Reduction of WDR81 impairs autophagic clearance of aggregated proteins and cell viability in neurodegenerative phenotypes.

Neurodegenerative diseases are characterized by neuron loss and accumulation of undegraded protein aggregates. These phenotypes are partially due to defective protein degradation in neuronal cells. Autophagic clearance of aggregated proteins is critical to protein quality control, but the underlying mechanisms are still poorly understood. Here we report the essential role of WDR81 in autophagic clearance of protein aggregates in models of Huntington's disease (HD), Parkinson's disease (PD) and Alzheimer's disease (AD). In hippocampus and cortex of patients with HD, PD and AD, protein level of endogenous WDR81 is decreased but autophagic receptor p62 accumulates significantly. WDR81 facilitates the recruitment of autophagic proteins onto Htt polyQ aggregates and promotes autophagic clearance of Htt polyQ subsequently. The BEACH and MFS domains of WDR81 are sufficient for its recruitment onto Htt polyQ aggregates, and its WD40 repeats are essential for WDR81 interaction with covalent bound ATG5-ATG12. Reduction of WDR81 impairs the viability of mouse primary neurons, while overexpression of WDR81 restores the viability of fibroblasts from HD patients. Notably, in Caenorhabditis elegans, deletion of the WDR81 homolog (SORF-2) causes accumulation of p62 bodies and exacerbates neuron loss induced by overexpressed α-synuclein. As expected, overexpression of SORF-2 or human WDR81 restores neuron viability in worms. These results demonstrate that WDR81 has crucial evolutionarily conserved roles in autophagic clearance of protein aggregates and maintenance of cell viability under pathological conditions, and its reduction provides mechanistic insights into the pathogenesis of HD, PD, AD and brain disorders related to WDR81 mutations.

TFEB acetylation promotes lysosome biogenesis and ameliorates Alzheimer's disease-relevant phenotypes in mice.

Lysosomes are one of the major centers for regulating cargo degradation and protein quality control. Transcription factor EB (TFEB)-promoted lysosome biogenesis enhances lysosome-mediated degradation and alleviates neurodegenerative diseases, but the mechanisms underlying TFEB modification and activation are still poorly understood. Here, we report essential roles of TFEB acetylation in TFEB nuclear translocation and lysosome biogenesis, which are independent of TFEB dephosphorylation. By screening small molecules, we find that Trichostatin A (TSA), the pan-inhibitor of histone deacetylases (HDACs), promotes nuclear translocation of TFEB. TSA enhances the staining of cells by LysoTracker Red and increases the expression of lysosomal and autophagic genes. We identify four novel acetylated lysine residues in TFEB, which are important for TFEB nuclear translocation and lysosome biogenesis. We show that TFEB acetylation is regulated by HDACs (HDAC5, HDAC6, and HDAC9) and lysine acetyltransferases (KATs), including ELP3, CREBBP, and HAT1. During TSA-induced cytosol-to-nucleus translocation of TFEB, acetylation is independent of TFEB dephosphorylation, since the mTORC1- or GSK3ß-related phosphorylation sites on TFEB are still phosphorylated. Administration of TSA to APP/PS1 mice increases the expression of lysosomal and autophagic genes in mouse brains and also improves memory. Accordingly, the ß-amyloid plaque burden is decreased. These results show that the acetylation of TFEB, as a novel mechanism of TFEB activation, promotes lysosome biogenesis and alleviates the pathogenesis of Alzheimer's disease. Our results also suggest that HDAC inhibition can promote lysosome biogenesis, and this may be a potential therapeutic approach for the treatment of neurodegenerative diseases and disorders related to HDAC hyperactivation.

Homogeneous Gold-Catalyzed Oxidation Reactions.

Homogeneous gold catalysis has experienced extraordinary development since the dawn of this millennium. Oxidative gold catalysis is a vibrant and fertile subfield and has over the years delivered a diverse array of versatile synthetic methods of exceptional value to synthetic practices. This review aims to cover this topic in a comprehensive manner. The discussions are organized by the mechanistic aspects of the metal oxidation states and further by the types of oxidants or oxidizing functional groups. Synthetic applications of oxidative gold catalysis are also discussed.

