Synergistic effects of the KDM4C inhibitor SD70 and the menin inhibitor MI-503 against MLL::AF9-driven acute myeloid leukaemia.

MLL-rearranged (MLL-r) leukaemia is observed in approximately 10% of acute myeloid leukaemia (AML) and is associated with a relatively poor prognosis, highlighting the need for new treatment regimens. MLL fusion proteins produced by MLL rearrangements recruit KDM4C to mediate epigenetic reprogramming, which is required for the maintenance of MLL-r leukaemia. In this study, we used a combinatorial drug screen to selectively identify synergistic treatment partners for the KDM4C inhibitor SD70. The results showed that the drug combination of SD70 and MI-503, a potent menin-MLL inhibitor, induced synergistically enhanced apoptosis in MLL::AF9 leukaemia cells without affecting normal CD34+ cells. In vivo treatment with SD70 and MI-503 significantly prolonged survival in AML xenograft models. Differential gene expression analysis by RNA-seq following combined pharmacological inhibition of SD70 and MI-503 revealed changes in numerous genes, with MYC target genes being the most significantly downregulated. Taken together, these data provide preclinical evidence that the combination of SD70 and MI-503 is a potential dual-targeted therapy for MLL::AF9 AML.

Twist family BHLH transcription factor 1 is required for the maintenance of leukemia stem cell in MLL-AF9+ acute myeloid leukemia.

Leukemia stem cells (LSC) are a rare population capable of limitless self-renewal and are responsible for the initiation, maintenance, and relapse of leukemia. Elucidation of the mechanisms underlying the regulation of LSC function could provide novel treatment strategies. Here, we show that TWIST1 is extremely highly expressed in the LSC of MLL-AF9+ acute myeloid leukemia (AML), and its upregulation is positively regulated by KDM4C in a H3K9me3 demethylation-dependent manner. We further demonstrate that TWIST1 is essential for the viability, dormancy, and self-renewal capacities of LSC, and that it promotes the initiation and maintenance of MLL-AF9-mediated AML. In addition, TWIST1 directly interacts and collaborates with HOXA9 in inducing AML in mice. Mechanistically, TWIST1 exerts its oncogenic function by activating the WNT5a/RAC1 axis. Collectively, our study uncovers a critical role of TWIST1 in LSC function and provides new mechanistic insights into the pathogenesis of MLL-AF9+ AML.

Dielectric Metasurface Enabled Compact, Single-Shot Digital Holography for Quantitative Phase Imaging.

Quantitative phase imaging (QPI) enables nondestructive, real-time, label-free imaging of transparent specimens and can reveal information about their fundamental properties such as cell size and morphology, mass density, particle dynamics, and cellular fluctuations. Development of high-performance and low-cost quantitative phase imaging systems is thus required in many fields, including on-site biomedical imaging and industrial inspection. Here, we propose an ultracompact, highly stable interferometer based on a single-layer dielectric metasurface for common path off-axis digital holography and experimentally demonstrate quantitative phase imaging. The interferometric imaging system leveraging an ultrathin multifunctional metasurface captures image plane holograms in a single shot and provides quantitative phase information on the test samples for extraction of its physical properties. With the benefits of planar engineering and high integrability, the proposed metasurface-based method establishes a stable miniaturized QPI system for reliable and cost-effective point-of-care devices, live cell imaging, 3D topography, and edge detection for optical computing.

Generation of Perfect Electron Vortex Beam with a Customized Beam Size Independent of Orbital Angular Momentum.

The electron vortex beam (EVB)-carrying quantized orbital angular momentum (OAM) plays an essential role in a series of fundamental research. However, the radius of the transverse intensity profile of a doughnut-shaped EVB strongly depends on the topological charge of the OAM, impeding its wide applications in electron microscopy. Inspired by the perfect vortex in optics, herein, we demonstrate a perfect electron vortex beam (PEVB), which completely unlocks the constraint between the beam size and the beam's OAM. We design nanoscale holograms to generate PEVBs carrying different quanta of OAM but exhibiting almost the same beam size. Furthermore, we show that the beam size of the PEVB can be readily controlled by only modifying the design parameters of the hologram. The generation of PEVB with a customized beam size independent of the OAM can promote various in situ applications of free electrons carrying OAM in electron microscopy.

GADD45g acts as a novel tumor suppressor, and its activation suggests new combination regimens for the treatment of AML.

Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy for which there is an unmet need for novel treatment strategies. Here, we characterize the growth arrest and DNA damage-inducible gene gamma (GADD45g) as a novel tumor suppressor in AML. We show that GADD45g is preferentially silenced in AML, especially in AML with FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations and mixed-lineage leukemia (MLL)-rearrangements, and reduced expression of GADD45g is correlated with poor prognosis in patients with AML. Upregulation of GADD45g impairs homologous recombination DNA repair, leading to DNA damage accumulation, and dramatically induces apoptosis, differentiation, and growth arrest and increases sensitivity of AML cells to chemotherapeutic drugs, without affecting normal cells. In addition, GADD45g is epigenetically silenced by histone deacetylation in AML, and its expression is further downregulated by oncogenes FLT3-ITD and MLL-AF9 in patients carrying these genetic abnormalities. Combination of the histone deacetylase 1/2 inhibitor romidepsin with the FLT3 tyrosine kinase inhibitor AC220 or the bromodomain inhibitor JQ1 exerts synergistic antileukemic effects on FLT3-ITD+ and MLL-AF9+ AML, respectively, by dually activating GADD45g. These findings uncover hitherto unreported evidence for the selective antileukemic role of GADD45g and provide novel strategies for the treatment of FLT3-ITD+ and MLL-AF9+ AML.

Feeling unloved is the most robust sign of adolescent depression linking to family communication patterns.

Using network analysis, this study investigated how family communication patterns (Conversation and Conformity) were related to and predictive of adolescent overall depression severity and specific symptoms. A community sample of adolescents (10-17 years, n = 1327) completed the Children's Depression Inventory and the Revised Family Communication Pattern Instrument. Depressive symptoms were also re-assessed 6 months later. Results showed that Conversation orientation protected against, whereas Conformity orientation increased the risk of adolescent depression. Family communication particularly influenced the child's feeling of being unloved, and feeling unloved was the only symptom prospectively predicted by two communication orientations at baseline. These findings revealed the path linking family factors to adolescent depression and may have implications for future family-based interventions.

Precise Phase Measurement for Fringe Reflection Technique through Optimized Camera Response.

The Fringe Reflection is a robust and non-contact technique for optical measurement and specular surface characterization. The periodic alternation between dark and light cycles of the fringe patterns encodes the geometric information and provides a non-contact method of spatial measurement through phase extraction. Precisely expressing the positions of the points of the fringe pattern is a fundamental requirement for an accurate fringe reflection measurement. However, the nonlinear processes, both in generating the fringe pattern on a screen and capturing it using pixel values, cause inevitable errors in the phase measurement and eventually reduce the system's precision. Aiming at reducing these nonlinear errors, we focus on constructing a new quantity from the pixel values of the photos of the fringe patterns that could linearly respond to the ideal fringe pattern. To this end, we hypothesize that the process of displaying the fringe pattern on a screen using a control function is similar to the process of capturing the pattern and converting the illuminating information into pixel values, which can be described using the camera's response function. This similarity allows us to build a scaled energy quantity that could have a better linear relation with the control function. We optimize the extracted camera response function using an objective to increase the precision and reduce the quoted error. Experiments designed to determine the positions of points along the quartile lines verify the effectiveness of the proposed method in improving fringe reflection measurement precision.

Gene Expression Profiling Reveals Potential Players of Sex Determination and Asymmetrical Development in Chicken Embryo Gonads.

Despite the notable progress made in recent years, the understanding of the genetic control of gonadal sex differentiation and asymmetrical ovariogenesis in chicken during embryonic development remains incomplete. This study aimed to identify potential key genes and speculate about the mechanisms associated with ovary and testis development via an analysis of the results of PacBio and Illumina transcriptome sequencing of embryonic chicken gonads at the initiation of sexual differentiation (E4.5, E5.5, and E6.5). PacBio sequencing detected 328 and 233 significantly up-regulated transcript isoforms in females and males at E4.5, respectively. Illumina sequencing detected 95, 296 and 445 DEGs at E4.5, E5.5, and E6.5, respectively. Moreover, both sexes showed asymmetrical expression in gonads, and more DEGs were detected on the left side. There were 12 DEGs involved in cell proliferation shared between males and females in the left gonads. GO analysis suggested that coagulation pathways may be involved in the degradation of the right gonad in females and that blood oxygen transport pathways may be involved in preventing the degradation of the right gonad in males. These results provide a comprehensive expression profile of chicken embryo gonads at the initiation of sexual differentiation, which can serve as a theoretical basis for further understanding the mechanism of bird sex determination and its evolutionary process.

