A Nitroreductase-activatable Metabolic Reporter for Covalent Labeling of Pathological Hypoxic Cells in Tumorigenesis.

Aberrant hypoxic stress will initiate a cascade of pathological consequence observed prominently in tumorigenesis. Understanding of hypoxia's role in tumorigenesis is  highly essential for developing effective therapeutics, which necessitates reliable tools to specifically distinguish hypoxic tumor cells (or tissues) and correlate their dynamics with the status of disease in complex living settings for precise theranostics. So far, disparate hypoxia-responsive probe molecules and prodrugs were designed via chemical or enzymatic reactions, yet their capability in real-time reporting pathogenesis development is often compromised due to unrestricted diffusion and less selectivity towards the environmental responsiveness. Herein we present an oxygen-insensitive nitroreductase (NTR)-activatable glycan metabolic reporter (pNB-ManNAz) capable of covalently labeling hypoxic tumor cells and tissues. Under pathophysiological hypoxic environments, the caged non-metabolizable precursor pNB-ManNAz exhibited unique responsiveness to cellular NTR, culminating in structural self-immolation and the resultant ManNAz could incorporate onto cell surface glycoproteins, thereby facilitating fluorescence labeling via bioorthogonal chemistry. This NTR-responsive metabolic reporter demonstrated broad applicability for multicellular hypoxia labeling, particularly in the dynamic monitoring of orthotopic tumorigenesis and targeted tumor phototherapy in vivo. We anticipate that this approach holds promise for investigating hypoxia-related pathological progression, offering valuable insights for accurate diagnosis and treatment.

A Deep-Red Emissive Sulfur-Doped Double [7]Helicene Photosensitizer: Synthesis, Structure and Chiral Optical Properties.

Doping of polycyclic conjugated hydrocarbons (PCHs) with sulfur atoms is becoming more and more important as a means of creating unique functional materials. Recently, thiophene-containing multiple helicenes have garnered enormous attention due to their intriguing electronic and (chir)optical properties compared with carbohelicenes. However, the efficient synthesis of thiopyran-containing multiple helicenes and the underlying sulfur doping mechanisms are rather unexplored. Herein, the synthesis and structural analysis of a thiopyran-containing double [7]helicene 3 are reported. X-ray crystallographic analysis reveals 3 and its dication with C2-symmetric propeller-shape structure and compact p-p interaction in the solid state. 3 exhibits deep-red to near-infrared (NIR) fluorescence emission. Tunable aromaticity of the central benzene ring and thiopyran rings is found by chemical oxidation, which is further confirmed by nucleus-independent chemical shift (NICS), anisotropy of the induced current density (AICD) and harmonic oscillator model of aromaticity (HOMA) analysis. Furthermore, the chiral and photosensitizing characters of 3 are investigated. The excellent deep-red to NIR fluorescence, circularly polarized luminescence (CPL) and photosensitizing activities suggest that 3 can be used as an outstanding photosensitizer in photodynamic therapy (PDT) and bioimaging, especially paving the way for future CPL-PDT and CPL-bio-probe applications.

Overcoming High-Quality Limitations in Plasmonic Metasurfaces for Ultrasensitive Terahertz Applications.

In photonics, achieving high-quality (Q) resonance is crucial for high-sensitivity devices used in applications, such as switching, sensing, and lasing. However, high-Q resonances are highly susceptible to internal losses of plasmonic devices, impeding their integration into broader systems across terahertz and visible light bands. Here, we overcome this challenge by proposing a low-Q plasmonic metasurface for ultrasensitive terahertz (THz) switching and sensing. Theoretically, we reveal an approach to constructing a low-Q resonator possessing high sensitivity to nonradiative losses. Leveraging this mechanism, we design a highly sensitive plasmonic metasurface induced by strong coupling between a quasi-bound state in the continuum and a dipole mode. By hybridizing with the germanium layer, the metadevice exhibits an ultralow pump threshold of 192 µJ/cm2 and an ultrafast switching cycle time of 7 ps. Furthermore, it also shows a high sensitivity of 224 GHz/RIU in refractive index sensing. The proposed paradigm of constructing low-Q and high-sensitivity photonic devices can be applied to biosensing, wide-band filters, and sensitive modulators.

Color coded metadevices toward programmed terahertz switching.

Terahertz modulators play a critical role in high-speed wireless communication, non-destructive imaging, and so on, which have attracted a large amount of research interest. Nevertheless, all-optical terahertz modulation, an ultrafast dynamical control approach, remains to be limited in terms of encoding and multifunction. Here we experimentally demonstrated an optical-programmed terahertz switching realized by combining optical metasurfaces with the terahertz metasurface, resulting in 2-bit dual-channel terahertz encoding. The terahertz metasurface, made up of semiconductor islands and artificial microstructures, enables effective all-optical programming by providing multiple frequency channels with ultrafast modulation at the nanosecond level. Meanwhile, optical metasurfaces covered in terahertz metasurface alter the spatial light field distribution to obtain color code. According to the time-domain coupled mode theory analysis, the energy dissipation modes in terahertz metasurface can be independently controlled by color excitation, which explains the principle of 2-bit encoding well. This work establishes a platform for all-optical programmed terahertz metadevices and may further advance the application of composite metasurface in terahertz manipulation.

Creating Anti-Chiral Exceptional Points in Non-Hermitian Metasurfaces for Efficient Terahertz Switching.

