Ribosome profiling reveals novel regulation of C9ORF72 GGGGCC repeat-containing RNA translation.

GGGGCC (G4C2) repeat expansion in the first intron of C9ORF72 causes amyotrophic lateral sclerosis and frontotemporal dementia. Repeat-containing RNA is translated into dipeptide repeat (DPR) proteins, some of which are neurotoxic. Using dynamic ribosome profiling, we identified three translation initiation sites in the intron upstream of (G4C2) repeats; these sites are detected irrespective of the presence or absence of the repeats. During translocation, ribosomes appear to be stalled on the repeats. An AUG in the preceding C9ORF72 exon initiates a uORF that inhibits downstream translation. Polysome isolation indicates that unspliced (G4C2) repeat-containing RNA is a substrate for DPR protein synthesis. (G4C2) repeat-containing RNA translation is 5' cap-independent but inhibited by the initiation factor DAP5, suggesting an interplay with uORF function. These results define novel translational mechanisms of expanded (G4C2) repeat-containing RNA in disease.

Structure Engineering of Acridine Donor to Optimize Color Purity of Blue Thermally Activated Delayed Fluorescence Emitters.

9,9-Dimethyl-9,10-dihydroacridine (DMAC) is one of the most widely used electron donor for constructing high-performance thermally activated delayed fluorescence (TADF) emitters. However, DMAC-based emitters often suffer from the imperfect color purity, particularly in blue emitters, due to its strong electron-donating capability. To modulate donor strength, 2,7-F-Ph-DMAC and 2,7-CF3-Ph-DMAC were designed by introducing the electron-withdrawing 2-fluorophenyl and 2-(trifluoromethyl)phenyl at the 2,7-positions of DMAC. These donors were used, in combination with 2,4,6-triphenyl-1,3,5-triazine (TRZ) acceptor, to develop novel TADF emitters 2,7-F-Ph-DMAC-TRZ and 2,7-CF3-Ph-DMAC-TRZ. Compared to the F- or CF3-free reference emitter, both two emitters showed hypsochromic effect in fluorescence and comparable photoluminescence quantum yields without sacrificing the reverse intersystem crossing rate constants. In particular, 2,7-CF3-Ph-DMAC-TRZ based OLED exhibited a blue shift by up to 39 nm and significantly improved Commission International de l'Éclairage (CIE) coordinates from (0.36, 0.55) to (0.22, 0.41), while the external quantum efficiency kept stable at about 22.5 %. This donor engineering strategy should be valid for improving the color purity of large amount of acridine based TADF emitters. It can be predicted that pure blue TADF emitters should be feasible if these F- or CF3-modifed acridine donors are combined with other weaker electron acceptors.

A Novel Lightweight Model for Underwater Image Enhancement.

Underwater images suffer from low contrast and color distortion. In order to improve the quality of underwater images and reduce storage and computational resources, this paper proposes a lightweight model Rep-UWnet to enhance underwater images. The model consists of a fully connected convolutional network and three densely connected RepConv blocks in series, with the input images connected to the output of each block with a Skip connection. First, the original underwater image is subjected to feature extraction by the SimSPPF module and is processed through feature summation with the original one to be produced as the input image. Then, the first convolutional layer with a kernel size of 3 × 3, generates 64 feature maps, and the multi-scale hybrid convolutional attention module enhances the useful features by reweighting the features of different channels. Second, three RepConv blocks are connected to reduce the number of parameters in extracting features and increase the test speed. Finally, a convolutional layer with 3 kernels generates enhanced underwater images. Our method reduces the number of parameters from 2.7 M to 0.45 M (around 83% reduction) but outperforms state-of-the-art algorithms by extensive experiments. Furthermore, we demonstrate our Rep-UWnet effectively improves high-level vision tasks like edge detection and single image depth estimation. This method not only surpasses the contrast method in objective quality, but also significantly improves the contrast, colorimetry, and clarity of underwater images in subjective quality.

Deep Learning-Based Technique for Remote Sensing Image Enhancement Using Multiscale Feature Fusion.

