Targeting Recycling Endosomes to Potentiate mRNA Lipid Nanoparticles.

mRNA lipid nanoparticles (LNPs) have emerged as powerful modalities for gene therapies to control cancer and infectious and immune diseases. Despite the escalating interest in mRNA-LNPs over the past few decades, endosomal entrapment of delivered mRNAs vastly impedes therapeutic developments. In addition, the molecular mechanism of LNP-mediated mRNA delivery is poorly understood to guide further improvement through rational design. To tackle these challenges, we characterized LNP-mediated mRNA delivery using a library of small molecules targeting endosomal trafficking. We found that the expression of delivered mRNAs is greatly enhanced via inhibition of endocytic recycling in cells and in live mice. One of the most potent small molecules, endosidine 5 (ES5), interferes with recycling endosomes through Annexin A6, thereby promoting the release and expression of mRNA into the cytoplasm. Together, these findings suggest that targeting endosomal trafficking with small molecules is a viable strategy to potentiate the efficacy of mRNA-LNPs.

SiSGC: A Drug Repositioning Prediction Model Based on Heterogeneous Simplifying Graph Convolution.

Drug repositioning plays a key role in disease treatment. With the large-scale chemical data increasing, many computational methods are utilized for drug-disease association prediction. However, most of the existing models neglect the positive influence of non-Euclidean data and multisource information, and there is still a critical issue for graph neural networks regarding how to set the feature diffuse distance. To solve the problems, we proposed SiSGC, which makes full use of the biological knowledge information as initial features and learns the structure information from the constructed heterogeneous graph with the adaptive selection of the information diffuse distance. Then, the structural features are fused with the denoised similarity information and fed to the advanced classifier of CatBoost to make predictions. Three different data sets are used to confirm the robustness and generalization of SiSGC under two splitting strategies. Experiment results demonstrate that the proposed model achieves superior performance compared with the six leading methods and four variants. Our case study on breast neoplasms further indicates that SiSGC is trustworthy and robust yet simple. We also present four drugs for breast cancer treatment with high confidence and further give an explanation for demonstrating the rationality. There is no doubt that SiSGC can be used as a beneficial supplement for drug repositioning.

Anomalous absorption in TM polarization light by echelle gratings.

Echelle grating plays an essential role in spectral analysis due to its broadband blaze, high dispersion, and high resolution; however, its absorption properties have received no attention. In this paper, we investigate the effect of parameters including incident wavelength, incident angle, and blaze angle on the absorption properties of the Al echelle grating. Based on calculations by the boundary integral equation method, we observe that the Al grating with a large blaze angle has an absorption enhancement effect on TM-polarized waves, and its intensity increases as the incident angle approaches the pseudo-Brewster angle (maximum absorption over 87%). In particular, this absorption enhancement effect is present in the wideband and somewhat generalizable to other metallic materials. In addition, the potential physical mechanisms underlying the absorption enhancement of the echelle grating are analyzed in detail through the electric field distribution. The resonance between the grating anomaly and the pseudo-Brewster effect results in the appearance of surface plasmon polariton and strong absorption. These findings will bring new understanding to the study of echelle gratings in case of high energy loss when the light incidents with a high angle for high resolution and will also show potential applications in electromagnetic stealth, photothermal conversion, and photodetection.

Effect on the diffraction efficiency from the surface absorption of echelle grating in Littrow mounting.

[Opt. Express31, 26156202310.1364/OE.495525] shows an anomalous absorption of the echelle grating in TM polarization light near the pseudo-Brewster angle. On top of that, more generally, we relate the absorptions of echelle grating to the Al materials with an absorption spectral band. The blaze diffraction efficiencies (DEs), absorption strengths and electric field distributions, and the energy of non-blaze diffraction orders of the echelle are analyzed in detail. The computing reveals that the interaction between the incident light for TM polarization and the echelle structure leads to amplifying the absorption strength of Al materials with an absorption spectral band from visible to near IR. The deepening groove depth not only suppresses the absorption strength of the Al-echelle grating under TM polarization closer to the absorption spectra of Al materials but improves the light-collecting ability (LCA) at both polarizations. Therefore, the DE differences of different blaze wavelengths for the wideband blaze are explained. The Ag materials echelle with lower absorption is to further validate the results. From the point of view of the effects of absorption and LCA, the novel echelles with high DE can be designed and fabricated.