Non-Hermitian degeneracies, also known as exceptional points (EPs), have presented remarkable singular characteristics such as the degeneracy of eigenvalues and eigenstates and enable limitless opportunities for achieving fascinating phenomena in EP photonic systems. Here, the general theoretical framework and experimental verification of a non-Hermitian metasurface that holds a pair of anti-chiral EPs are proposed as a novel approach for efficient terahertz (THz) switching. First, based on the Pancharatnam-Berry (PB) phase and unitary transformation, it is discovered that the coupling variation of ±1 spin eigenstates will lead to asymmetric modulation in two orthogonal linear polarizations (LP). Through loss-induced merging of a pair of anti-chiral EPs, the decoupling of ±1 spin eigenstates are then successfully realized in a non-Hermitian metasurface. Final, the efficient THz modulation is experimentally demonstrated, which exhibits modulation depth exceeding 70% and Off-On-Off switching cycle less than 9 ps in one LP while remains unaffected in another one. Compared with conventional THz modulation devices, the metadevice shows several figures of merits, such as a single frequency operation, high modulation depth, and ultrafast switching speed. The proposed theory and loss-induced non-Hermitian device are general and can be extended to numerous photonic systems varying from microwave, THz, infrared, to visible light.

Transient Loss-Induced Non-Hermitian Degeneracies for Ultrafast Terahertz Metadevices.

Non-Hermitian degeneracies, also known as exceptional points (EPs), have attracted considerable attention due to their unique physical properties. In particular, metasurfaces related to EPs can open the way to unprecedented devices with functionalities such as unidirectional transmission and ultra-sensitive sensing. Herein, an active non-Hermitian metasurface with a loss-induced parity-time symmetry phase transition for ultrafast terahertz metadevices is demonstrated. Specifically, the eigenvalues of the non-Hermitian transmission matrix undergo a phase transition under optical excitation and are degenerate at EPs in parameter space, which is accompanied by the collapse of chiral transmission. Ultrafast EP modulation on a picosecond time scale can be realized through variations in the transient loss at a non-Hermitian metasurface pumped by pulsed excitation. Furthermore, by exploiting the physical characteristics of chiral transmission EPs, a switchable quarter-wave plate based on the photoactive metasurface is designed and experimentally verified and realized the corresponding function of polarization manipulation. This work opens promising possibilities for designing functional terahertz metadevices and fuses EP physics with active metasurfaces.

Generation of Albino Phenotype in Ornamental Fish by CRISPR/Cas9-Mediated Genome Editing of slc45a2 Gene.

Albinism is the most common color variation described in fish and is a fascinating trait of some ornamental fish species. Albino mutants can be generated by knocking out core genes affecting melanin synthesis like slc45a2 in several fish species. However, genetic mutation remains challenging for species with unknown genome information. In this study, we generated albino mutants in two selected ornamental fish species, royal farlowella (Sturisoma panamense), and redhead cichlid (Vieja melanura). For this purpose, we carried out phylogenetic analyses of fish slc45a2 sequences and identified a highly conserved region among different fish species. A pair of degenerate primers spanning this region was designed and used to amplify a conserved slc45a2 fragment of 340 bp from the two fish species. Based on the amplified sequences, a target site in the 6th exon was used for designing guide RNA and this targeted site was first verified by the CRISPR/Cas9 system in the zebrafish (Danio rerio) model for the effectiveness. Then, specific guide RNAs were designed for the two ornamental fish species and tested. Most of the injected larvae completely lost black pigment over the whole body and eyes. DNA sequencing confirmed a high degree of mutation at the targeted site. Overall, we described a fast and efficient method to generate albino phenotype in fish species by targeting the conserved 6th exon of slc45a2 gene for genome editing via CRISPR/Cas9 and this approach could be a new genetic tool to generate desirable albino ornamental fish.

Systematic Characterization of the Disruption of Intestine during Liver Tumor Progression in the xmrk Oncogene Transgenic Zebrafish Model.

The crosstalk between tumors and their local microenvironment has been well studied, whereas the effect of tumors on distant tissues remains understudied. Studying how tumors affect other tissues is important for understanding the systemic effect of tumors and for improving the overall health of cancer patients. In this study, we focused on the changes in the intestine during liver tumor progression, using a previously established liver tumor model through inducible expression of the oncogene xmrk in zebrafish. Progressive disruption of intestinal structure was found in the tumor fish, displaying villus damage, thinning of bowel wall, increase in goblet cell number, decrease in goblet cell size and infiltration of eosinophils, most of which were observed phenotypes of an inflammatory intestine. Intestinal epithelial cell renewal was also disrupted, with decreased cell proliferation and increased cell death. Analysis of intestinal gene expression through RNA-seq suggested deregulation of genes related to intestinal function, epithelial barrier and homeostasis and activation of pathways in inflammation, epithelial mesenchymal transition, extracellular matrix organization, as well as hemostasis. Gene set enrichment analysis showed common gene signatures between the intestine of liver tumor fish and human inflammatory bowel disease, the association of which with cancer has been recently noticed. Overall, this study represented the first systematic characterization of the disruption of intestine under the liver tumor condition and suggested targeting intestinal inflammation as a potential approach for managing cancer cachexia.

Transgenic Expression and Genome Editing by Electroporation of Zebrafish Embryos.

Microinjection is predominantly used to produce genetically modified fish. However, there are certain difficulties involved in some fish species. In this study, we tested an alternative method to produce genetically modified zebrafish by delivering DNA and other materials into embryos by electroporation. We optimized the electroporation conditions of a square wave electroporation system that work efficiently for the introduction of plasmid DNA, recombinant Cas9 nuclease and synthetic dual guide RNAs. Transgenic expression was observed in a wide range of tissues, which is comparable with those obtained by microinjection. We further determined that efficient gene delivery can be achieved during the cleavage stage. This study describes detailed electroporation parameters for gene delivery with high efficiency and low toxicity, providing a novel method to generate transgenic lines and genome editing.