Failure to achieve reduction on developmental dysplasia of hip: an ultrasound evaluation.

BACKGROUND: Ultrasound examination of the medial side of the hip joint has been rarely used to evaluate the status of developmental dysplasia of the hip (DDH) in Pavlik harness treatment according to the literature. PURPOSE: To analyze the effects of cartilaginous acetabulum, hip joint labrum, and acetabular tissue on the reduction of DDH. MATERIAL AND METHODS: A total of 50 cases (100 hips) were detected by the Graf method with a high-frequency linear transducer (L 5-12), and there were 59 dislocated hips and 41 non-dislocated hips. Patients were treated with a Pavlik harness. Ultrasound examination of the medial side of the hip joint was performed for follow-up. The hip joints were divided into three groups: the non-dislocated group; the reducible group; and the non-reducible group. RESULTS: The success rate of reduction was significantly higher when the acetabulum cartilage was located on the cephalic side (chi-square = 28.12, P < 0.001). The success rate was also significantly higher when the hip joint labrum was located on the cephalic side (chi-square = 17.21, P < 0.001). Type III and D had a higher success rate of reduction than type IV (P < 0.001). The pairwise comparison of the measurements of acetabular tissue between the non-dislocated group, the reducible group, and the non-reducible group showed statistical differences (P < 0.001). CONCLUSION: The present study confirmed that the location of acetabulum cartilage and hip joint labrum affected the outcome of treatment. The degree of dislocation and the amount of acetabular tissue were correlated with the success rate of treatment.

An augmented diffusion algorithm with bidirectional communication for a distributed active noise control system.

Recent studies on diffusion adaptation for distributed active noise control (DANC) systems have attracted significant research interest due to their balance between computational burden and stability compared to conventional centralized and decentralized adaptation schemes. The conventional multitask diffusion FxLMS algorithm assumes that the converged solutions of all control filters are consistent to each other, which is unrealistic in practice hence results in inferior performance in noise reduction. An augmented diffusion FxLMS algorithm has been proposed to overcome this problem, which adopts a neighborhood-wide adaptation and node-based combination approach to mitigate the bias in the converged solution of the multitask diffusion algorithms. However, the improvement comes at the expense of a higher computational burden and communication cost. All existing DANC systems, including the multitask and augmented diffusion algorithms, assume one-way communication between nodes. By contrast, this paper proposes a bidirectional communication scheme for the augmented diffusion algorithm to further reduce the memory requirement, computational burden, and communication cost. Simulation results in the free field and with measured room impulse responses both demonstrate that the proposed augmented diffusion algorithm with bidirectional communication can achieve a faster convergence speed than that based on one-way communication with a lower memory, computation, and communication burden.

Object Detection of Flexible Objects with Arbitrary Orientation Based on Rotation-Adaptive YOLOv5.

It is challenging to accurately detect flexible objects with arbitrary orientation from monitoring images in power grid maintenance and inspection sites. This is because these images exhibit a significant imbalance between the foreground and background, which can lead to low detection accuracy when using a horizontal bounding box (HBB) as the detector in general object detection algorithms. Existing multi-oriented detection algorithms that use irregular polygons as the detector can improve accuracy to some extent, but their accuracy is limited due to boundary problems during the training process. This paper proposes a rotation-adaptive YOLOv5 (R_YOLOv5) with a rotated bounding box (RBB) to detect flexible objects with arbitrary orientation, effectively addressing the above issues and achieving high accuracy. Firstly, a long-side representation method is used to add the degree of freedom (DOF) for bounding boxes, enabling accurate detection of flexible objects with large spans, deformable shapes, and small foreground-to-background ratios. Furthermore, the further boundary problem induced by the proposed bounding box strategy is overcome by using classification discretization and symmetric function mapping methods. Finally, the loss function is optimized to ensure training convergence for the new bounding box. To meet various practical requirements, we propose four models with different scales based on YOLOv5, namely R_YOLOv5s, R_YOLOv5m, R_YOLOv5l, and R_YOLOv5x. Experimental results demonstrate that these four models achieve mean average precision (mAP) values of 0.712, 0.731, 0.736, and 0.745 on the DOTA-v1.5 dataset and 0.579, 0.629, 0.689, and 0.713 on our self-built FO dataset, exhibiting higher recognition accuracy and a stronger generalization ability. Among them, R_YOLOv5x achieves a mAP that is about 6.84% higher than ReDet on the DOTAv-1.5 dataset and at least 2% higher than the original YOLOv5 model on the FO dataset.