Design of single-layer color echelle grating optical waveguide for augmented-reality display.

We proposed a single-layer color echelle grating combined optical waveguide structure for an augmented-reality display. In this structure, we used echelle gratings with super-wavelength periodic scale as in-coupling, relay, and out-coupling elements. The combined propagation of three light beams in the waveguide was realized by overlapping different high diffraction orders of the RGB three primary colors, and deflection of the beam direction between gratings was achieved by conical diffraction generated by the inclined grating. Using the vector diffraction theory, the structural parameters and tolerance ranges of the three types of gratings were optimized, rendering average diffraction efficiencies of the three primary colors of the in-coupling, relay, and out-coupling gratings greater than 74%, 21%, and 35%, respectively. As a result, we obtained dual-channel one-dimensional pupil dilation of the original image and a field-of-view angle of h18.9° × v36.87°.

MVNMDA: A Multi-View Network Combing Semantic and Global Features for Predicting miRNA-Disease Association.

A growing body of experimental evidence suggests that microRNAs (miRNAs) are closely associated with specific human diseases and play critical roles in their development and progression. Therefore, identifying miRNA related to specific diseases is of great significance for disease screening and treatment. In the early stages, the identification of associations between miRNAs and diseases demanded laborious and time-consuming biological experiments that often carried a substantial risk of failure. With the exponential growth in the number of potential miRNA-disease association combinations, traditional biological experimental methods face difficulties in processing massive amounts of data. Hence, developing more efficient computational methods to predict possible miRNA-disease associations and prioritize them is particularly necessary. In recent years, numerous deep learning-based computational methods have been developed and have demonstrated excellent performance. However, most of these methods rely on external databases or tools to compute various auxiliary information. Unfortunately, these external databases or tools often cover only a limited portion of miRNAs and diseases, resulting in many miRNAs and diseases being unable to match with these computational methods. Therefore, there are certain limitations associated with the practical application of these methods. To overcome the above limitations, this study proposes a multi-view computational model called MVNMDA, which predicts potential miRNA-disease associations by integrating features of miRNA and diseases from local views, global views, and semantic views. Specifically, MVNMDA utilizes known association information to construct node initial features. Then, multiple networks are constructed based on known association to extract low-dimensional feature embedding of all nodes. Finally, a cascaded attention classifier is proposed to fuse features from coarse to fine, suppressing noise within the features and making precise predictions. To validate the effectiveness of the proposed method, extensive experiments were conducted on the HMDD v2.0 and HMDD v3.2 datasets. The experimental results demonstrate that MVNMDA achieves better performance compared to other computational methods. Additionally, the case study results further demonstrate the reliable predictive performance of MVNMDA.

Design and analysis of broadband guided-mode resonant reflectors with coated triangular and trapezoidal profiles in TE polarization.

A low-refractive-index grating layer with symmetrical triangular/trapezoidal grooves covered with a high-refractive-index Si layer is used to design a broadband guided-mode resonant reflector. Software Rsoft is used to simulate the reflection and transmission spectra as well as the internal electric field distribution at the resonant wavelength. It is discovered that the interaction between resonant modes promotes the formation of a wideband spectrum. The reflector has been proven to provide wideband (Δλ > 450 nm) and high reflectivity (R > 98.4%) spectra over a wide range of base angles from 44° to 72°, and the maximum high reflectivity (R > 99%) spectral range in transverse electric polarization is 458 nm, spanning 1422 to 1880nm. The results not only demonstrate excellent tolerance to the base angle and grating depth but also provide more possibilities for the design of broadband reflectors.

High-quality and large-area echelle grating ruled on 500-mm ruling engine for the fiber array solar optical telescope (FASOT).

