Non-classical Mode Research Articles

Paraptosis: a non-classical paradigm of cell death for cancer therapy.

Due to the sustained proliferative potential of cancer cells, inducing cell death is a potential strategy for cancer therapy. Paraptosis is a mode of cell death characterized by endoplasmic reticulum (ER) and/or mitochondrial swelling and cytoplasmic vacuolization, which is less investigated. Considerable evidence shows that paraptosis can be triggered by various chemical compounds, particularly in cancer cells, thus highlighting the potential application of this non-classical mode of cell death in cancer therapy. Despite these findings, there remain significant gaps in our understanding of the role of paraptosis in cancer. In this review, we summarize the current knowledge on chemical compound-induced paraptosis. The ER and mitochondria are the two major responding organelles in chemical compound-induced paraptosis, which can be triggered by the reduction of protein degradation, disruption of sulfhydryl homeostasis, overload of mitochondrial Ca2+, and increased generation of reactive oxygen species. We also discuss the stumbling blocks to the development of this field and the direction for further research. The rational use of paraptosis might help us develop a new paradigm for cancer therapy.

Tensile cracks can shatter classical speed limits.

Brittle materials fail by means of rapid cracks. Classical fracture mechanics describes the motion of tensile cracks that dissipate released elastic energy within a point-like zone at their tips. Within this framework, a "classical" tensile crack cannot exceed the Rayleigh wave speed, [Formula: see text]. Using brittle neo-hookean materials, we experimentally demonstrate the existence of "supershear" tensile cracks that exceed shear wave speeds, [Formula: see text]. Supershear cracks smoothly accelerate beyond [Formula: see text], to speeds that could approach dilatation wave speeds. Supershear dynamics are governed by different principles than those guiding "classical" cracks; this fracture mode is excited at critical (material dependent) applied strains. This nonclassical mode of tensile fracture represents a fundamental shift in our understanding of the fracture process.

Non-Classical Molecular Activation by Phosphines and N-Heterocyclic Carbenes and Its Application to Catalytic Reactions

Abstract This Award Account reports our recent studies concerning the catalytic transformations that involve a non-classical mode of molecular activation by tertiary phosphines and N-heterocyclic carbenes (NHCs). Regarding organophosphine catalysis, we successfully designed reactions based on a P(III)/P(V) redox couple. A catalytic protocol for generating pentacoordinate P(V) species was devised by the reaction of tertiary phosphines, acyl fluorides and alkynoates. The ability of the thus generated fluorophosphoranes to participate in ligand coupling and ligand metathesis with organosilicon nucleophiles enables synthetic transformations that are otherwise unattainable, including the intermolecular carbofluorination of alkynes and the hydroalkenylation of enol ethers. Regarding nucleophilic NHC catalysis, the use of imidazolium-based NHCs can generate deoxy-Breslow intermediates that are sufficiently nucleophilic to promote the aromatic substitution of aryl halides, aryl ethers and anilides. The protocol can also be used for the nucleophilic activation of styrene derivatives, allowing for the generation of a series of ylide intermediates that can serve as non-stabilized vinyl anion equivalents. These results demonstrate that synthetic transformations involving non-stabilized carbanions can be conducted under catalytic conditions without the use of strong organometallic nucleophiles.

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.

Reconstruction of coherence matrix in x-representation using nonclassical Hartmann sensor

We show the coherence properties of a signal can be measured by a Hartmann wavefront sensor in a nonclassical regime. Recasting the detection theory of the classical Hartmann sensor in the sense of quantum tomography enables to measure the coherence function, which is an analogy to the density matrix of mixed quantum states. Two methods were tested for the reconstruction of the coherence matrix from the intensity scan in the nonclassical mode of the Hartmann sensor. The reconstruction was performed in a classic way using the POVM matrix and using data pattern tomography.

LCR並列型電磁シャントダンパを有する超電導磁気浮上系の非古典的モード解析

LCR並列型電磁シャントダンパを有する超電導磁気浮上系の非古典的モード解析

Poissonian twin-beam states and the effect of symmetrical photon subtraction in loss estimations

We have devised an experimentally realizable model generating twin beam states whose individual beam photon statistics are varied from thermal to Poissonian keeping the non-classical mode correlation intact. We have studied the usefulness of these states for loss measurement by considering three different estimators, comparing with the correlated thermal twin beam states generated from spontaneous parametric down conversion or four-wave mixing. We then incorporated the photon subtraction operation into the model and demonstrate their advantage in loss estimations with respect to un-subtracted states at both fixed squeezing and per photon exposure of the absorbing sample. For instance, at fixed squeezing, for two photon subtraction, up to three times advantage is found. In the latter case, albeit the advantage due to photon subtraction mostly subsides in standard regime, an unexpected result is that in some operating regimes the photon subtraction scheme can also give up to 20% advantage over the correlated Poisson beam result. We have also made a comparative study of these estimators for finding the best measurement for loss estimations. We present results for all the values of the model parameters changing the statistics of twin beam states from thermal to Poissonian.