Research on Photoacoustic Synthetic Aperture Focusing Technology Imaging Method of Internal Defects in Cylindrical Components.

Cylindrical components are parts with curved surfaces, and their high-precision defect testing is of great significance to industrial production. This paper proposes a noncontact internal defect imaging method for cylindrical components, and an automatic photoacoustic testing platform is built. A synthetic aperture focusing technology in the polar coordinate system based on laser ultrasonic (LU-pSAFT) is established, and the relationship between the imaging quality and position of discrete points is analyzed. In order to verify the validity of this method, small holes of Φ0.5 mm in the aluminum alloy rod are tested. During the imaging process, since a variety of waveforms can be excited by the pulsed laser synchronously, the masked longitudinal waves reflected by small holes need to be filtered and windowed to achieve high-quality imaging. In addition, the influence of ultrasonic beam angle and signal array spacing on imaging quality is analyzed. The results show that the method can accurately present the outline of the small hole, the circumferential resolution of the small hole is less than 1° and the dimensional accuracy and position error are less than 0.1 mm.

Inhibition of the dopamine transporter promotes lysosome biogenesis and ameliorates Alzheimer's disease-like symptoms in mice.

INTRODUCTION: Lysosomes are degradative organelles that maintain cellular homeostasis and protein quality control. Transcription factor EB (TFEB)-mediated lysosome biogenesis enhances lysosome-dependent degradation and alleviates neurodegenerative diseases, but the mechanisms underlying TFEB regulation and modification are still poorly understood. METHODS: By screening novel small-molecule compounds, we identified a group of lysosome-enhancing compounds (LYECs) that promote TFEB activation and lysosome biogenesis. RESULTS: One of these compounds, LH2-051, significantly inhibited the function of the dopamine transporter (DAT) and subsequently promoted lysosome biogenesis. We uncovered cyclin-dependent kinase 9 (CDK9) as a novel regulator of DAT-mediated lysosome biogenesis and identified six novel CDK9-phosphorylated sites on TFEB. We observed that signal transduction by the DAT-CDK9-TFEB axis occurs on lysosomes. Finally, we found that LH2-051 enhanced the degradation of amyloid beta plaques and improved the memory of amyloid precursor protein (APP)/Presenilin 1 (PS1) mice. DISCUSSION: We identified the DAT-CDK9-TFEB signaling axis as a novel regulator of lysosome biogenesis. Our study sheds light on the mechanisms of protein quality control under pathophysiological conditions.

A Risk Model for Prognosis and Treatment Response Prediction in Colon Adenocarcinoma Based on Genes Associated with the Characteristics of the Epithelial-Mesenchymal Transition.

The epithelial-mesenchymal transition (EMT) is an important process during metastasis in various tumors, including colorectal cancer (CRC). Thus, the study of its characteristics and related genes is of great significance for CRC treatment. In this study, 26 EMT-related gene sets were used to score each sample from The Cancer Genome Atlas program (TCGA) colon adenocarcinoma (COAD) database. Based on the 26 EMT enrichment scores for each sample, we performed unsupervised cluster analysis and classified the TCGA-COAD samples into three EMT clusters. Then, weighted gene co-expression network analysis (WGCNA) was used to investigate the gene modules that were significantly associated with these three EMT clusters. Two gene modules that were strongly positively correlated with the EMT cluster 2 (worst prognosis) were subjected to Cox regression and least absolute shrinkage and selection operator (LASSO) regression analysis. Then, a prognosis-related risk model composed of three hub genes GPRC5B, LSAMP, and PDGFRA was established. The TCGA rectal adenocarcinoma (READ) dataset and a CRC dataset from the Gene Expression Omnibus (GEO) were used as the validation sets. A novel nomogram that incorporated the risk model and clinicopathological features was developed to predict the clinical outcomes of the COAD patients. The risk model served as an independent prognostic factor. It showed good predictive power for overall survival (OS), immunotherapy efficacy, and drug sensitivity in the COAD patients. Our study provides a comprehensive evaluation of the clinical relevance of this three-gene risk model for COAD patients and a deeper understanding of the role of EMT-related genes in COAD.