A 300 mm×500 mm large-area echelle grating with groove density of 79 grooves/mm is fabricated for the spectrometer of the fiber array solar optical telescope (FASOT). This paper focusses on measurement methods of the grating performance. We present a method to evaluate the grating's stray light intensity, which is measured to a level of 10-4. The directly measured grating efficiency is approximately 90% of the designed value, and an indirect measurement method based on the grating groove profile is proposed. Based on the Rayleigh criterion and the grating diffraction wavefront, a physical optics method and a geometric grating method are proposed and are used to calculate the actual grating resolving power; the calculated results exceed 95% of the grating's theoretical resolving power. These results show that the CIOMP-6 ruling engine has sufficient precision to fabricate high-quality, large-area echelle gratings.

Identification and Heterologous Expression of the Kendomycin B Biosynthetic Gene Cluster from Verrucosispora sp. SCSIO 07399.

Verrucosispora sp. SCSIO 07399, a rare marine-derived actinomycete, produces a set of ansamycin-like polyketides kendomycin B-D (1-3) which possess potent antibacterial activities and moderate tumor cytotoxicity. Structurally, kendomycin B-D contain a unique aliphatic macrocyclic ansa scaffold in which the highly substituted pyran ring is connected to the quinone moiety. In this work, a type I/type III polyketide synthase (PKS) hybrid biosynthetic gene cluster coding for assembly of kendomycin B (kmy), and covering 33 open reading frames, was identified from Verrucosispora sp. SCSIO 07399. The kmy cluster was found to be essential for kendomycin B biosynthesis as verified by gene disruption and heterologous expression. Correspondingly, a biosynthetic pathway was proposed based on bioinformatics, cluster alignments, and previous research. Additionally, the role of type III PKS for generating the precursor unit 3,5-dihydroxybenzoic acid (3,5-DHBA) was demonstrated by chemical complementation, and type I PKS executed the polyketide chain elongation. The kmy cluster was found to contain a positive regulatory gene kmy4 whose regulatory effect was identified using real-time quantitative PCR (RT-qPCR). These advances shed important new insights into kendomycin B biosynthesis and help to set the foundation for further research aimed at understanding and exploiting the carbacylic ansa scaffold.

Numerical calculation of the mosaic error between mosaic gratings.

The theoretical calculation model for a mosaic error was established based on the plane equation for a grating surface and the relationship equation for a mosaic grating surface. A mosaic grating was obtained based on this model. In the experiment, the mosaic error was calculated based on the diffraction wavefronts of two groups of mosaic gratings that were obtained simultaneously with a Zygo interferometer. The difference between the wavefront of the mosaic grating and the average wavefront of the mosaic grating element was 0.031λ. The maximum far-field intensity of the mosaic grating was 90% of that without an error. This model provides a theoretical basis for the numerical mosaic between gratings. In addition, the mosaic error can be calculated with this model, and the quality of the mosaic grating can be evaluated.

Effect of the measuring mirror surface shape error on ruled groove straightness and the grating diffraction wavefront.

Measuring mirror requirements and their impact on groove errors are related to the error compensation strategy for a ruling engine. We analyze why the measuring mirror of the CIOMP-6 engine affects the groove straightness and the grating diffraction wavefront. We study a theoretical model of the relationship between the measuring mirror's surface shape error and the grating wavefront, propose a requirement for the measuring mirror surface shape error, and reprocess the measuring mirror. Comparative ruling experiments prove that the grating's wavefront quality at the diffraction order along the groove direction improved significantly after reprocessing of the measuring mirror.

Ruling engine using adjustable diamond and interferometric control for high-quality gratings and large echelles.

A concept for position adjustment of the diamond in a ruling engine to enable nanoscale groove positioning is proposed. Based on this concept, we fabricate a diamond carriage, design an optical path, and propose an appropriate control method. Several high-quality gratings are ruled for spectrometer or interferometer applications. After implementation of the improvements, the maximum intensity of ghosts and scattered light of the echelle grating with 79 grooves/mm is reduced to half of that before the improvement, and the highest achievable groove density is increased from 6000 grooves/mm to 8000 grooves/mm. The grating ruling results indicate that the proposed concept and the related improvements to the engine significantly improve the accuracy of the CIOMP-6 ruling engine.