Functionalized Tumor‐Targeting Nanosheets Exhibiting Fe(II) Overloading and GSH Consumption for Ferroptosis Activation in Liver Tumor

Liver tumor is difficult to cure for its high degree of malignancy and rapid progression characteristics. Ferroptosis as a new model of inducing cell death is expected to break the treatment bottleneck of liver tumors. Here, a strategy to induce ferroptosis in HepG2 cells with acid-degradable tumor targeted nanosheets Cu-Hemin-PEG-Lactose acid (Cu-Hemin-PEG-LA) is proposed. After highly ingested by HepG2 cells, Cu-Hemin-PEG-LA nanosheets are degraded by weak acid and release Cu(II) and hemin, which consuming intracellular glutathione (GSH) content and increasing the expression of heme oxygenase 1 (HMOX1) protein, respectively. Furthermore, the expression of glutathione peroxidase 4 protein (GPX4) is down-regulated by consumption intracellular GSH content via converting GSH into glutathione oxidized (GSSG), which is named the classical mode. The intracellular Fe2+ content is overloaded by the significant up-regulation of HMOX1 expression, which is denoted as nonclassical mode. The synergistic effect of classical and nonclassical mode increased the intracellular lipid reactive oxide species, induced the occurrence of ferroptosis and up-regulated the expression of BH3 interacting domain death agonist (BID), apoptosis-inducing factor (AIF), and endonuclease G proteins (EndoG). The synergistic strategy demonstrate the excellent ferroptosis induction ability and antitumor efficacy in vivo, which provides great potential for the clinical transformation of ferroptosis.

Effects of photon statistics in wave mixing on a single qubit

We theoretically consider wave mixing under the irradiation of a single qubit by two photon fields. The first signal is a classical monochromatic drive, while the second one is a nonclassical light. Particularly, we address two examples of a nonclassical light: (i) a broadband squeezed light and (ii) a periodically excited quantum superposition of Fock states with 0 and 1 photons. The mixing of classical and nonclassical photon fields gives rise to side peaks due to the elastic multiphoton scattering. We show that side peaks structure is distinct from the situation when two classical fields are mixed. The most striking feature is that some peaks are absent. The analysis of peak amplitudes can be used to probe photon statistics in the nonclassical mode.

Dynamics of Development of Folklore Festivals in Volyn in the Late 20th Century. Features of Formation

The paper addresses the problems of Volyn festival movement. The aim of this study is to consider the specifics of Volyn folklore festivals “Berehynia” and “Polissia Summer With Folklore” as prominent international projects. The research included collecting information from various sources (books, magazine and newspaper articles, interviews with organizers and participants, observations), analytical processing of this information, description of important facts, comparison of festivals by project size, age and social status of the audience, festival goal and scope, frequency, as well as social, demographic, geographical, professional status of their participants, conceptual differences and features, place and nature of events, ways to present projects to the general public and others. As a result, it was concluded that “Berehynia” is a festival of a classical mode while “Polissia Summer With Folklore” is a festival of a non-classical mode.

Monitoring hydrogen polysulfide during ferroptosis with a two-photon fluorescent probe

Hydrogen polysulfide (H2Sn, n > 1), a member of reactive sulfur species (RSS), is primarily generated during the crosstalk between H2S and reactive oxygen species (ROS), which plays important role in physiological and pathological processes. Ferroptosis is a new non-classical mode of cell death, in which ROS-associated lipid peroxidation and iron-dependent accumulation are the main features. However, the biological effects of H2Sn on ferroptosis and the detailed mechanisms of action remain poorly understood. Thus, there is an urgent need to develop highly selective and sensitive chemical tools for monitoring H2Sn in living cells. Herein, we develop a two-photon fluorescent probe (PSP) for specifically imaging H2Sn in live cells and tumor spheroids. This probe exhibited a sensitive and selective response to H2Sn, which had been used for imaging exogenous and endogenous H2Sn in living cells by confocal imaging and high content imaging. PSP exhibits excellent photo-stability and two-photon imaging performance when irradiating at 880 nm in 3D HeLa multicellular tumor spheroids. Importantly, our studies revealed that H2Sn levels were significantly up-regulated during ferroptosis. These excellent properties ensure that PSP is a promising two-photon probe for exploring the biological and pathological effects of H2Sn during ferroptosis.