Environmental impact assessment of multi-source solid waste based on a life cycle assessment, principal component analysis, and random forest algorithm.

As a national pilot city for solid waste disposal and resource reuse, Dongguan in Guangdong Province aims to vigorously promote the high-value utilization of solid waste and contribute to the sustainable development of the Greater Bay Area. In this study, life cycle assessment (LCA) coupled with principal component analysis (PCA) and the random forest (RF) algorithm was applied to assess the environmental impact of multi-source solid waste disposal technologies to guide the environmental protection direction. In order to improve the technical efficiency and reduce pollution emissions, some advanced technologies including carbothermal reduction‒oxygen-enriched side blowing, directional depolymerization‒flocculation demulsification, anaerobic digestion and incineration power generation, were applied for treating inorganic waste, organic waste, kitchen waste and household waste in the park. Based on the improved techniques, we proposed a cyclic model for multi-source solid waste disposal. Results of the combined LCA-PCA-RF calculation indicated that the key environmental load type was human toxicity potential (HTP), came from the technical units of carbothermal reduction and oxygen-enriched side blowing. Compared to the improved one, the cyclic model was proved to reduce material and energy inputs by 66%-85% and the pollution emissions by 15%-88%. To sum up, the environmental impact assessment and systematic comparison suggest a cyclic mode for multi-source solid waste treatments in the park, which could be promoted and contributed to the green and low-carbon development of the city.

Genotype-Phenotype Relationship and Follow-up Analysis of a Chinese Cohort With Osteogenesis Imperfecta.

OBJECTIVE: To evaluate the genotype-phenotype relationship and the effect of treatment on the clinical course of osteogenesis imperfecta (OI). METHODS: We established a Chinese hospitalized cohort with OI and followed them up for an average of 6 years. All patients were confirmed as having OI using whole-exome sequencing. We analyzed the genotype-phenotype relationship based on different types, pathogenic mechanisms, and gene inheritance patterns of OI. Additionally, we assessed whether there was a difference in treatment efficacy based on genotype. RESULTS: One hundred sixteen mutations in 6 pathogenic genes (COL1A1, COL1A2, IFITM5, SERPINF1, FKBP10, and WNT1) were identified in 116 patients with type I, III, IV, V, VI, XI, or XV OI. Compared with patients with COL1A1 mutations, patients with COL1A2 mutations were younger at the time of the first fracture, whereas other phenotypes were similar. When 3 groups (helical, haploinsufficiency, and non-collagen I gene mutations) were compared, patients with helical mutations were the shortest and most prone to dentinogenesis imperfecta. Patients with haploinsufficiency mutations were the oldest at the time of the first fracture. Moreover, patients with non-collagen I gene mutations were least susceptible to blue sclerae and had the highest fracture frequency. Furthermore, there were some minor phenotypic differences among non-collagen I gene mutations. Interestingly, pamidronate achieved excellent results in the treatment of patients with OI, and the treatment effect appeared to be unrelated to their genotypes. CONCLUSION: Our findings indicated a genotype-phenotype relationship and a similar effect of pamidronate treatment in patients with OI, which could provide a basis for guiding clinical treatment and predicting OI prognosis.

Use of ultrasonography to evaluate early outcomes of reduction in developmental dysplasia of the hip.