Cytotoxic Kendomycins Containing the Carbacylic Ansa Scaffold from the Marine-Derived Verrucosispora sp. SCSIO 07399.

Three new kendomycin analogues, kendomycins B-D (1-3), were discovered from the marine-derived actinomycete Verrucosispora sp. SCSIO 07399. The structures of 1-3 were elucidated using diverse spectroscopic data analyses, X-ray crystallography, and semisynthetic derivatization. In vitro antimicrobial assays revealed that 1-3 all display good antibacterial activities against six Gram-positive bacteria with MIC values ranging from 0.5 to 8.0 µg/mL. Additionally, 1-3 were found to be moderately cytotoxic against MGC803, A549, HeLa, HepG2, MCF-7, and RKO human tumor cell lines; IC50 values ranged from 2.2 to 44 µM.

Cytotoxic Anthracycline Metabolites from a Recombinant Streptomyces.

The C7 (C9 or C10)- O-l-rhodosamine-bearing anthracycline antibiotic cytorhodins and their biosynthetic intermediates were recently isolated from Streptomyces sp. SCSIO 1666. Cosmid p17C4 from the Streptomyces lydicus genomic library, which harbors both the biosynthetic genes for l-rhodinose (or 2-deoxy-l-fucose) and its glycosyltransferase (encoded by slgG), was introduced into SCSIO 1666 to yield the recombinant strain Streptomyces sp. SCSIO 1666/17C4. Chemical investigations of this strain's secondary metabolic potential revealed the production of different anthracyclines featuring C7- O-l-rhodinose (or 2-deoxy-l-fucose) instead of the typically observed l-rhodosamine. Purification of the fermentation broth yielded 12 new anthracycline antibiotics including three new ε-rhodomycinone derivatives, 1, 4, and 8, nine new ß-rhodomycinone derivatives, 2, 3, 5-7, and 9-12, and three known compounds, l-rhodinose-l-rhodinose-l-rhodinoserhodomycinone (13), ε-rhodomycinone (14), and γ-rhodomycinone (15). All compounds were characterized on the basis of detailed spectroscopic analyses and comparisons with previously reported data. These compounds exhibited cytotoxicity against a panel of human cancer cell lines. Significantly, compounds 4 and 13 displayed pronounced activity against HCT-116 as characterized by IC50 values of 0.3 and 0.2 µM, respectively; these IC50 values are comparable to that of the positive control epirubicin.

Backscattering Raman spectroscopy using multi-grating spatial heterodyne Raman spectrometer.

Spatial heterodyne Raman spectrometry (SHRS) is a spectral analysis technique used to study material structures and compositions. We propose a multi-grating SHRS system that uses a multi-grating module rather than the single grating used to terminate each arm in traditional spatial heterodyne spectrometry (SHS). The proposed system not only retains the advantages of traditional SHS but also resolves the mutual limitation between system spectral range and resolution. The increased spectral range and resolution that can be achieved in detection are dependent on the number of sub-gratings used in the module. A verification system was built using 130 gr/mm and 150 gr/mm sub-gratings and calibrated. Under different experimental conditions (including laser power, integration time, container material and thickness, pure and mixed samples, and standoff experiments), the backscattered Raman spectra of different types of targets (including organic solutions, inorganic powders, and minerals) were tested. The multi-grating SHRS shows good performance for broad spectral range and high-resolution Raman detection.

Using a unique mirror to minimize the effect of ruling engine cosine error on grating performance.

The cosine error of the diffraction grating ruling engine is a systematic error caused by the measurement system. This error affects grating performance directly. To reduce the effects of the cosine error on grating performance, we analyze the cause of the cosine error, establish a mathematical model based on the error and the related grating indicators, and propose a method to reduce the error. To validate the proposed method, we present the results of grating ruling experiments performed before and after cosine error correction, which show that the method effectively reduces the cosine error effects.

Angucycline Glycosides from Mangrove-Derived Streptomycesdiastaticus subsp. SCSIO GJ056.