The present study proposes a novel deep-learning model for remote sensing image enhancement. It maintains image details while enhancing brightness in the feature extraction module. An improved hierarchical model named Global Spatial Attention Network (GSA-Net), based on U-Net for image enhancement, is proposed to improve the model's performance. To circumvent the issue of insufficient sample data, gamma correction is applied to create low-light images, which are then used as training examples. A loss function is constructed using the Structural Similarity (SSIM) and Peak Signal-to-Noise Ratio (PSNR) indices. The GSA-Net network and loss function are utilized to restore images obtained via low-light remote sensing. This proposed method was tested on the Northwestern Polytechnical University Very-High-Resolution 10 (NWPU VHR-10) dataset, and its overall superiority was demonstrated in comparison with other state-of-the-art algorithms using various objective assessment indicators, such as PSNR, SSIM, and Learned Perceptual Image Patch Similarity (LPIPS). Furthermore, in high-level visual tasks such as object detection, this novel method provides better remote sensing images with distinct details and higher contrast than the competing methods.

FMRP links optimal codons to mRNA stability in neurons.

Fragile X syndrome (FXS) is caused by inactivation of the FMR1 gene and loss of encoded FMRP, an RNA binding protein that represses translation of some of its target transcripts. Here we use ribosome profiling and RNA sequencing to investigate the dysregulation of translation in the mouse brain cortex. We find that most changes in ribosome occupancy on hundreds of mRNAs are largely driven by dysregulation in transcript abundance. Many down-regulated mRNAs, which are mostly responsible for neuronal and synaptic functions, are highly enriched for FMRP binding targets. RNA metabolic labeling demonstrates that, in FMRP-deficient cortical neurons, mRNA down-regulation is caused by elevated degradation and is correlated with codon optimality. Moreover, FMRP preferentially binds mRNAs with optimal codons, suggesting that it stabilizes such transcripts through direct interactions via the translational machinery. Finally, we show that the paradigm of genetic rescue of FXS-like phenotypes in FMRP-deficient mice by deletion of the Cpeb1 gene is mediated by restoration of steady-state RNA levels and consequent rebalancing of translational homeostasis. Our data establish an essential role of FMRP in codon optimality-dependent mRNA stability as an important factor in FXS.

Tunable composite lattice structure for low-frequency and ultra-broadband underwater sound absorption.

The underwater sound absorption technique in low-frequency and broadband has far-reaching prospects since it is essential for noise reduction of deep-sea operation requirements and evading advanced underwater target detection. Here, we propose an underwater sound-absorbing composite lattice with low-frequency and ultra-broadband characteristics. The composite lattice is constructed by regular spatially stacking cells with different sizes of metallic core spheres. All the core spheres are coated with silicon rubbers, and cells are embedded in the rubber matrix. In the composite lattice stereostructure, the lattice cells convert incident longitudinal waves into transverse waves through multiple local resonance coupling and multiple scattering. The energy is localized and dissipated in the composite lattice. We analyze the relationship among the corresponding absorption spectrums, the displacement clouds, and the resonance modes of lattice cells. Then, we construct a composite lattice and realize low-frequency broadband absorption from 693 to 1106 Hz with absorptance above 0.8. Further, our investigation demonstrates that the absorption bandwidth can be extended to ultra-broadband from 1077 to 10 000 Hz, where the thickness of the composite lattice is λ/17.05. The proposed composite lattice provides a practical approach to designing ultrathin low-frequency and ultra-broadband acoustic absorption coating for underwater noise suppression.

The prevalence and management of chronic pain in the Chinese population: findings from the China Pain Health Index (2020).