Nonlinear rotation of spin-orbit coupled states in hollow ring-core fibers.

We experimentally demonstrate that when two spin-orbit coupled orbital angular momentum (OAM) modes of opposite topological charge co-propagate in the Kerr nonlinear regime in a hollow ring-core optical fiber, the vectorial mode superposition exhibits a unique power-dependent rotation effect. This effect is analogous to nonlinear polarization rotation in single-mode fibers, however, the added spatial dimension produces a visually observable rotation of the spatial pattern emerging from the fiber when imaged through a linear polarizer. A dielectric metasurface q-plate was designed and fabricated to excite the desired mode combination in a hollow ring-core fiber that supports stable propagation of OAM modes. The observed spatial patterns show strong agreement with numerical simulations of the vector coupled nonlinear Schrödinger equations. These results constitute the first measurements of what can be described as the spin-orbit coupled generalization of the nonlinear polarization rotation effect.

Genetic bioaugmentation with triclocarban-catabolic plasmid effectively removes triclocarban from wastewater.

Triclocarban, one of the emerging pollutants, has been accumulating, and it is frequently detected in wastewater. Due to its toxicity and persistence, the efficient removal of triclocarban from wastewater systems is challenging. Genetic bioaugmentation with transferable catabolic plasmids has been considered to be a long-lasting method to clean up pollutants in continuous flow wastewater treatment systems. In this study, bioaugmentation with Pseudomonas putida KT2440, harboring the transferrable triclocarban-catabolic plasmid pDCA-1-gfp-tccA2, rapidly converted 50 µM triclocarban in wastewater into 3,4-dichloroaniline and 4-chloroaniline, which are further mineralized more easily. RT-qPCR results showed that the ratio of the copy number of pDCA-1-gfp-tccA2 to the cell number of strain KT2440 gradually increased during genetic bioaugmentation, suggesting horizontal transfer and proliferation of the plasmid. By using DNA stable isotope probing (SIP) and amplicon sequencing, OTU86 (Escherichia-Shigella), OTU155 (Citrobacter), OTU5 (Brucella), and OTU15 (Enterobacteriaceae) were found to be the potential recipients of the plasmid pDCA-1-gfp-tccA2 in the wastewater bacterial community. Furthermore, three transconjugants in the genera of Escherichia, Citrobacter, and Brucella showing triclocarban-degrading abilities were isolated from the wastewater. This study develops a new method for removing triclocarban from wastewater and provides insights into the environmental behavior of transferrable catabolic plasmids in bacterial community in wastewater systems.

Chiroptical Response of Aluminum Nanocrescents at Ultraviolet Wavelengths.

Manipulation of plasmon modes at ultraviolet wavelengths using engineered nanophotonic devices allows for the development of high-sensitivity chiroptical spectroscopy systems. We present here an experimental framework based on aluminum-based crescent-shaped nanostructures that exhibit a strong chiroptical response at ultraviolet wavelengths. Through utilization of higher-order plasmon modes in wavelength-scale nanostructures, we address the inherent fabrication challenges in scaling the response to higher frequencies. Additionally, the distinct far-field spectral response types are analyzed within a coupled-oscillator model framework. We find two competing chiroptical response types that contribute toward potential ambiguity in the interpretation of the circular dichroism spectra. The first, optical activity, originates from the interaction between hybridized eigenmodes, whereas the second manifests as a response superficially similar to optical activity but originating instead from differential near-field absorption modes. The study of the chiroptical response from nanoplasmonic devices presented here is expected to aid the development of next-generation chiroptical spectroscopy systems.

Photonic Spin-Multiplexing Metasurface for Switchable Spiral Phase Contrast Imaging.

As the two most representative operation modes in an optical imaging system, bright-field imaging and phase contrast imaging can extract different morphological information on an object. Developing a miniature and low-cost system capable of switching between these two imaging modes is thus very attractive for a number of applications, such as biomedical imaging. Here, we propose and demonstrate that a Fourier transform setup incorporating an all-dielectric metasurface can perform a two-dimensional spatial differentiation operation and thus achieve isotropic edge detection. In addition, the metasurface can provide two spin-dependent, uncorrelated phase profiles across the entire visible spectrum. Therefore, based on the spin-state of incident light, the system can be used for either diffraction-limited bright-field imaging or isotropic edge-enhanced phase contrast imaging. Combined with the advantages of planar architecture and ultrathin thickness of the metasurface, we envision this approach may open new vistas in the very interdisciplinary field of imaging and microscopy.

