Samarium-Oxo/Hydroxy Cluster: A Solar Photocatalyst for Chemoselective Aerobic Oxidation of Thiols for Disulfide Synthesis.

Oxidation contributes as a secondary driver of the prevailing carbon emission in the chemical industries. To address this issue, photocatalytic aerobic oxidation has emerged as a promising alternative. However, the challenge of achieving satisfactory chemoselectivity and effective use of solar light has hindered progress in this area. In this context, the present study introduces a novel homogeneous photocatalyst, [Sm6O(OH)8(H2O)24]I8(H2O)8 cluster (Sm-OC), via a unique auxiliary ligand-free oxidative hydrolysis. Using Sm-OC as catalyst, a solar photocatalyzed aerobic oxidation of thiols has been developed for the synthesis of valuable disulfides. Remarkably, this catalyst manifested a significant turnover number ≥2000 under tested conditions. Sm-OC-catalyzed aerobic oxidation showcased remarkable chemoselectivity. In thiol oxidations, despite the vulnerability of disulfides toward overoxidation, overoxidized byproducts or oxidation of nontarget functional groups was not detected across all 28 tested substrates. This investigation presents the first application of a lanthanide-oxo/hydroxy cluster in photocatalysis.

SIRT1 maintains bone homeostasis by regulating osteoblast glycolysis through GOT1.

The silent information regulator T1 (SIRT1) is linked to longevity and is a crucial mediator of osteoblast function. We investigated the direct role of Sirt1 during bone modeling and remodeling stages in vivo using Tamoxifen-inducible osteoblast-specific Sirt1 conditional knockout (cKO) mice. cKO mice exhibited lower trabecular and cortical bone mass in the distal femur. These phenotypes were coupled with lower bone formation and bone resorption. Metabolomics analysis revealed that the metabolites involved in glycolysis were significantly decreased in cKO mice. Further analysis of the quantitative acetylome revealed 11 proteins with upregulated acetylation levels in both the femur and calvaria of cKO mice. Cross-analysis identified four proteins with the same upregulated lysine acetylation site in both the femur and calvaria of cKO mice. A combined analysis of the metabolome and acetylome, as well as immunoprecipitation, gene knockout, and site-mutation experiments, revealed that Sirt1 deletion inhibited glycolysis by directly binding to and increasing the acetylation level of Glutamine oxaloacetic transaminase 1 (GOT1). In conclusion, our study suggested that Sirt1 played a crucial role in regulating osteoblast metabolism to maintain bone homeostasis through its deacetylase activity on GOT1. These findings provided a novel insight into the potential targeting of osteoblast metabolism for the treatment of bone-related diseases.

Calcified apoptotic vesicles from PROCR+ fibroblasts initiate heterotopic ossification.

Heterotopic ossification (HO) comprises the abnormal formation of ectopic bone in extraskeletal soft tissue. The factors that initiate HO remain elusive. Herein, we found that calcified apoptotic vesicles (apoVs) led to increased calcification and stiffness of tendon extracellular matrix (ECM), which initiated M2 macrophage polarization and HO progression. Specifically, single-cell transcriptome analyses of different stages of HO revealed that calcified apoVs were primarily secreted by a PROCR+ fibroblast population. In addition, calcified apoVs enriched calcium by annexin channels, absorbed to collagen I via electrostatic interaction, and aggregated to produce calcifying nodules in the ECM, leading to tendon calcification and stiffening. More importantly, apoV-releasing inhibition or macrophage deletion both successfully reversed HO development. Thus, we are the first to identify calcified apoVs from PROCR+ fibroblasts as the initiating factor of HO, and might serve as the therapeutic target for inhibiting pathological calcification.

Interorgan communication in neurogenic heterotopic ossification: the role of brain-derived extracellular vesicles.