BACKGROUND: Chronic pain is a common disease; about 20% of people worldwide suffer from it. While compared with the research on the prevalence and management of chronic pain in developed countries, there is a relative lack of research in this field in China. This research aims to construct the China Pain Health Index (CPHI) to evaluate the current status of the prevalence and management of chronic pain in the Chinese population. METHODS: The dimensions and indicators of CPHI were determined through literature review, Delphi method, and analytical hierarchy process model, and the original values ​​of relevant indicators were obtained by collecting multi-source data. National and sub-provincial scores of CPHI (2020) were calculated by co-directional transformation, standardization, percentage transformation of the aggregate, and weighted summation. RESULTS: The highest CPHI score in 2020 is Beijing, and the lowest is Tibet. The top five provinces are Beijing (67.64 points), Shanghai (67.04 points), Zhejiang (65.74 points), Shandong (61.16 points), and Tianjin (59.99 points). The last five provinces are Tibet (33.10 points), Ningxia (37.24 points), Guizhou (39.85 points), Xinjiang (39.92 points), and Hainan (40.38 points). The prevalence of chronic pain is severe in Heilongjiang, Chongqing, Guizhou, Sichuan, and Fujian. Guizhou, Hainan, Xinjiang, Beijing, and Guangdong display a high burden of chronic pain. The five provinces of Guangdong, Shanghai, Beijing, Jiangsu, and Zhejiang have better treatment for chronic pain, while Tibet, Qinghai, Jilin, Ningxia, and Xinjiang have a lower quality of treatment. Beijing, Shanghai, Qinghai, Guangxi, and Hunan have relatively good development of chronic pain disciplines, while Tibet, Sichuan, Inner Mongolia, Hebei, and Guizhou are relatively poor. CONCLUSION: The economically developed provinces in China have higher CPHI scores, while economically underdeveloped areas have lower scores. The current pain diagnosis and treatment situation in economically developed regions is relatively good, while that in financially underdeveloped areas is rather poor. According to the variations in the prevalence and management of chronic pain among populations in different provinces in China, it is necessary to implement chronic pain intervention measures adapted to local conditions.

Adaptive Aggregate Stereo Matching Network with Depth Map Super-Resolution.

In order to avoid the direct depth reconstruction of the original image pair and improve the accuracy of the results, we proposed a coarse-to-fine stereo matching network combining multi-level residual optimization and depth map super-resolution (ASR-Net). First, we used the u-net feature extractor to obtain the multi-scale feature pair. Second, we reconstructed global disparity in the lowest resolution. Then, we regressed the residual disparity using the higher-resolution feature pair. Finally, the lowest-resolution depth map was refined by using the disparity residual. In addition, we introduced deformable convolution and group-wise cost volume into the network to achieve adaptive cost aggregation. Further, the network uses ABPN instead of the traditional interpolation method. The network was evaluated on three datasets: scene flow, kitti2015, and kitti2012 and the experimental results showed that the speed and accuracy of our method were excellent. On the kitti2015 dataset, the three-pixel error converged to 2.86%, and the speed was about six times and two times that of GC-net and GWC-net.

Cotranslational response to proteotoxic stress by elongation pausing of ribosomes.

Translational control permits cells to respond swiftly to a changing environment. Rapid attenuation of global protein synthesis under stress conditions has been largely ascribed to the inhibition of translation initiation. Here we report that intracellular proteotoxic stress reduces global protein synthesis by halting ribosomes on transcripts during elongation. Deep sequencing of ribosome-protected messenger RNA (mRNA) fragments reveals an early elongation pausing, roughly at the site where nascent polypeptide chains emerge from the ribosomal exit tunnel. Inhibiting endogenous chaperone molecules by a dominant-negative mutant or chemical inhibitors recapitulates the early elongation pausing, suggesting a dual role of molecular chaperones in facilitating polypeptide elongation and cotranslational folding. Our results further support the chaperone "trapping" mechanism in promoting the passage of nascent chains. Our study reveals that translating ribosomes fine tune the elongation rate by sensing the intracellular folding environment. The early elongation pausing represents a cotranslational stress response to maintain the intracellular protein homeostasis.

Optimization of ribosome profiling using low-input brain tissue from fragile X syndrome model mice.