Independent Amplitude Control of Arbitrary Orthogonal States of Polarization via Dielectric Metasurfaces.

Exquisite polarization control using optical metasurfaces has attracted considerable attention thanks to their ability to manipulate multichannel independent wavefronts with subwavelength resolution. Here we present a new class of metasurface polarization optics, which enables imposition of two arbitrary and independent amplitude profiles on any pair of orthogonal states of polarization. The implementation method involves a polarization-dependent interference mechanism achieved by constructing a metasurface composed of an array of nanoscale birefringent waveplates. Based on this principle, we experimentally demonstrate chiral grayscale metasurface and chiral shadow rendering of structured light. These results illustrate a general approach interlinking amplitude profiles and orthogonal states of polarization and expands the scope of metasurface polarization shaping optics.

Broadband Generation of Photonic Spin-Controlled Arbitrary Accelerating Light Beams in the Visible.

Bending light along arbitrary curvatures is a captivating and popular notion, triggering unprecedented endeavors in achieving diffraction-free propagation along a curved path in free-space. Much effort has been devoted to achieving this goal in homogeneous space, which solely relies on the transverse acceleration of beam centroid exerted by a beam generator. Here, based on an all-dielectric metasurface, we experimentally report a synthetic strategy of encoding and multiplexing acceleration features on a freely propagating light beam, synergized with photonic spin states of light. Independent switching between two arbitrary visible accelerating light beams with distinct acceleration directions and caustic trajectories is achieved. This proof-of-concept recipe demonstrates the strength of the designed metasurface chip: subwavelength pixel size, independent control over light beam curvature, broadband operation in the visible, and ultrathin scalable planar architecture. Our results open up the possibility of creating ultracompact, high-pixel density, and flat-profile nanophotonic platforms for efficient generation and dynamical control of structured light beams.

Revisiting the Photon-Drag Effect in Metal Films.

The photon-drag effect, the rectified current in a medium induced by conservation of momentum of absorbed or redirected light, is a unique probe of the detailed mechanisms underlying radiation pressure. We revisit this effect in gold, a canonical Drude metal. We discover that the signal for p-polarized illumination in ambient air is affected in both sign and magnitude by adsorbed molecules, opening previous measurements for reinterpretation. Further, we show that the intrinsic sign of the photon-drag effect is contrary to the prevailing intuitive model of direct momentum transfer to free electrons.

Study on Synthesis and Biological Evaluation of 3-Aryl Substituted Xanthone Derivatives as Novel and Potent Tyrosinase Inhibitors.

Tyrosinase plays a key role in the melanin biosynthesis since it catalyzes the transformation of tyrosine into L-dopaquinone. A large number of studies have also shown that molecules to efficiently inhibit the activity of tyrosinase would be potentially used in treating many depigmentation-related disorders. In this study, we targeted a series of structure-based 3-aryl substituted xanthone derivatives in which diverse functional groups were respectively attached on 3-aromatic ring moiety as new tyrosinase inhibitors. The results demonstrated that all obtained compounds had potent tyrosinase inhibitory activities with IC50 values at micromolar range. Especially, compound 4t was found to be the most active tyrosinase inhibitor with the IC50 value of 11.3 µM, uncovering that the introduction of the proper hydroxyl group in the 3-aromatic ring was beneficial for enhancing the inhibitory potency against tyrosinase. Moreover, the inhibition mechanism and inhibition kinetics studies revealed that compound 4t presented such inhibitory effect by acting as the reversible and competitive-uncompetitive mixed-II type inhibitor. Further molecular docking simulation showed that 3-aromatic ring of compound 4t was inserted into the narrow regions of binuclear copper-binding site at the bottom of the enzyme binding pocket, while the xanthone skeleton was positioned at the surface of tyrosinase. Taken together, these data suggested that such type of molecules might be utilized for the development of new and promising candidate for the treatment of depigmentation-related disorders.

Expression patterns of endogenous avian retrovirus ALVE1 and its response to infection with exogenous avian tumour viruses.