In situ imaging of two-dimensional surface growth reveals the prevalence and role of defects in zeolite crystallization

Zeolite crystallization predominantly occurs by nonclassical pathways involving the attachment of complex (alumino)silicate precursors to crystal surfaces, yet recurrent images of fully crystalline materials with layered surfaces are evidence of classical growth by molecule attachment. Here we use in situ atomic force microscopy to monitor three distinct mechanisms of two-dimensional (2D) growth of zeolite A where we show that layer nucleation from surface defects is the most common pathway. Direct observation of defects was made possible by the identification of conditions promoting layered growth, which correlates to the use of sodium as an inorganic structure-directing agent, whereas its replacement with an organic results in a nonclassical mode of growth that obscures 2D layers and markedly slows the rate of crystallization. In situ measurements of layered growth reveal that undissolved silica nanoparticles in the synthesis medium can incorporate into advancing steps on crystal surfaces to generate defects (i.e., amorphous silica occlusions) that largely go undetected in literature. Nanoparticle occlusion in natural and synthetic crystals is a topic of wide-ranging interest owing to its relevance in fields spanning from biomineralization to the rational design of functional nanocomposites. In this study, we provide unprecedented insight into zeolite surface growth by molecule addition through time-resolved microscopy that directly captures the occlusion of silica nanoparticles and highlights the prevalent role of defects in zeolite crystallization.

Phosphine-NHC Manganese Hydrogenation Catalyst Exhibiting a Non-Classical Metal-Ligand Cooperative H2 Activation Mode.

Deprotonation of the MnI NHC-phosphine complex fac-[MnBr(CO)3 (κ2 P,C-Ph2 PCH2 NHC)] (2) under a H2 atmosphere readily gives the hydride fac-[MnH(CO)3 (κ2 P,C-Ph2 PCH2 NHC)] (3) via the intermediacy of the highly reactive 18-e NHC-phosphinomethanide complex fac-[Mn(CO)3 (κ3 P,C,C-Ph2 PCHNHC)] (6 a). DFT calculations revealed that the preferred reaction mechanism involves the unsaturated 16-e mangana-substituted phosphonium ylide complex fac-[Mn(CO)3 (κ2 P,C-Ph2 P=CHNHC)] (6 b) as key intermediate able to activate H2 via a non-classical mode of metal-ligand cooperation implying a formal λ5 -P-λ3 -P phosphorus valence change. Complex 2 is shown to be one of the most efficient pre-catalysts for ketone hydrogenation in the MnI series reported to date (TON up to 6200).

Asymptotic analysis of the Guyer–Krumhansl–Stefan model for nanoscale solidification

Nanoscale solidification is becoming increasingly relevant in applications involving ultra-fast freezing processes and nanotechnology. However, thermal transport on the nanoscale is driven by infrequent collisions between thermal energy carriers known as phonons and is not well described by Fourier's law. In this paper, the role of non-Fourier heat conduction in nanoscale solidification is studied by coupling the Stefan condition to the Guyer--Krumhansl (GK) equation, which is an extension of Fourier's law, valid on the nanoscale, that includes memory and non-local effects. A systematic asymptotic analysis reveals that the solidification process can be decomposed into multiple time regimes, each characterised by a non-classical mode of thermal transport and unique solidification kinetics. For sufficiently large times, Fourier's law is recovered. The model is able to capture the change in the effective thermal conductivity of the solid during its growth, consistent with experimental observations. The results from this study provide key quantitative insights that can be used to control nanoscale solidification processes.