Brain-derived extracellular vesicles participate in interorgan communication after traumatic brain injury by transporting pathogens to initiate secondary injury. Inflammasome-related proteins encapsulated in brain-derived extracellular vesicles can cross the blood‒brain barrier to reach distal tissues. These proteins initiate inflammatory dysfunction, such as neurogenic heterotopic ossification. This recurrent condition is highly debilitating to patients because of its relatively unknown pathogenesis and the lack of effective prophylactic intervention strategies. Accordingly, a rat model of neurogenic heterotopic ossification induced by combined traumatic brain injury and achillotenotomy was developed to address these two issues. Histological examination of the injured tendon revealed the coexistence of ectopic calcification and fibroblast pyroptosis. The relationships among brain-derived extracellular vesicles, fibroblast pyroptosis and ectopic calcification were further investigated in vitro and in vivo. Intravenous injection of the pyroptosis inhibitor Ac-YVAD-cmk reversed the development of neurogenic heterotopic ossification in vivo. The present work highlights the role of brain-derived extracellular vesicles in the pathogenesis of neurogenic heterotopic ossification and offers a potential strategy for preventing neurogenic heterotopic ossification after traumatic brain injury. Brain-derived extracellular vesicles (BEVs) are released after traumatic brain injury. These BEVs contain pathogens and participate in interorgan communication to initiate secondary injury in distal tissues. After achillotenotomy, the phagocytosis of BEVs by fibroblasts induces pyroptosis, which is a highly inflammatory form of lytic programmed cell death, in the injured tendon. Fibroblast pyroptosis leads to an increase in calcium and phosphorus concentrations and creates a microenvironment that promotes osteogenesis. Intravenous injection of the pyroptosis inhibitor Ac-YVAD-cmk suppressed fibroblast pyroptosis and effectively prevented the onset of heterotopic ossification after neuronal injury. The use of a pyroptosis inhibitor represents a potential strategy for the treatment of neurogenic heterotopic ossification.

Lysosomal destabilization: A missing link between pathological calcification and osteoarthritis.

Calcification of cartilage by hydroxyapatite is a hallmark of osteoarthritis and its deposition strongly correlates with the severity of osteoarthritis. However, no effective strategies are available to date on the prevention of hydroxyapatite deposition within the osteoarthritic cartilage and its role in the pathogenesis of this degenerative condition is still controversial. Therefore, the present work aims at uncovering the pathogenic mechanism of intra-cartilaginous hydroxyapatite in osteoarthritis and developing feasible strategies to counter its detrimental effects. With the use of in vitro and in vivo models of osteoarthritis, hydroxyapatite crystallites deposited in the cartilage are found to be phagocytized by resident chondrocytes and processed by the lysosomes of those cells. This results in lysosomal membrane permeabilization (LMP) and release of cathepsin B (CTSB) into the cytosol. The cytosolic CTSB, in turn, activates NOD-like receptor protein-3 (NLRP3) inflammasomes and subsequently instigates chondrocyte pyroptosis. Inhibition of LMP and CTSB in vivo are effective in managing the progression of osteoarthritis. The present work provides a conceptual therapeutic solution for the prevention of osteoarthritis via alleviation of lysosomal destabilization.

A-D-A Type Nonfullerene Acceptors Synthesized by Core Segmentation and Isomerization for Realizing Organic Solar Cells with Low Nonradiative Energy Loss.

Reducing non-radiative recombination energy loss (ΔEnonrad ) in organic solar cells (OSCs) has been considered an effective method to improve device efficiency. In this study, the backbone of PTBTT-4F/4Cl is divided into D1-D2-D3 segments and reconstructed. The isomerized TPBTT-4F/4Cl obtains stronger intramolecular charge transfer (ICT), thus leading to elevated highest occupied molecular orbital (HOMO) energy level and reduced bandgap (Eg ). According to ELoss  = Eg- qVOC , the reduced Eg and enhanced open circuit voltage (VOC ) result in lower ELoss , indicating that ELoss has been effectively suppressed in the TPBTT-4F/4Cl based devices. Furthermore, compared to PTBTT derivatives, the isomeric TPBTT derivatives exhibit more planar molecular structure and closer intermolecular stacking, thus affording higher crystallinity of the neat films. Therefore, the reduced energy disorder and corresponding lower Urbach energy (Eu ) of the TPBTT-4F/4Cl blend films lead to low ELoss and high charge-carrier mobility of the devices. As a result, benefitting from synergetic control of molecular stacking and energetic offsets, a maximum power conversion efficiency (PCE) of 15.72% is realized from TPBTT-4F based devices, along with a reduced ΔEnonrad of 0.276 eV. This work demonstrates a rational method of suppressing VOC loss and improving the device performance through molecular design engineering by core segmentation and isomerization.