Dysregulated protein synthesis is a major underlying cause of many neurodevelopmental diseases including fragile X syndrome. In order to capture subtle but biologically significant differences in translation in these disorders, a robust technique is required. One powerful tool to study translational control is ribosome profiling, which is based on deep sequencing of mRNA fragments protected from ribonuclease (RNase) digestion by ribosomes. However, this approach has been mainly applied to rapidly dividing cells where translation is active and large amounts of starting material are readily available. The application of ribosome profiling to low-input brain tissue where translation is modest and gene expression changes between genotypes are expected to be small has not been carefully evaluated. Using hippocampal tissue from wide type and fragile X mental retardation 1 (Fmr1) knockout mice, we show that variable RNase digestion can lead to significant sample batch effects. We also establish GC content and ribosome footprint length as quality control metrics for RNase digestion. We performed RNase titration experiments for low-input samples to identify optimal conditions for this critical step that is often improperly conducted. Our data reveal that optimal RNase digestion is essential to ensure high quality and reproducibility of ribosome profiling for low-input brain tissue.

Regulatory discrimination of mRNAs by FMRP controls mouse adult neural stem cell differentiation.

Fragile X syndrome (FXS) is caused by the loss of fragile X mental retardation protein (FMRP), an RNA binding protein whose deficiency impacts many brain functions, including differentiation of adult neural stem cells (aNSCs). However, the mechanism by which FMRP influences these processes remains unclear. Here, we performed ribosome profiling and transcriptomic analysis of aNSCs in parallel from wild-type and Fmr1 knockout mice. Our data revealed diverse gene expression changes at both mRNA and translation levels. Many mitosis and neurogenesis genes were dysregulated primarily at the mRNA level, while numerous synaptic genes were mostly dysregulated at the translation level. Translational "buffering", whereby changes in ribosome association with mRNA are compensated by alterations in RNA abundance, was also evident. Knockdown of NECDIN, an FMRP-repressed transcriptional factor, rescued neuronal differentiation. In addition, we discovered that FMRP regulates mitochondrial mRNA expression and energy homeostasis. Thus, FMRP controls diverse transcriptional and posttranscriptional gene expression programs critical for neural differentiation.

Low-frequency multi-order acoustic absorber based on spiral metasurface.

In this work, we propose a spiral metasurface for multi-order sound absorption in the low-frequency range (<1000 Hz). By dividing the long channel of the spiral metasurface into a series of tunable sub-cavities and employing recessed necks, the metasurface can quasi-perfectly (>0.95 in experiments) absorb airborne sound at multiple low-frequency orders without being limited by the number of equivalent cavities. Owing to the superior impedance manipulation provided by the spiral metasurface, each absorption order can be tuned flexibly with a constant external shape. By suitably modulating the sub-cavities and the recessed necks, we obtained multi-order high-absorption metasurfaces with dual-chamber, tri-chamber, and four-chamber designs. The ratio of the lowest resonant wavelength to the thickness is as high as 78. The samples, which are fabricated by three-dimensional printing technology, were measured to verify the theoretical results. We also investigate the relationship between the geometric parameters of the recessed necks and the sound absorption performance, which facilitates the more feasibly designed multi-order metasurfaces. The concept can be further applied to broadband absorption with ultra-thin thickness and has potential applications for noise reduction.

Dispersed copper nanoparticles promote the electron mobility of nitrogen-rich graphitized carbon aerogel for electrochemical determination of 4-nitrophenol.

