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Abstract As the Internet of Vehicles advances, the demand for timely data acquisition by vehicle users continues to escalate, albeit confronted with the challenge of excessive data retrieval latency. The emergence of edge computing provides technical support for the development of vehicular networks by caching data in advance to reduce data acquisition latency. Therefore, how to effectively cache and query data becomes a key issue in addressing the timeliness of data acquisition in vehicular networks. In this paper, we investigate an efficient query optimization model to minimize data acquisition latency. Firstly, based on the distribution of data query frequencies across different servers, we propose an edge collaborative caching strategy using a tabu search algorithm. This strategy prioritizes high-traffic data by finding two optimal storage nodes for each high-traffic data in descending order of data popularity, ensuring a backup within the collaborative domain for each data segment. This not only reduces data transmission latency between nodes during task execution but also prevents single-point failures. Secondly, we deploy cuckoo filters on edge nodes to enable rapid localization of cached data nodes when users query data, thus reducing data processing latency. Finally, simulation results demonstrate that the proposed query optimization model outperforms other schemes in terms of average data query latency.

Boron has been considered a promising powdered metal fuel for enhancing composite propellants' energy output due to its high energy density. However, the high ignition temperature and low combustion efficiency limit the application of boron powder due to the high boiling point of the boron oxide layer. Much research is ongoing to overcome these shortcomings, and one potential approach is to introduce a small quantity of metal oxide additives to promote the reaction of boron. This study prepared boron-rich fuels with 10 wt% of eight nano-metal oxide additives by mechanical ball milling. The effect of metal oxides on the thermo-oxidation, ignition, and combustion properties of boron powder was comprehensively studied by the thermogravimetric analysis (TG), the electrically heated filament setup (T-jump), and the laser-induced combustion experiments. TG experiments at 5 K/min found that Bi2O3, MoO3, TiO2, Fe2O3, and CuO can promote thermo-oxidation of boron. Compared to pure boron, Tonset can be reduced from 569 °C to a minimum of 449 °C (B/Bi2O3). Infrared temperature measurement in T-jump tests showed that when heated by an electric heating wire at rates from 1000 K/s to 25000 K/s, the ignition temperatures of B/Bi2O3 are the lowest, even lower than the melting point of boron oxide. Ignition images and SEM for the products further showed that the high heating rate is beneficial to the rapid reaction of boron powder in the single-particle combustion state. Fuels (B/Bi2O3, B/MoO3, and B/CuO) were mixed with the oxidant AP and ignited by laser to study the combustion performance. The results showed that B/CuO/AP has the largest flame area, the highest BO2 characteristic spectral intensity, and the largest burn rate for powder lines. To combine the advantages of CuO and Bi2O3, binary metal oxide (CBO, mass ratio of 3:1) was prepared and the test results showed that CBO can very well improve both ignition and combustion properties of boron. Especially B/CBO/AP has the highest burn rate compared with all fuels containing other additives. It was found that multi-component metal-oxide additive can more synergistically improve the reaction characteristics of boron powder than unary additive. These findings contribute to the development of boron-rich fuels and their application in propellants.

Plant basic helix-loop-helix (bHLH) transcription factors (TFs) play central roles in various abiotic stresses. However, its role in plant cold resistance is largely unknown. Previously, we characterised CaNAC035 in pepper, which positively regulates tolerance to cold, salt and drought stresses tolerance. Here, we identified CabHLH035, a CaNAC035-interacting protein in pepper. To explore its functions in cold stress tolerance, we silenced the gene in pepper via virus-induced gene silencing (VIGS) and overexpressed the gene in Arabidopsis. The results showed that CabHLH035 expression was induced by cold treatment, and silencing of CabHLH035 decreased cold stress tolerance. Conversely, overexpression of CabHLH035 in Arabidopsis increased cold stress tolerance. To investigate homologs genes of C-repeat binding factor (CBF) pathway proteins and reactive oxygen species (ROS) marker gene expression blocking by CabHLH035, we performed yeast one-hybrid (Y1H), dual luciferase and electrophoretic mobility shift assay experiments. The results showed that CabHLH035 bound to the region upstream of the CaCBF1A and CaAPX promoters. Additionally, CaCBF1A bound to the CaDHN4 promoter. Taken together, our results showed that CabHLH035 plays a crucial role in cold stress tolerance and its potential as a target for breeding cold-resistant crops. The findings provide a basis for studying the functions and regulatory network of cold stress tolerance in pepper.