The osteoporosis susceptibility SNP rs188303909 at 2q14.2 regulates EN1 expression by modulating DNA methylation and E2F6 binding.

EN1 encodes a homeodomain-containing transcription factor and is a determinant of bone density and fracture. Previous powerful genome-wide association studies (GWASs) have identified multiple single-nucleotide polymorphisms (SNPs) near EN1 at 2q14.2 locus for osteoporosis, but the causal SNPs and functional mechanisms underlying these associations are poorly understood. The target genes regulated by the transcription factor EN1 are also unclear. In this study, we identified rs188303909, a functional CpG-SNP, as a causal SNP for osteoporosis at 2q14.2 through the integration of functional and epigenomic analyses. Functional experiments demonstrated that unmethylated rs188303909 acted as a strong allele-specific distal enhancer to regulate EN1 expression by modifying the binding of transcription factor E2F6, but rs188303909 methylation attenuated the active effect of E2F6 on EN1 expression. Importantly, transcription factor EN1 could differentially bind osteoporosis GWAS lead SNPs rs4869739-T and rs4355801-G to upregulate CCDC170 and COLEC10 expression, thus promoting bone formation. Our study provided a mechanistic insight into expression regulation of the osteoporosis susceptibility gene EN1, which could be a potential therapeutic target for osteoporosis precision medicine. KEY MESSAGES: CpG-SNP rs188303909 is a causal SNP at the osteoporosis susceptibility locus 2q14.2. Rs188303909 distally regulates EN1 expression by modulating DNA methylation and E2F6 binding. EN1 upregulates CCDC170 and COLEC10 expression through osteoporosis GWAS lead SNPs rs4869739 and rs4355801.

Application of Iodine as a Catalyst in Aerobic Oxidations: A Sustainable Approach for Thiol Oxidations.

Iodine is a well-known oxidant that is widely used in organic syntheses. Thiol oxidation by stoichiometric iodine is one of the most commonly employed strategies for the synthesis of valuable disulfides. While recent advancements in catalytic aerobic oxidation conditions have eliminated the need for stoichiometric oxidants, concerns persist regarding the use of toxic or expensive catalysts. In this study, we discovered that iodine can be used as a cheap, low-toxicity catalyst in the aerobic oxidation of thiols. In the catalytic cycle, iodine can be regenerated via HI oxidation by O2 at 70 °C in EtOAc. This protocol harnesses sustainable oxygen as the terminal oxidant, enabling the conversion of primary and secondary thiols with remarkable efficiency. Notably, all 26 tested thiols, encompassing various sensitive functional groups, were successfully converted into their corresponding disulfides with yields ranging from >66% to 98% at a catalyst loading of 5 mol%.

Machine learning-based anomaly detection of groundwater microdynamics: case study of Chengdu, China.

Detection of subsurface hydrodynamic anomalies plays a significant role in groundwater resource management and environmental monitoring. In this paper, based on data from the groundwater level, atmospheric pressure, and precipitation in the Chengdu area of China, a method for detecting outliers considering the factors affecting groundwater levels is proposed. By analyzing the factors affecting groundwater levels in the monitoring site and eliminating them, simplified groundwater data is obtained. Applying sl-Pauta (self-learning-based Pauta), iForest (Isolated Forest), OCSVM (One-Class SVM), and KNN to synthetic data with known outliers, testing and evaluating the effectiveness of 4 technologies. Finally, the four methods are applied to the detection of outliers in simplified groundwater levels. The results show that in the detection of outliers in synthesized data, the OCSVM method has the best detection performance, with a precision rate of 88.89%, a recall rate of 91.43%, an F1 score of 90.14%, and an AUC value of 95.66%. In the detection of outliers in simplified groundwater levels, a qualitative analysis of the displacement data within the field of view indicates that the outlier detection performance of iForest and OCSVM is better than that of KNN. The proposed method for considering the factors affecting groundwater levels can improve the efficiency and accuracy of detecting outliers in groundwater level data.