Normal human immune cells are sensitive to telomerase inhibition by Brassica -derived 3,3-diindolylmethane,partly mediated via ERα/β-AP1 signaling

Indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM) from Brassica plants are regarded as promising anticancer phytochemicals. The enzyme telomerase is a very attractive target for cancer therapeutics; in normal cells such as lymphocytes, it plays a decisive role for cell maintenance. The effect of I3C and DIM on telomerase in normal human immune cells (PBMC) was studied compared to leukaemia cells (HL-60). Signalling of telomerase regulation via estrogen receptor (ER) was addressed. Short-term treatment with I3C and DIM inhibited telomerase activity in leukaemia cells (>30 μM I3C; >3 μM DIM). In CD3/CD28 activated PBMC, inhibition was stronger, though (>3 μM I3C; >1 μM DIM). DIM long-term treatment resulted in DNA damage induction and proliferation inhibition in PBMC as determined by the comet assay and CFSE staining, respectively. A relevance of ERα/β-AP1 signaling for telomerase inhibition on enzyme activity, but not transcription level became evident indicating a nonclassical mode for ER regulation of telomerase by DIM. Although desired in cancer cells, this study identified a potential adverse impact of I3C and DIM on telomerase action in normal human immune cells, partly mediated by an ER-dependent mechanism. These new findings should be considered for potential chronic high-dose chemoprevention strategies using these compounds.

Imaging flow cytometry and GST pulldown assays provide new insights into channel catfish leukocyte immune-type receptor-mediated phagocytic pathways

Channel catfish (Ictalurus punctatus) leukocyte immune-type receptors (IpLITRs) control various innate immune cell effector responses including the phagocytic process. This large immunoregulatory receptor family also consists of multiple receptor-types with variable signaling abilities that is dependent on their inherent or acquired tyrosine-containing cytoplasmic tail (CYT) regions. For example, IpLITR 2.6b associates with the immunoreceptor tyrosine-based activation motif (ITAM)-containing adaptor molecule IpFcRγ-L, and when expressed in mammalian cells it activates phagocytosis using a similar profile of intracellular signaling mediators that also regulate the prototypical mammalian Fc receptor (FcR) phagocytic pathway. Alternatively, IpLITR 1.1b contains a long tyrosine-containing CYT with multifunctional capabilities including both inhibitory and stimulatory actions. Recently, we demonstrated that IpLITR 1.1b activates a unique phagocytic pathway involving the generation of multiple plasma membrane extensions that rapidly capture extracellular targets and secure them on the cell surface in phagocytic cup-like structures. Occasionally, these captured targets are completely engulfed albeit at a significantly lower rate than what was observed for IpLITR 2.6b. While this novel IpLITR 1.1b phagocytic activity is insensitive to classical blockers of phagocytosis, its distinct target capture and engulfment actions depend on the engagement of the actin polymerization machinery. However, it is not known how this protein translates target recognition into intracellular signaling events during this atypical mode of phagocytosis. Using imaging flow cytometry and GST pulldown assays, the aims of this study were to specifically examine what regions of the IpLITR 1.1b CYT trigger phagocytosis and to establish what profile of intracellular signaling molecules likely participate in its actions. Our results show that in stably transfected AD293 cells, the membrane proximal and distal CYT segments of IpLITR 1.1b independently regulate its phagocytic activities. These CYT regions were also shown to differentially recruit various SH2 domain-containing intracellular mediators, which provides new information about the dynamic immunoregulatory abilities of IpLITR 1.1b. Overall, this work further advances our understanding of how certain immunoregulatory receptor-types link extracellular target binding events to the actin polymerization machinery during a non-classical mode of phagocytosis.

Nonclassical crystallization in vivo et in vitro (I): Process-structure-property relationships of nanogranular biominerals.

A distinct nanogranular fine structure is shared by a wealth of biominerals from several species, classes and taxa. This nanoscopic organization affects the properties and behavior of the biogenic ceramic material and confers on them attributes that are essential to their function. We present a set of structure-relationship properties that are rooted in the nanogranular organization and we propose that they rest on a common pathway of formation, a colloid-driven and hence nonclassical mode of crystallization. With this common modus operandi, we reveal the most fundamental and wide spread process-structure-property relationship in biominerals. With the recent increase in our understanding of nonclassical crystallization in vitro and in vivo, this significant process-structure-property relationship will serve as a source for new design approaches of bio-inspired materials.

