Tunable entangled photon-pair generation in a liquid crystal.

Liquid crystals, with their ability to self-assemble, strong response to an electric field and integrability into complex systems, are key materials in light-beam manipulation1. The recently discovered ferroelectric nematic liquid crystals2,3 also have considerable second-order optical nonlinearity, making them a potential material for nonlinear optics4,5. Their use as sources of quantum light could considerably extend the boundaries of photonic quantum technologies6. However, spontaneous parametric down-conversion, the basic source of entangled photons7, heralded single photons8 and squeezed light9, has so far not been observed in liquid crystals-or in any liquids or organic materials. Here we implement spontaneous parametric down-conversion in a ferroelectric nematic liquid crystal and demonstrate electric-field tunable broadband generation of entangled photons, with an efficiency comparable to that of the best nonlinear crystals. The emission rate and polarization state of photon pairs is markedly varied by applying a few volts or twisting the molecular orientation along the sample. A liquid-crystal source enables a special type of quasi-phase matching10, which is based on the molecular twist structure and is therefore reconfigurable for the desired spectral and polarization properties of photon pairs. Such sources promise to outperform standard nonlinear optical materials in terms of functionality, brightness and the tunability of the generated quantum state. The concepts developed here can be extended to complex topological structures, macroscopic devices and multi-pixel tunable quantum light sources.

Quantifying local stiffness and forces in soft biological tissues using droplet optical microcavities.

Mechanical properties of biological tissues fundamentally underlie various biological processes and noncontact, local, and microscopic methods can provide fundamental insights. Here, we present an approach for quantifying the local mechanical properties of biological materials at the microscale, based on measuring the spectral shifts of the optical resonances in droplet microcavities. Specifically, the developed method allows for measurements of deformations in dye-doped oil droplets embedded in soft materials or biological tissues with an error of only 1 nm, which in turn enables measurements of anisotropic stress inside tissues as small as a few pN/µm2. Furthermore, by applying an external strain, Young's modulus can be measured in the range from 1 Pa to 35 kPa, which covers most human soft tissues. Using multiple droplet microcavities, our approach could enable mapping of stiffness and forces in inhomogeneous soft tissues and could also be applied to in vivo and single-cell experiments. The developed method can potentially lead to insights into the mechanics of biological tissues.

Non-contact monitoring of glucose concentration and pH by integration of wearable and implantable hydrogel sensors with optical coherence tomography.

Optical coherence tomography (OCT) is a noninvasive imaging technique with large penetration depth into the tissue, but limited chemical specificity. By incorporating functional co-monomers, hydrogels can be designed to respond to specific molecules and undergo reversible volume changes. In this study, we present implantable and wearable biocompatible hydrogel sensors combined with OCT to monitor their thickness change as a tool for continuous and real-time monitoring of glucose concentration and pH. The results demonstrate the potential of combining hydrogel biosensors with OCT for non-contact continuous in-vivo monitoring of physiological parameters.

Topological liquid crystal superstructures as structured light lasers.

Liquid crystals (LCs) form an extremely rich range of self-assembled topological structures with artificially or naturally created topological defects. Some of the main applications of LCs are various optical and photonic devices, where compared to their solid-state counterparts, soft photonic systems are fundamentally different in terms of unique properties such as self-assembly, self-healing, large tunability, sensitivity to external stimuli, and biocompatibility. Here we show that complex tunable microlasers emitting structured light can be generated from self-assembled topological LC superstructures containing topological defects inserted into a thin Fabry-Pérot microcavity. The topology and geometry of the LC superstructure determine the structuring of the emitted light by providing complex three-dimensionally varying optical axis and order parameter singularities, also affecting the topology of the light polarization. The microlaser can be switched between modes by an electric field, and its wavelength can be tuned with temperature. The proposed soft matter microlaser approach opens directions in soft matter photonics research, where structured light with specifically tailored intensity and polarization fields could be designed and implemented.

Bifunctional Duocarmycin Analogues as Inhibitors of Protein Tyrosine Kinases.