An electrochemical method was designed for the determination and simultaneous reduction of 4-nitrophenol (4-NP). A nitrogen-rich carbon aerogel was synthesized from the precursor of phenol, formaldehyde and melamine. Then, copper nanoparticles were embedded into the aerogel, and the resulting material was used to modify a glassy carbon electrode (GCE), which displayed excellent electrocatalytic activity. Sensitive determination of 4-NP by cyclic voltammetry in 0.5 M sulfuric acid was accomplished. Among the various compositions of Cux@NC, the electrode modified with Cu3@NC showed the strongest reduction peak, typically at a potential of -0.30 V vs. reversible hydrogen electrode (RHE). A further study shows the cyclic voltammetry potential range to extend from -0.46 to +0.44 V (vs. RHE) at a scan rate of 100 mV s-1. Differential pulse voltammetric determination of 4-NP gave a lower detection limit of 53 nM and a current sensitivity of 0.7 µA µM-1 cm-2. The method was applied to the determination of 4-NP in spiked water samples, with comparable results of HPLC. The excellent performance was attributed to the highly graphitized structure of the aerogel with its large surface area and small pore size, and the presence of Cu-N structures as active sites. Graphical abstractSchematic representation of electrochemical determination and reduction of 4-nitrophenol under the glassy carbon electrode modified with highly dispersed Cu nanoparticles embedded on nitrogen-rich carbon aerogel. W: working electrode; R: reference electrode; C: counter electrode). Left: copper nanoparticles embedded in an aerogel.

Quantitative profiling of initiating ribosomes in vivo.

Cells have evolved exquisite mechanisms to fine-tune the rate of protein synthesis in response to stress. Systemic mapping of start-codon positions and precise measurement of the corresponding initiation rate would transform our understanding of translational control. Here we present quantitative translation initiation sequencing (QTI-seq), with which the initiating ribosomes can be profiled in real time at single-nucleotide resolution. Resultant initiation maps not only delineated variations of start-codon selection but also highlighted a dynamic range of initiation rates in response to nutrient starvation. The integrated data set provided unique insights into principles of alternative translation and mechanisms controlling different aspects of translation initiation. With RiboTag mice, QTI-seq permitted tissue-specific profiling of initiating ribosomes in vivo. Liver cell-specific ribosome profiling uncovered a robust translational reprogramming of the proteasome system in fasted mice. Our findings illuminated the prevalence and dynamic nature of translational regulation pivotal to physiological adaptation in vivo.

Ce(iii)-catalyzed highly efficient synthesis of pyridyl benzamides from aminopyridines and nitroolefins without external oxidants.

An efficient synthesis of a variety of pyridyl benzamides from 2-aminopyridines and nitroolefins is described. This rare-earth-metal-catalyzed reaction provides the corresponding products with broad substrate scope in moderate to excellent yields, in the absence of additives and external oxidants. Water is used as the source of the carbonyl oxygen atom in pyridyl benzamides. Furthermore, 2-substituted oxazolo[4,5-b]pyridines are formed in good yields under the standard conditions when 2-aminopyridin-3-ols are used as the substrates.

A facile tandem decyanation/cyanation reaction of α-iminonitriles toward cyano-substituted amides.

A new tandem decyanation/cyanation reaction of α-iminonitriles has been developed. A variety of cyano-substituted aryl amides and heteroaryl amides are synthesized in good yields. Both electron-rich and electron-deficient groups are compatible with the standard conditions. This reaction features a nonmetallic cyano source, tandem decyanation and cyanation reaction, waste utilization of the HCN from the hydrolysis of α-iminonitriles, formation of two important functional groups in one-step operation, etc.

Enhanced stability of vitamin A palmitate microencapsulated by γ-cyclodextrin metal-organic frameworks.

γ-Cyclodextrin metal-organic frameworks (γ-CD-MOFs) are highly porous and bio-friendly novel materials formed by γ-CD as an organic ligand and potassium ion as an inorganic metal centre. The aim of this study was to enhance the stability of vitamin A palmitate (VAP) using γ-CD-MOFs as the carrier. Herein, γ-CD-MOFs displayed VAP microencapsulating capacity of 9.77 ± 0.24% with molar ratio as nMOFs:nVAP = 3.2:1.0. It was important to find that the improved stability of VAP microencapsulated by γ-CD-MOFs without addition of any antioxidant(s) was better than that of the best available reference product in the market, with 1.6-fold elongated half-life. The protecting mechanism of γ-CD-MOFs for VAP contributed that VAP molecules preferentially curled inside the cavities of dual γ-CD pairs in γ-CD-MOFs. It was proved that γ-CD-MOFs were an efficient new carrier to deliver and protect VAP for food and pharmaceutical applications.