Phenotype anchoring in zebrafish reveals a potential role for matrix metalloproteinases (MMPs) in tamoxifen's effects on skin epithelium

The zebrafish is a powerful alternative model used to link phenotypes with molecular effects to discover drug mode of action. Using a zebrafish embryo-larval toxicity bioassay, we evaluated the effects of tamoxifen — a widely used anti-estrogen chemotherapeutic. Zebrafish exposed to ≥10μM tamoxifen exhibited a unique necrotic caudal fin phenotype that was rapidly induced regardless of developmental life-stage when treatment was applied. To define tamoxifen's bioactivity resulting in this phenotype, targeted gene expression was used to evaluate 100 transcripts involved in tissue remodeling, calcium signaling, cell cycle and cell death, growth factors, angiogenesis and hypoxia. The most robustly misregulated transcripts in the tail were matrix metalloproteinases mmp9 and mmp13a, induced 127 and 1145 fold, respectively. Expression of c-fos, c-jun, and ap1s1 were also moderately elevated (3–7 fold), consistent with AP-1 activity — a transcription factor that regulates MMP expression. Immunohistochemistry confirmed high levels of induction for MMP13a in affected caudal fin skin epithelial tissue. The necrotic caudal fin phenotype was significantly attenuated or prevented by three functionally unique MMP inhibitors: EDTA (metal chelator), GM 6001 (broad MMP inhibitor), and SR 11302 (AP-1 transcription factor inhibitor), suggesting MMP-dependence. SR 11302 also inhibited induction of mmp9, mmp13a, and a putative MMP target, igfbp1a. Overall, our studies suggest that tamoxifen's effect is the result of perturbation of the MMP system in the skin leading to ectopic expression, cytotoxicity, and the necrotic caudal fin phenotype. These studies help advance our understanding of tamoxifen's non-classical mode of action and implicate a possible role for MMPs in tissues such as skin.

Synthesis, DNA-binding Properties and Quantitative Structure-Activity Relationships on Ruthenium(II) Complexes with Calf-Thymus DNA

A series of novel ruthenium(II) complexes with electron-donor or electron-acceptor groups in intercalative ligands, [Ru(phen)2(o-MOPIP)]2+(1), [Ru(phen)2(o-MPIP)]2+(2), [Ru(phen)2(o-CPIP)]2+(3) and [Ru(phen)2(o-NPIP)]2+(4) have been synthesized and characterized with elementary, ES-MS, 1H NMR, electronic absorption and emission spectra. The binding properties of these complexes to CT-DNA have been investigated by spectroscopy and viscosity experiments. It’s illustrated that these complexes bind to DNA in a non-classical intercalation mode and their intrinsic binding constants (Kb) for 1, 2, 3 and 4 are calculated as 1.1, 0.35, 0.53 and 1.7 × 105 M-1, respectively. The Quantitative Structure-Activity Relationships (QSAR) of these ruthenium complexes, as well as some other ruthenium complexes congers has been investigated, and a linearity equation have been obtained: logKb=0.2429π+0.0429π2+0.2907σ+0.6 389I+4.3491 (n=12; R=0.9338; F=11.9134; p=0.0030). This results show that the electron-acceptor group and a large hydrophobic group will enhance the DNA binding affinity of ruthenium complexes.

Behaviour of corroded reinforced concrete beams repaired with NSM CFRP rods, experimental and finite element study

Abstract The near surface mounted reinforcement (NSM) technique is one of the promising techniques used nowadays to strengthen reinforced concrete RC structures. In the NSM technique, the Carbon Fibre Reinforced Polymer (CFRP) rods are placed inside pre-cut grooves and are bonded to the concrete with epoxy adhesive. This paper investigates corroded RC beams repaired with NSM CFRP rods and studies the failure mode of the repaired beam according to experimental and numerical modelling results. Experimental results and numerical modelling results of a 2D finite element (FE) model using the FEMIX computer code were obtained on five, 3-m-long beams: three corroded RC beams that had been exposed to natural corrosion for 25 years and two control beams with no corrosion. Two beams, one corroded and one control (A1CL3-R and A1T-R) were each repaired in bending with one 6-mm-diameter NSM CFRP rod and were then tested in three-point bending up to failure. The corrosion of the tensile steel bars and steel stirrups was studied. Ultimate capacity, yielding capacity and failure modes are also discussed. The experimental results showed that the NSM technique increased the overall capacity (ultimate load capacity and yielding capacity) of control and corroded beams despite a non-classical mode of failure with separation of the concrete cover occurring in the corroded beam due to damage induced by corrosion. The FE numerical modelling results from FEMIX were compatible with the experimental ones except for the repaired corroded beam A1CL3-R, for which a three-dimensional model using the commercial software ABAQUS was required. Finally some comparisons were made between the experimental and FE numerical modelling results obtained using ABAQUS in order to study the specific mode of failure of the corroded beam, which occurred by the separation of concrete cover.