Bifunctional duocarmycin analogues are highly cytotoxic compounds that have been shown to be irreversible aldehyde dehydrogenase 1 inhibitors. Interestingly, cells with low aldehyde dehydrogenase 1 expression are also sensitive to bifunctional duocarmycin analogues, suggesting the existence of another target. Through in silico approaches, including principal component analysis, structure-similarity search, and docking calculations, protein tyrosine kinases, and especially the vascular endothelial growth factor receptor 2 (VEGFR-2), were predicted as targets of bifunctional duocarmycin analogues. Biochemical validation was performed in vitro, confirming the in silico results. Structural optimization was performed to mainly target VEGFR-2, but not aldehyde dehydrogenase 1. The optimized bifunctional duocarmycin analogue was synthesized. In vitro assays revealed this bifunctional duocarmycin analogue as a strong inhibitor of VEGFR-2, with low residual aldehyde dehydrogenase 1 activity. Altogether, studies revealed bifunctional duocarmycin analogues as a new class of naturally derived compounds that express a very high cytotoxicity to cancer cells overexpressing aldehyde dehydrogenase 1 as well as VEGFR-2.

Remote and autonomous temperature measurement based on 3D liquid crystal microlasers.

We demonstrate non-contact temperature measurement with one tenth of a kelvin precision at distances of several meters using omnidirectional laser emission from dye-doped cholesteric liquid crystal droplets freely floating in a fluid medium. Upon the excitation with a pulsed laser the liquid crystal droplet emits laser light due to 3D Bragg lasing in all directions. The spectral position of the lasing is highly dependent on temperature, which enables remote and contact-less temperature measurement with high precision. Both laser excitation and collection of light emitted by microlasers is performed through a wide telescope aperture optics at a distance of up to several meters. The optical excitation volume, where the droplets are excited and emitting the laser light is of the order of ten cubic millimeters. The measurement is performed with ten second accumulation time, when several droplets pass through the excitation volume due to their motion. The time of measurement could easily be shortened to less than a second by increasing the rate of the excitation laser. Since the method is based solely on measuring the spectral position of a single and strong laser line, it is quite insensitive to scattering, absorption and background signals, such as autofluorescence. This enables a wide use in science and industry, with a detection range exceeding tens of meters.

Lasing properties of polymerized chiral nematic Bragg onion microlasers.

Dye doped photocurable cholesteric liquid crystal was used to produce solid Bragg onion omnidirectional lasers. The lasers were produced by dispersing and polymerizing chiral nematic LC with parallel surface anchoring of LC molecules at the interface, extracted and transferred into another medium. Lasing characteristics were studied in carrier medium with different refractive index. The lasing in spherical cholesteric liquid crystal was attributed to two mechanisms, photonic bandedge lasing and lasing of whispering-gallery modes. The latter can be suppressed by using a higher index carrier fluid to prevent total internal reflection on the interface of the spheres. Pulse-to-pulse stability and threshold characteristics were also studied and compared to non-polymerized lasers. The polymerization process greatly increases the lasing stability.

Laser Particle Stimulated Emission Microscopy.

We introduce an optical microscopy technique that utilizes micro- or nanolasers embedded in a sample as imaging probes. The narrow spectra and nonlinear power dependence of stimulated emission from the laser particles yield optical sectioning, subdiffraction resolution, and low out-of-focus background. A proof of concept is demonstrated using perovskite nanowires.

Isolation of Flavonoids from Deguelia duckeana and Their Effect on Cellular Viability, AMPK, eEF2, eIF2 and eIF4E.

Preparations of Deguelia duckeana, known in Brazil as timbó, are used by indigenous people to kill fish. Reinvestigation of its extracts resulted in the isolation and identification of 11 known flavonoids identified as 3,5,4'-trimethoxy-4-prenylstilbene (1), 4-methoxyderricidine (2), lonchocarpine (3), 4-hydroxylonchocarpine (4), 4-methoxylonchocarpine (5), 5-hydroxy-4',7-dimethoxy-6-prenylflavanone (6), 4'-hydroxyisolonchocarpine (7), 4'-methoxyisolonchocarpine (8), 3',4',7-trimethoxyflavone (9), 3',4'-methylenedioxy-7-methoxyflavone (10), and 2,2-dimethyl-chromone-5,4'-hydroxy-5'-methoxyflavone (11). Except for 1, 3, and 4 all of these flavonoids have been described for the first time in D. duckeana and the flavanone 6 for the first time in nature. Compounds 2, 3, 4, 7, 9, and 10 were studied for their potential to induce cell death in neuronal SK-N-SH cells. Only the chalcone 4 and the flavanone 7 significantly induced lactate dehydrogenase (LDH) release, which was accompanied by activation of caspase-3 and impairment of energy homeostasis in the MTT assay and may explain the killing effect on fish. Interestingly, the flavone 10 reduced cell metabolism in the MTT assay without inducing cytotoxicity in the LDH assay. Furthermore, the flavonoids 2, 3, 4, 7, and 10 induced phosphorylation of the AMP-activated protein kinase (AMPK) and the eukaryotic elongation factor 2 (eEF2). The initiation factor eIF4E was dephosphorylated in the presence of these compounds. The initiation factor eIF2alpha was not affected. Further studies are needed to elucidate the importance of the observed effects on protein synthesis and potential therapeutic perspectives.