The immunomodulatory effects of RNA-based biomaterials on bone regeneration.

The use of RNA as therapeutic agents is a visionary idea in contemporary medicine. Some forms of RNA can modulate the immune response of the host to enhance tissue regeneration events such as osteogenesis. Herein, RNA molecules commercially available for immunomodulatory applications (imRNA) were used to prepare biomaterials for bone regeneration. The polyanionic imRNA stabilized calcium phosphate ionic clusters to produce imRNA-ACP that had the capacity to mineralize the intrafibrillar compartments of collagen fibrils. For the first time, it was shown that incorporating imRNA-ACP into collagen scaffolds resulted in rapid new bone formation in cranial defects of mice. Both in vivo and in vitro results demonstrated that macrophage polarization was highly-sensitive to the imRNA-ACP containing collagen scaffolds. Macrophages were polarized into the anti-inflammatory M2 phenotype that produced anti-inflammation cytokines and growth factors. The favorable osteoimmunological microenvironment created by the scaffolds prevented their immunorejection and facilitated osteogenesis. The potential of RNA in creating immunomodulatory biomaterials has been underestimated in the past. The overall aim of this study was to explore the potential application of imRNA-based biomaterials in bone tissue engineering, with the competitive edge of facile synthesis and excellent biocompatibility. STATEMENT OF SIGNIFICANCE: In this work, commercially available RNA extracted from bovine spleens for immunomodulatory applications (imRNA) were used to stabilize amorphous calcium phosphate (ACP) and induce mineralization within collagen fibrils. Incorporation of imRNA-ACP into collagen scaffolds regenerated new bone in-situ. Because of its immunomodulatory effects, the imRNA-ACP that was incorporated into collagen scaffolds modulated the local immune environment of murine cranial defects by altering the macrophage phenotype through JAK2/STAT3 signaling pathway. The novelty of this work existed in the discovery of RNA's potential in creating immunomodulatory biomaterials. With the competitive edge of facile synthesis and excellent biocompatibility, the imRNA-based biomaterials are potentially useful for future bone tissue engineering applications.

Uncertainty-Aware Aggregation for Federated Open Set Domain Adaptation.

Open set domain adaptation (OSDA) methods have been proposed to leverage the difference between the source and target domains, as well as to recognize the known and unknown classes in the target domain. Such methods typically require the entire source and target data simultaneously to train the target model. However, in real scenarios, data are distributed and stored in various clients. They cannot be exchanged among clients because of privacy protection. Federated learning (FL) is a decentralized approach for training an effective global model with the training data distributed among the clients. Despite its potential in addressing the privacy concerns of data sharing, FL methods for OSDA that can handle unknown classes is not yet available. To tackle this problem, we have developed a novel federated OSDA (FOSDA) algorithm. More specifically, FOSDA adopts an uncertainty-aware mechanism to generate a global model from all client models. It reduces the uncertainty of the federated aggregation by focusing on the contribution of source clients with high uncertainty while retaining those with high consistency. Moreover, a federated class-based weighted strategy is also implemented in FOSDA to maintain the category information of the source clients. We have conducted comprehensive experiments on three benchmark datasets to evaluate the performance of the proposed method, and the results demonstrate the effectiveness of FOSDA.

A CW-CNN regression model-based real-time system for virtual hand control.