OBJECTIVE: To compare pubo-femoral distance (PFD) in normal hips and those treated for developmental dysplasia of the hip (DDH) and to investigate the value of ultrasonography from the medial hip in early follow-up of dislocated DDH after reduction. MATERIALS AND METHODS: This study included 58 infants (49 females) with DDH who presented with 65 dislocated hips (51 unilateral and 7 bilateral). Dislocation was treated by closed reduction for 53 and open reduction for 12 hips. Ultrasonography on the medial side of the hip was performed within 1-2 weeks and 4 weeks after reduction. The distance from the pubic bone to the femoral head (PFD) was measured to assess the reduction and stability of the femoral head and compared to that on the contralateral side (control) in cases of unilateral DDH. RESULTS: The PFD value for the normal group (2.9 ± 0.4 mm) was significantly less than that for the closed reduction group (4.9 ± 2.8 mm, P<0.001) and that for the open reduction group (4.4 ± 1.6 mm; P=0.02), but no difference in the PFD was observed between the closed reduction and the open reduction groups (P=0.73). Despite successful reduction, the PFD values in the successful reduction group remained higher than those of the normal hips. CONCLUSION: PFD measurement by ultrasonography of the medial hip can be used to evaluate the effectiveness of reduction procedures in DDH. The clinical implications of post-reduction ultrasound evaluation in the diagnosis and long-term follow-up of outcomes require further research.

Chiral Bifunctional Phosphine Ligand-Enabled Cooperative Cu Catalysis: Formation of Chiral α,ß-Butenolides via Highly Enantioselective γ-Protonation.

α,ß-Butenolides with ≥96% enantiomeric excess are synthesized from ß,γ-butenolides via a novel Cu(I)-ligand cooperative catalysis. The reaction is enabled by a chiral biphenyl-2-ylphosphine ligand featuring a remote tertiary amino group. Density functional theory studies support the cooperation between the metal center and the ligand basic amino group during the initial soft deprotonation and the key asymmetric γ-protonation. Remarkably, other coinage metals, that is, Ag and Au, can readily assume the same role as Cu in this asymmetric isomerization chemistry.

Contribution of neural crest-derived stem cells and nasal chondrocytes to articular cartilage regeneration.

Due to poor self-regenerative potential of articular cartilage, stem cell-based regeneration becomes a hopeful approach for the treatment of articular cartilage defects. Recent studies indicate that neural crest-derived cells (NCDCs) have the potential for repairing articular cartilage with even greater chondrogenic capacity than mesoderm-derived cells (MDCs): a conventional stem cell source for cartilage regeneration. Given that NCDCs originate from a different germ layer in the early embryo compared with MDCs that give rise to articular cartilage, a mystery remains regarding their capacity for articular cartilage regeneration. In this review, we summarize the similarities and differences between MDCs and NCDCs including articular and nasal chondrocytes in cell origin, anatomy, and chondrogenic differentiation and propose that NCDCs might be promising cell origins for articular cartilage regeneration.

Establishing reference values for the pubofemoral distance in normal infant medial hips by ultrasound.

BACKGROUND: Measuring the pubofemoral distance (PFD) is important for evaluating the effectiveness of hip reduction in the treatment of developmental dysplasia of the hip (DDH). However, reference PFD values have not been established in normal infants. PURPOSE: To investigate variations in PFD values measured in normal infant medial hips stratified by age, laterality, and gender. MATERIAL AND METHODS: A total of 240 infants diagnosed with Graf type Ia and/or Graf type Ib hips by ultrasonography were stratified into eight age groups: 0-1 month; 1-2 months; 2-3 months; 3-4 months; 4-5 months; 5-6 months; 6-7 months; and 7-12 months. The bilateral medial hips were scanned with transinguinal ultrasound. The PFD was defined as the distance between the lateral edge of the superior ramus of pubic bone and the medial edge of the femoral head. Inter-observer reproducibility was assessed. RESULTS: Among the 240 infants, there were 371 Graf type Ia hips and 109 Graf type Ib hips. Mean ± SD bilateral PFD values of eight groups were measured separately. There were no significant differences in mean PFD values for left or right hips (t = 0.946, P = 0.345) or mean bilateral PFD values in male and female infants (t = 1.445, P = 0.149). Mean PFD values increased linearly with age (left: r = 0.680, P < 0.0001; right: r = 0.682, P < 0.0001). Inter-observer reproducibility was excellent. CONCLUSION: This study established reference PFD values from the medial hip in infants aged 0-12 months. PFD values increased with age, but were not significantly influenced by laterality or gender. These data provide detailed information that can support follow-up of infants treated for DDH.