Cellular dye lasers: lasing thresholds and sensing in a planar resonator.

Biological cell lasers are promising novel building blocks of future biocompatible optical systems and offer new approaches to cellular sensing and cytometry in a microfluidic setting. Here, we demonstrate a simple method for providing optical gain by using a variety of standard fluorescent dyes. The dye gain medium can be located inside or outside a cell, or in both, which gives flexibility in experimental design and makes the method applicable to all cell types. Due to the higher refractive index of the cytoplasm compared to the surrounding medium, a cell acts as a convex lens in a planar Fabry-Perot cavity. Its effect on the stability of the laser cavity is analyzed and utilized to suppress lasing outside cells. The resonance modes depend on the shape and internal structure of the cell. As proof of concept, we show how the laser output modes are affected by the osmotic pressure.

Intracellular biocompatible hexagonal boron nitride quantum emitters as single-photon sources and barcodes.

Color centers in hexagonal boron nitride (hBN) have been emerging as a multifunctional platform for various optical applications including quantum information processing, quantum computing and imaging. Simultaneously, due to its biocompatibility and biodegradability hBN is a promising material for biomedical applications. In this work, we demonstrate single-photon emission from hBN color centers embedded inside live cells and their application to cellular barcoding. The generation and internalization of multiple color centers into cells was performed via simple and scalable procedure while keeping the cells unharmed. The emission from live cells was observed as multiple diffraction-limited spots, which exhibited excellent single-photon characteristics with high single-photon purity of 0.1 and superb emission stability without photobleaching or spectral shifts over several hours. Due to different emission wavelengths and peak widths of the color centers, they were employed as barcodes. We term them Quantum Photonic Barcodes (QPBs). Each QPB can exist in one out of 470 possible distinguishable states and a combination of a few QPBs per cell can be used to uniquely tag virtually an unlimited number of cells. The barcodes developed here offer some excellent properties, including ease of production by a single-step procedure, biocompatibility and biodegradability, emission stability, no photobleaching, small size and a huge number of unique barcodes. This work provides a basis for the use of hBN color centers for robust barcoding of cells and due to the single photon emission, presented concepts could in future be extended to quantum-limited sensing and super-resolution imaging.

Carbimazole is an inhibitor of protein synthesis and protects from neuronal hypoxic damage in vitro.

Oxygen deprivation during ischemic or hemorrhagic stroke results in ATP depletion, loss of ion homeostasis, membrane depolarization, and excitotoxicity. Pharmacologic restoration of cellular energy supply may offer a promising concept to reduce hypoxic cell injury. In this study, we investigated whether carbimazole, a thionamide used to treat hyperthyroidism, reduces neuronal cell damage in oxygen-deprived human SK-N-SH cells or primary cortical neurons. Our results revealed that carbimazole induces an inhibitory phosphorylation of eukaryotic elongation factor 2 (eEF2) that was associated with a marked inhibition of global protein synthesis. Translational inhibition resulted in significant bioenergetic savings, preserving intracellular ATP content in oxygen-deprived neuronal cells and diminishing hypoxic cellular damage. Phosphorylation of eEF2 was mediated by AMP-activated protein kinase and eEF2 kinase. Carbimazole also induced a moderate calcium influx and a transient cAMP increase. To test whether translational inhibition generally diminishes hypoxic cell damage when ATP availability is limiting, the translational repressors cycloheximide and anisomycin were used. Cycloheximide and anisomycin also preserved ATP content in hypoxic SK-N-SH cells and significantly reduced hypoxic neuronal cell damage. Taken together, these data support a causal relation between the pharmacologic inhibition of global protein synthesis and efficient protection of neurons from ischemic damage by preservation of high-energy metabolites in oxygen-deprived cells. Furthermore, our results indicate that carbimazole or other translational inhibitors may be interesting candidates for the development of new organ-protective compounds. Their chemical structure may be used for computer-assisted drug design or screening of compounds to find new agents with the potential to diminish neuronal damage under ATP-limited conditions.

Microcavity- and Microlaser-Based Optical Barcoding: A Review of Encoding Techniques and Applications.