Nine new angucycline glycosides designated urdamycins N1⁻N9 (1⁻9), together with two known congener urdamycins A (10) and B (11), were obtained from a mangrove-derived Streptomycesdiastaticus subsp. SCSIO GJ056. The structures of new compounds were elucidated on the basis of extensive spectroscopic data analysis. The absolute configurations of 6⁻9 were assigned by electronic circular dichroism calculation method. Urdamycins N6 (6) and N9 (9) represent the first naturally occurring (5R, 6R)-angucycline glycosides, which are diastereomers of urdamycins N7 (7) and N8 (8), respectively.

Prediction of microbe-disease association from the integration of neighbor and graph with collaborative recommendation model.

BACKGROUND: Accumulating clinical researches have shown that specific microbes with abnormal levels are closely associated with the development of various human diseases. Knowledge of microbe-disease associations can provide valuable insights for complex disease mechanism understanding as well as the prevention, diagnosis and treatment of various diseases. However, little effort has been made to predict microbial candidates for human complex diseases on a large scale. METHODS: In this work, we developed a new computational model for predicting microbe-disease associations by combining two single recommendation methods. Based on the assumption that functionally similar microbes tend to get involved in the mechanism of similar disease, we adopted neighbor-based collaborative filtering and a graph-based scoring method to compute association possibility of microbe-disease pairs. The promising prediction performance could be attributed to the use of hybrid approach based on two single recommendation methods as well as the introduction of Gaussian kernel-based similarity and symptom-based disease similarity. RESULTS: To evaluate the performance of the proposed model, we implemented leave-one-out and fivefold cross validations on the HMDAD database, which is recently built as the first database collecting experimentally-confirmed microbe-disease associations. As a result, NGRHMDA achieved reliable results with AUCs of 0.9023 ± 0.0031 and 0.9111 in the validation frameworks of fivefold CV and LOOCV. In addition, 78.2% microbe samples and 66.7% disease samples are found to be consistent with the basic assumption of our work that microbes tend to get involved in the similar disease clusters, and vice versa. CONCLUSIONS: Compared with other methods, the prediction results yielded by NGRHMDA demonstrate its effective prediction performance for microbe-disease associations. It is anticipated that NGRHMDA can be used as a useful tool to search the most potential microbial candidates for various diseases, and therefore boosts the medical knowledge and drug development. The codes and dataset of our work can be downloaded from https://github.com/yahuang1991/NGRHMDA .

Antimicrobial Spirotetronate Metabolites from Marine-Derived Micromonospora harpali SCSIO GJ089.

Two new spirotetronate aglycones, 22-dehydroxymethyl-kijanolide (1) and 8-hydroxy-22-dehydroxymethyl-kijanolide (2), along with seven new spirotetronate glycosides, microsporanates A-F (3-8) and tetrocarcin P (9), together with three known tetrocarcins [tetrocarcins A (10), B (11), and AC6H (12)], were isolated from fermentation broths of the marine-derived Micromonospora harpali SCSIO GJ089. The structures of 1-9 were elucidated on the basis of 1D and 2D NMR and MS spectroscopic data. Compounds 3-8 feature an α,ß-unsaturated carbonyl moiety within their spirotetronate skeletons. Moreover, compounds 3-12 displayed strong to moderate antibacterial activities against Gram positive bacteria Bacillus thuringiensis BT01 and B. subtilis BS01 with MIC values ranging from 0.016 to 8.0 µg/mL.

Correcting groove error in gratings ruled on a 500-mm ruling engine using interferometric control.

Groove error is one of the most important factors affecting grating quality and spectral performance. To reduce groove error, we propose a new ruling-tool carriage system based on aerostatic guideways. We design a new blank carriage system with double piezoelectric actuators. We also propose a completely closed-loop servo-control system with a new optical measurement system that can control the position of the diamond relative to the blank. To evaluate our proposed methods, we produced several gratings, including an echelle grating with 79 grooves/mm, a grating with 768 grooves/mm, and a high-density grating with 6000 grooves/mm. The results show that our methods effectively reduce groove error in ruled gratings.