Endogenous retroviruses (ERVs) are genomic elements that are present in a wide range of vertebrates and have been implicated in a variety of human diseases, including cancer. However, the characteristic expression patterns of ERVs, particularly in virus-induced tumours, is not fully clear. DNA methylation was analysed by bisulfite pyrosequencing, and gene expression was analysed by RT-qPCR. In this study, we first found that the endogenous avian retrovirus ALVE1 was highly expressed in some chicken tissues (including the heart, bursa, thymus, and spleen) at 2 days of age, but its expression was markedly decreased at 35 days of age. In contrast, the CpG methylation level of ALVE1 was significantly lower in heart and bursa at 2 days than at 35 days of age. Moreover, we found that the expression of ALVE1 was significantly inhibited in chicken embryo fibroblast cells (CEFs) and MSB1 cells infected with avian leukosis virus subgroup J (ALVJ) and reticuloendotheliosis virus (REV) at the early stages of infection. In contrast, the expression of the ALVE1 env gene was significantly induced in CEFs and MSB1 cells infected with Marek's disease virus (MDV). However, the methylation and expression levels of the ALVE1 long terminal repeat (LTR) did not show obvious alterations in response to viral infection. The present study revealed the expression patterns of ALVE1 in a variety of chicken organs and tissues and in chicken cells in response to avian tumour virus infection. These findings may be of significance for understanding the role and function of ERVs that are present in the host genome.

Expression of the env gene from the avian endogenous retrovirus ALVE and regulation by miR-155.

Endogenous retroviruses (ERVs) are important retroelements that reside in host genomes. However, ERV expression patterns and regulatory mechanisms are poorly understood. In this study, chicken embryo fibroblasts (CEFs) and MSB1 cells infected with Marek's disease virus (MDV) exhibited significantly increased expression of env from the endogenous retrovirus ALVE. In contrast, env expression was significantly lower in CEF and MSB1 cells infected with exogenous avian leukosis virus J (ALVJ) at the early infection stage. Furthermore, env was found to be ubiquitously expressed in various chicken tissues, with high expression in certain tissues at 2 days of age and low levels in most tissues, including immune organs (thymus, spleen and bursa) as well as the brain and heart, at 35 days of age. Sequence analysis revealed miR-155 target sites in env transcripts, which was verified using a firefly luciferase reporter assay, and treatment with miR-155 agomir significantly decreased levels of env transcripts in MSB1 and CEF cells. Together, these findings suggest that the env gene from the endogenous retrovirus ALVE is regulated by miR-155.

The Vector Matching Method in Geomagnetic Aiding Navigation.

In this paper, a geomagnetic matching navigation method that utilizes the geomagnetic vector is developed, which can greatly improve the matching probability and positioning precision, even when the geomagnetic entropy information in the matching region is small or the geomagnetic contour line's variety is obscure. The vector iterative closest contour point (VICCP) algorithm that is proposed here has better adaptability with the positioning error characteristics of the inertial navigation system (INS), where the rigid transformation in ordinary ICCP is replaced with affine transformation. In a subsequent step, a geomagnetic vector information fusion algorithm based on Bayesian statistical analysis is introduced into VICCP to improve matching performance further. Simulations based on the actual geomagnetic reference map have been performed for the validation of the proposed algorithm.

Development of skeletal muscle and expression of myogenic regulatory factors during embryonic development in Jinding ducks (Anas platyrhynchos domestica).

The important roles of myogenic regulatory factors (MRF) in mammalian skeletal myogenesis have been well studied, but few equivalent studies have been performed in poultry. The expression pattern of MRF during the embryonic development of skeletal muscle in ducks remains unknown. In this study, we identified Myf5, Myf6, MyoD, and myogenin genes in Jinding ducks (Anas platyrhynchos domestica) and quantified their expression levels in breast muscle (BM) and leg muscle (LM) at embryonic d 13, 17, 21, 25, and 27 by real-time reverse-transcription PCR. Body weight and muscle weight show different developmental patterns. The MRF genes were expressed in both BM and LM, but with different expression patterns. The MyoD gene showed lower expression levels in BM before embryonic d 21 compared with LM, whereas the opposite pattern was found later. The higher expression level of MyoD, as well its lagged expression pattern in BM, suggest that the MyoD gene may be involved in maintaining the development of different muscles. Correlation analysis showed that myogenin gene expression levels were significantly negatively correlated with BW and muscle weight in both BM and LM (P < 0.001), and MyoD and Myf6 gene expression levels were more strongly correlated with muscle weight in LM than in BM. The results of this study provide novel evidence for MRF expression in ducks in embryonic stage- and skeletal muscle-dependent manners, and provide a foundation for understanding the molecular control of skeletal muscle growth in duck breeds.