For upper limb amputees, wearing a myoelectric prosthetic hand is the only way for them to continue normal life. Even until now, the proposal of a high-precision and natural performance real-time control system based on surface electromyography (sEMG) signals is still challenging. Researchers have proposed many strategies for motion classification or regression prediction tasks based on sEMG signals. However, most of them have been limited to offline analysis only. There are even few papers on real-time control based on deep learning models, almost all of which are about motion classification. Rare studies tried to use deep learning-based regression models in real-time control systems for multi-joint angle estimation via sEMG signals. This paper proposed a CW-CNN regression model-based real-time control system for virtual hand control. We designed an Adaptive Kalman Filter to smooth the joint angles output before sending them as control commands to control a virtual hand. Eight healthy participants were invited, and three sessions experiments were conducted on two different days for all of them. During the real-time experiment, we analyzed the joint angles estimation accuracy and computational latency. Moreover, target achievement control (TAC) test was applied to emphasize motion regression in real-time. The experimental results show that the proposed control system has high precision for 3-DOFs motion regression in simultaneously, and the system remains stable and low computational latency. In the future, the proposed real-time control system can be applied to actual prosthetic hand.

Multi-Joint Angles Estimation of Forearm Motion Using a Regression Model.

To improve the life quality of forearm amputees, prosthetic hands with high accuracy, and robustness are necessary. The application of surface electromyography (sEMG) signals to control a prosthetic hand is challenging. In this study, we proposed a time-domain CNN model for the regression prediction of joint angles in three degrees of freedom (3-DOFs, include two wrist joint motion and one finger joint motion), and five-fold cross validation was used to evaluate the correlation coefficient (CC). The CC value results of wrist flexion/extension motion obtained from 10 participants was 0.87-0.92, pronation/supination motion was 0.72-0.95, and hand grip/open motion was 0.75-0.94. We backtracked the fully connected layer weights to create a geometry plot for analyzing the motion pattern to investigate the learning of the proposed model. In order to discuss the daily updateability of the model by transfer learning, we performed a second experiment on five of the participants in another day and conducted transfer learning based on smaller amount of dataset. The CC results improved (wrist flexion/extension was 0.90-0.97, pronation/supination was 0.84-0.96, hand grip/open was 0.85-0.92), suggesting the effectiveness of the transfer learning by incorporating the small amounts of sEMG data acquired in different days. We compared our CNN-based model with four conventional regression models, the result illustrates that proposed model significantly outperforms the four conventional models with and without transfer learning. The offline result suggests the reliability of the proposed model in real-time control in different days, it can be applied for real-time prosthetic control in the future.

Tandem H/D Exchange-SET Reductive Deuteration Strategy for the Synthesis of α,ß-Deuterated Amines Using D2O.

α,ß-Deuterated amines are crucial for the development of deuterated drugs. We intend to introduce the novel tandem H/D exchange-single electron transfer (SET) reductive deuteration strategy with high pot- and reagent-economy by the synthesis of α,ß-deuterated amine using nitrile as the precursor. The H/D exchange of the -CH2CN group was achieved by D2O/Et3N, which were also the required reagents in the tandem SmI2-mediated SET reductive deuteration of the α-deuterated nitrile. The potential application of this method was further showcased by the synthesis of bevantolol-d4.

Generation of diverse insect-like gait patterns using networks of coupled Rössler systems.

The generation of walking patterns is central to bio-inspired robotics and has been attained using methods encompassing diverse numerical as well as analog implementations. Here, we demonstrate the possibility of synthesizing viable gaits using a paradigmatic low-dimensional non-linear entity, namely, the Rössler system, as a dynamical unit. Through a minimalistic network wherein each instance is univocally associated with one leg, it is possible to readily reproduce the canonical gaits as well as generate new ones via changing the coupling scheme and the associated delays. Varying levels of irregularity can be introduced by rendering individual systems or the entire network chaotic. Moreover, through tailored mapping of the state variables to physical angles, adequate leg trajectories can be accessed directly from the coupled systems. The functionality of the resulting generator was confirmed in laboratory experiments by means of an instrumented six-legged ant-like robot. Owing to their simple form, the 18 coupled equations could be rapidly integrated on a bare-metal microcontroller, leading to the demonstration of real-time robot control navigating an arena using a brain-machine interface.