNS nerve terminals.

Sorptive Reconstruction of CuMCl4 (M = Al and Ga) upon Small-Molecule Binding and the Competitive Binding of CO and Ethylene

Carbonyl adducts to CuMCl(4) (M = Al and Ga) have been characterized by single-crystal and/or powder X-ray diffraction, IR and diffuse reflectance UV/vis spectroscopy. Up to two equivalents of carbon monoxide ( approximately 200 cm(3)/g relative to stp) are sorbed at room temperature, with equilibrium binding pressures of below 0.5 atm of CO. The carbonyl bonding is shown to be nonclassical, implicating the dominance of sigma-bonding and absence of pi-back-bonding. Analysis of the crystalline structures of the parent and adduct phases provides an atomistic picture of the sorptive reconstruction reaction. Comparison of the reactivity of CO and ethylene with these CuMCl(4) materials, as well as other copper(I) halide compounds that exhibit classical and nonclassical modes of bonding, demonstrates the ability to tune the reactivity of the crystalline frameworks with selectivity for carbon monoxide or olefins, respectively.