Optical microbarcodes have recently received a great deal of interest because of their suitability for a wide range of applications, such as multiplexed assays, cell tagging and tracking, anticounterfeiting, and product labeling. Spectral barcodes are especially promising because they are robust and have a simple readout. In addition, microcavity- and microlaser-based barcodes have very narrow spectra and therefore have the potential to generate millions of unique barcodes. This review begins with a discussion of the different types of barcodes and then focuses specifically on microcavity-based barcodes. While almost any kind of optical microcavity can be used for barcoding, currently whispering-gallery microcavities (in the form of spheres and disks), nanowire lasers, Fabry-Pérot lasers, random lasers, and distributed feedback lasers are the most frequently employed for this purpose. In microcavity-based barcodes, the information is encoded in various ways in the properties of the emitted light, most frequently in the spectrum. The barcode is dependent on the properties of the microcavity, such as the size, shape, and the gain materials. Various applications of these barcodes, including cell tracking, anticounterfeiting, and product labeling are described. Finally, the future prospects for microcavity- and microlaser-based barcodes are discussed.

Deep tissue localization and sensing using optical microcavity probes.

Optical microcavities and microlasers were recently introduced as probes inside living cells and tissues. Their main advantages are spectrally narrow emission lines and high sensitivity to the environment. Despite numerous novel methods for optical imaging in strongly scattering biological tissues, imaging at single-cell resolution beyond the ballistic light transport regime remains very challenging. Here, we show that optical microcavity probes embedded inside cells enable three-dimensional localization and tracking of individual cells over extended time periods, as well as sensing of their environment, at depths well beyond the light transport length. This is achieved by utilizing unique spectral features of the whispering-gallery modes, which are unaffected by tissue scattering, absorption, and autofluorescence. In addition, microcavities can be functionalized for simultaneous sensing of various parameters, such as temperature or pH value, which extends their versatility beyond the capabilities of standard fluorescent labels.

From coffee stains to uniform deposits: Significance of the contact-line mobility.

HYPOTHESIS: Contact-line motion upon drying of a sessile droplet strongly affects the solute transport and solvent evaporation profile. Hence, it should have a strong impact on the deposit formation and might be responsible for volcano-like, dome-like and flat deposit morphologies. EXPERIMENTS: A method based on a thin-film interference was used to track the drop height profile and contact line motion during the drying. A diverse set of drying scenarios was obtained by using inks with different solvent compositions and by adjusting the substrate wetting properties. The experimental data was compared to the predictions of a phenomenological model. FINDINGS: We highlight the essential role of contact-line mobility on the deposit morphology of solution-based inks. A pinned contact line produces exclusively ring-like deposits under normal conditions. On the contrary, drops with a mobile contact line can produce ring-, flat- or dome-like morphology. The developed phenomenological model shows that the deposit morphology depends on solvent evaporation profile, evolution of the drop radius relative to its contact angle, and the ratio between initial and maximal (gelling) solute concentration. These parameters can be adjusted by the ink solvent composition and substrate wetting behaviour, which provides a way for deposition of uniform and flat deposits via inkjet printing.

Carbon monoxide releasing molecule-2 inhibits pancreatic stellate cell proliferation by activating p38 mitogen-activated protein kinase/heme oxygenase-1 signaling.

Proliferation of pancreatic stellate cells (PSCs) plays a cardinal role during fibrosis development. Therefore, the suppression of PSC growth represents a therapeutic option for the treatment of pancreatic fibrosis. It has been shown that up-regulation of the enzyme heme oxygenase-1 (HO-1) could exert antiproliferative effects on PSCs, but no information is available on the possible role of carbon monoxide (CO), a catalytic byproduct of the HO metabolism, in this process. In the present study, we have examined the effect of CO releasing molecule-2 (CORM-2) liberated CO on PSC proliferation and have elucidated the mechanisms involved. Using primary rat PSCs, we found that CORM-2 inhibited PSC proliferation at nontoxic concentrations by arresting cells at the G(0)/G(1) phase of the cell cycle. This effect was associated with activation of p38 mitogen-activated protein kinase (MAPK) signaling, induction of HO-1 protein, and up-regulation of the cell cycle inhibitor p21(Waf1/Cip1). The p38 MAPK inhibitor 4-(4-flurophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)imidazole (SB203580) abolished the inhibitory effect of CORM-2 on PSC proliferation and prevented both CORM-2-induced HO-1 and p21(Waf1/Cip1) up-regulation. Treatment with tin protoporphyrin IX, an HO inhibitor, or transfection of HO-1 small interfering RNA abolished the inductive effect of CORM-2 on p21(Waf1/Cip1) and reversed the suppressive effect of CORM-2 on PSC growth. The ability of CORM-2 to induce cell cycle arrest was abrogated in p21(Waf1/Cip1)-silenced cells. Taken together, our results suggest that CORM-2 inhibits PSC proliferation by activation of the p38/HO-1 pathway. These findings may indicate a therapeutic potential of CO carriers in the treatment of pancreatic fibrosis.