Multilayer Choline Phosphate Molecule Modified Surface with Enhanced Cell Adhesion but Resistance to Protein Adsorption.

Choline phosphate (CP), which is a new zwitterionic molecule, and has the reverse order of phosphate choline (PC) and could bind to the cell membrane though the unique CP-PC interaction. Here we modified a glass surface with multilayer CP molecules using surface-initiated atom-transfer radical polymerization (SI-ATRP) and the ring-opening method. Polymeric brushes of (dimethylamino)ethyl methacrylate (DMAEMA) were synthesized by SI-ATRP from the glass surface. Then the grafted PDMAEMA brushes were used to introduce CP groups to fabricate the multilayer CP molecule modified surface. The protein adsorption experiment and cell culture test were used to evaluate the biocompatibility of the modified surfaces by using human umbilical veinendothelial cells (HUVECs). The protein adsorption results demonstrated that the multilayer CP molecule decorated surface could prevent the adsorption of fibrinogen and serum protein. The adhesion and proliferation of cells were improved significantly on the multilayer CP molecule modified surface. Therefore, the biocompatibility of the material surface could be improved by the modified multilayer CP molecule, which exhibits great potential for biomedical applications, e.g., scaffolds in tissue engineering.

Improvement in Thermal Stability of Sucralose by γ-Cyclodextrin Metal-Organic Frameworks.

PURPOSE: To explain thermal stability enhancement of an organic compound, sucralose, with cyclodextrin based metal organic frameworks. METHODS: Micron and nanometer sized basic CD-MOFs were successfully synthesized by a modified vapor diffusion method and further neutralized with glacial acetic acid. Sucralose was loaded into CD-MOFs by incubating CD-MOFs with sucralose ethanol solutions. Thermal stabilities of sucralose-loaded basic CD-MOFs and neutralized CD-MOFs were investigated using thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and high performance liquid chromatography with evaporative light-scattering detection (HPLC-ELSD). RESULTS: Scanning electron microscopy (SEM) and powder X-ray diffraction (PXRD) results showed that basic CD-MOFs were cubic crystals with smooth surface and uniform sizes. The basic CD-MOFs maintained their crystalline structure after neutralization. HPLC-ELSD analysis indicated that the CD-MOF crystal size had significant influence on sucralose loading (SL). The maximal SL of micron CD-MOFs (CD-MOF-Micro) was 17.5 ± 0.9% (w/w). In contrast, 27.9 ± 1.4% of sucralose could be loaded in nanometer-sized basic CD-MOFs (CD-MOF-Nano). Molecular docking modeling showed that sucralose molecules preferentially located inside the cavities of γ-CDs pairs in CD-MOFs. Raw sucralose decomposed fast at 90°C, with 86.2 ± 0.2% of the compound degraded within only 1 h. Remarkably, sucralose stability was dramatically improved after loading in neutralized CD-MOFs, with only 13.7 ± 0.7% degradation at 90°C within 24 h. CONCLUSIONS: CD-MOFs efficiently incorporated sucralose and maintained its integrity upon heating at elevated temperatures.

Monitoring cotranslational protein folding in mammalian cells at codon resolution.

How the ribosome-bound nascent chain folds to assume its functional tertiary structure remains a central puzzle in biology. In contrast to refolding of a denatured protein, cotranslational folding is complicated by the vectorial nature of nascent chains, the frequent ribosome pausing, and the cellular crowdedness. Here, we present a strategy called folding-associated cotranslational sequencing that enables monitoring of the folding competency of nascent chains during elongation at codon resolution. By using an engineered multidomain fusion protein, we demonstrate an efficient cotranslational folding immediately after the emergence of the full domain sequence. We also apply folding-associated cotranslational sequencing to track cotranslational folding of hemagglutinin in influenza A virus-infected cells. In contrast to sequential formation of distinct epitopes, the receptor binding domain of hemagglutinin follows a global folding route by displaying two epitopes simultaneously when the full sequence is available. Our results provide direct evidence of domain-wise global folding that occurs cotranslationally in mammalian cells.