Vancomycin-induced reversible pancytopenia and rash in a 16-month-old boy with osteomyelitis: A case report
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OBJECTIVE: Vancomycin is a commonly used glycopeptide antibiotic due to its effectiveness in treating serious Gram-positive bacterial infections, especially methicillin-resistant Staphylococcus aureus (MRSA) infection. Pancytopenia is a rare, yet serious, complication of vancomycin. Previous isolated cases have been reported in adults but none in children. CASE REPORT: A 16-month-old boy received vancomycin for treatment of osteomyelitis caused by MRSA. During his administration of vancomycin, reversible pancytopenia, pulmonary infection, and skin rash developed, which resolved after withdrawal. CONCLUSION: This is the first known case of vancomycin causing reversible pancytopenia and skin rash in a child, suggesting that pancytopenia caused by vancomycin could complicate treatment of children, and the hypothesis that pancytopenia is an immune-mediated reaction seems to be preferable. According to drug hypersensitivity syndrome (DHS) risk assessment in 10-D assessment system, this case was at grade of no risk.

Reconfigurable metasurface hologram by utilizing addressable dynamic pixels.

The flatness, compactness and high-capacity data storage capability make metasurfaces well-suited for holographic information recording and generation. However, most of the metasurface holograms are static, not allowing a dynamic modification of the phase profile after fabrication. Here, we propose and demonstrate a dynamic metasurface hologram by utilizing hierarchical reaction kinetics of magnesium upon a hydrogenation/dehydrogenation process. The metasurface is composed of composite gold/magnesium V-shaped nanoantennas as building blocks, leading to a reconfigurable phase profile in a hydrogen/oxygen environment. We have developed an iterative hologram algorithm based on the Fidoc method to build up a quantified phase relation, which allows the reconfigurable phase profile to reshape the reconstructed image. Such a strategy introduces actively controllable dynamic pixels through a hydrogen-regulated chemical process, showing unprecedented potentials for optical encryption, information processing and dynamic holographic image alteration.

Wilms tumor with inferior vena cava duplication: a rare case report.

BACKGROUND: Wilms tumor is the most common renal tumor of childhood. Duplication of the inferior vena cava is an uncommon anomaly. In the present study, we present a case of Wilms tumor with the inferior vena cava duplication, which has not been reported previously. CASE PRESENTATION: A 14-month-old female presented with an enlarging abdominal mass. Computed tomography imaging demonstrated a large mass in the right kidney, duplication of the inferior vena cava below the renal veins and compression of the right inferior vena cava caused by the enormous mass. A right radical nephrectomy was performed. Final pathology was consistent with Wilms tumor. Postoperative adjuvant chemotherapy was executed. Computed tomography imaging at 3 months postoperatively showed the right inferior vena cava played a dominant role and the left inferior vena cava was not detected clearly. During the follow-up of 18 months, no local recurrence or metastasis has been observed. CONCLUSION: It is important to recognize the case of Wilms tumor with the inferior vena cava duplication to avoid injury of retroperitoneal venous anomalies and life-threatening hemorrhage during surgery through preoperative computed tomography.

Tunable wave plate based on active plasmonic metasurfaces.

Polarization conversion is highly desired for numerous valuable applications such as remote detection and high-precision measurement. It is conventionally achieved through utilizing bulky birefringent crystals or by delicate tailored anisotropy materials. However, such schemes are not compatible with both dynamic and compact on-chip applications. We propose an active metasurface that can generate tunable ellipticity for arbitrary incident polarization with a non-volatile and reversible modulation method. The metasurface consists of V-shape plasmonic antenna arrays and an interval modulation layer made of the phase change material GST for active phase control. Our approach allows the generation of high-quality arbitrary elliptical polarization states in an ultrathin, non-mechanical, and flexible fashion, representing a significant advance compared with its conventional counterparts.