Optical-resonance-assisted generation of super monodisperse microdroplets and microbeads with nanometer precision.

Droplets with predefined sizes have been controllably produced at the tip of a micro-capillary immersed in an external fluid while tracking the high Q-factor whispering gallery modes (WGM). The modes were fitted to a model to give precise real-time size measurement, which was used as a feedback to control the pressure in the capillary and the release of the droplet from the capillary when it reached the target size. In this way a dispersion of highly monodisperse droplets anywhere in the size range from 5 µm to 50 µm were produced. To fabricate solid beads, the droplets were made from a liquid photopolymer and were later polymerized with UV light. The polymerized beads showed long term stability. The diameter of the generated oil droplets and polymerized microbeads could be reproduced with a standard deviation of 1.1 nm and 20 nm, respectively. Overall, the demonstrated method improves the size precision by three and two orders of magnitude for microdroplets and microbeads, respectively, compared to standard production methods such as reported in microfluidics. Encoding of short words and numbers has been demonstrated by producing three beads with predefined sizes. The stored information has been read from the emitted spectrum.

Particulate Matter (PM2.5) from Biomass Combustion Induces an Anti-Oxidative Response and Cancer Drug Resistance in Human Bronchial Epithelial BEAS-2B Cells.

Nearly half of the world's population relies on combustion of solid biofuels to cover fundamental energy demands. Epidemiologic data demonstrate that particularly long-term emissions adversely affect human health. However, pathological molecular mechanisms are insufficiently characterized. Here we demonstrate that long-term exposure to fine particulate matter (PM2.5) from biomass combustion had no impact on cellular viability and proliferation but increased intracellular reactive oxygen species (ROS) levels in bronchial epithelial BEAS-2B cells. Exposure to PM2.5 induced the nuclear factor erythroid 2-related factor 2 (Nrf2) and mediated an anti-oxidative response, including enhanced levels of intracellular glutathione (GSH) and nuclear accumulation of heme oxygenase-1 (HO-1). Activation of Nrf2 was promoted by the c-Jun N-terminal kinase JNK1/2, but not p38 or Akt, which were also induced by PM2.5. Furthermore, cells exposed to PM2.5 acquired chemoresistance to doxorubicin, which was associated with inhibition of apoptosis and elevated levels of GSH in these cells. Our findings propose that exposure to PM2.5 induces molecular defense mechanisms, which prevent cellular damage and may thus explain the initially relative rare complications associated with PM2.5. However, consistent induction of pro-survival pathways may also promote the progression of diseases. Environmental conditions inducing anti-oxidative responses may have the potential to promote a chemoresistant cellular phenotype.

Heterocyclic thioureylenes protect from calcium-dependent neuronal cell death.

Calcium-dependent cell death occurs in neurodegenerative diseases and ischemic or traumatic brain injury. We analyzed whether thioureylenes can act in a neuroprotective manner by pharmacological suppression of calcium-dependent pathological pathways. In human neuroblastoma (SK-N-SH) cells, thioureylenes (thiopental, carbimazole) inhibited the calcium-dependent neuronal protein phosphatase (PP)-2B, the activation of the proapoptotic transcription factor nuclear factor of activated T-cells, BAD-induced initiation of caspase-3, and poly-(ADP-ribose)-polymerase cleavage. Caspase-3-independent cell death was attenuated by carbimazole and the protein kinase C (PKC) delta inhibitor rottlerin by a PP-2B-independent mechanism. Neuroprotective effects were mediated by the redox-active sulfur of thioureylenes. Furthermore, we observed that the route of calcium mobilization was differentially linked to caspase-dependent or independent cell death and that BAD dephosphorylation did not necessarily induce intrinsic caspase activation. In addition, a new 30- to 35-kDa caspase-3 fragment with an unknown function was identified. In organotypic hippocampal slice cultures, thioureylenes inhibited caspase-3 activation or reduced N-methyl-d-aspartate and kainic acid receptor-mediated cell death that was independent of caspase-3. Because prolonged inhibition of caspase-3 resulted in caspase-independent cellular damage, different types of cell death must be taken under therapeutic consideration. Here we show that thioureylenes in combination with PKCdelta inhibitors might represent a promising therapeutic approach to attenuate neuronal damage.