Abstract Chiral spin textures, as exotic phases in magnetic materials, hold immense promise for revolutionizing logic, and memory applications. Recently, chiral spin textures have been observed in centrosymmetric magnetic insulators (FMI), due to an interfacial Dzyaloshinskii–Moriya interaction (iDMI). However, the source and origin of this iDMI remain enigmatic in magnetic insulator systems. Here, the source and origin of the iDMI in Pt/Y3Fe5O12 (YIG)/substrate structures are deeply delved by examining the spin‐Hall topological Hall effect (SH‐THE), an indication of chiral spin textures formed due to an iDMI. Through carefully modifying the interfacial chemical composition of Pt/YIG/substrate with a nonmagnetic Al3+ doping, the obvious dependence of SH‐THE on the interfacial chemical composition for both the heavy metal (HM)/FMI and FMI/substrate interfaces is observed. The results reveal that both interfaces contribute to the strength of the iDMI, and the iDMI arises due to strong spin−orbit coupling and inversion symmetry breaking at both interfaces in HM/FMI/substrate. Importantly, it is shown that nonmagnetic substitution and interface engineering can significantly tune the SH‐THE and iDMI in ferrimagnetic iron garnets. The approach offers a viable route to tailor the iDMI and associated chiral spin textures in low‐damping insulating magnetic oxides, thus advancing the field of spintronics.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide and presents a significant threat to human health. Despite its prevalence, the underlying regulatory mechanisms of HCC remain unclear. In this study, we integrated RNA-seq datasets, proteome dataset and survival analysis and unveiled Stratifin (SFN) as a potential prognostic biomarker for HCC. SFN knockdown inhibited HCC progression in cell cultures and mouse models. Conversely, ectopic expression of Sfn in primary mouse HCC model accelerated HCC progression. Mechanistically, SFN acted as an adaptor protein, activating AKT1 signaling by fostering the interaction between PDK1 and AKT1, with the R56 and R129 sites on SFN proving to be crucial for this binding. In the syngeneic implantation model, the R56A/R129A mutant of SFN inhibited Akt signaling activation and impeded HCC growth. Additionally, peptide inhibitors designed based on the binding motif of AKT1 to SFN significantly inhibited HCC progression. In summary, our findings establish that SFN promotes HCC progression by activating AKT signaling through the R56 and R129 binding sites. This discovery opens new avenues for a promising therapeutic strategy for the treatment of HCC.

Abstract Blockchain has penetrated in various fields, such as finance, healthcare, supply chain, and intelligent transportation, but the value exchange between different blockchains limits their expansion. Cross-chain technology, such as notary mechanism, enables asset exchanges between different blockchain networks. However, existing research still confronts problems such as single inherent value evaluation, collusion risk, credit evaluation and unreasonable resource allocation, making it difficult to ensure the security of cross-chain asset transactions. So this paper proposes a cross-chain asset trading scheme based on edge cloud storage to improve the reliability of notaries and the security of cross-chain value exchange. Firstly, introduce the entropy weight method to determine indicators and adopt multi indicator evaluation to reduce the risk of collusion between notaries and users; Secondly, design a multi-indicator credit evaluation method to improve the accuracy of the evaluation; Finally, design a new and old notary node share allocation method to improve the rationality of resource allocation.The experiment shows that the scheme designed in this paper can reduce the risk of collusion, more accurately screen out high credit nodes to act as notaries, and make resource allocation more reasonable.

Oxidative stress, infection, and vasculopathy caused by hyperglycemia are the main barriers for the rapid repair of foot ulcers in patients with diabetes mellitus (DM). In recent times, the discovery of neddylation, a new type of post-translational modification, has been found to regulate various crucial biological processes including cell metabolism and the cell cycle. Nevertheless, its capacity to control the healing of wounds in diabetic patients remains unknown. This study shows that MLN49224, a compound that inhibits neddylation at low concentrations, enhances the healing of diabetic wounds by inhibiting the polarization of M1 macrophages and reducing the secretion of inflammatory factors. Moreover, it concurrently stimulates the growth, movement, and formation of blood vessel endothelial cells, leading to expedited healing of wounds in individuals with diabetes. The drug is loaded into biomimetic macrophage-membrane-coated PLGA nanoparticles (M-NPs/MLN4924). The membrane of macrophages shields nanoparticles from being eliminated in the reticuloendothelial system and counteracts the proinflammatory cytokines to alleviate inflammation in the surrounding area. The extended discharge of MLN4924 from M-NPs/MLN4924 stimulates the growth of endothelial cells and the formation of tubes, along with the polarization of macrophages towards the anti-inflammatory M2 phenotype. By loading M-NPs/MLN4924 into a hydrogel, the final formulation is able to meaningfully repair a diabetic wound, suggesting that M-NPs/MLN4924 is a promising engineered nanoplatform for tissue engineering.

It is imperative to develop and implement newer, more effective strategies to address refractory diabetic wounds. As of now, there is currently no optimal solution for these wounds. Hypoxic human umbilical vein endothelial cells (HUVECs)-derived exosomes have been postulated to promote diabetic wound healing, however, its effect and molecular mechanism need further study. In this study, we aimed to investigate whether hypoxic exosomes enhance wound healing in diabetics. Based on our high-throughput sequencing, differentially expressed lncRNAs (including 64 upregulated lncRNAs and 94 downregulated lncRNAs) were found in hypoxic exosomes compared to normoxic exosomes. Interestingly, lncHAR1B was one of the prominently upregulated lncRNAs in hypoxic exosomes, showing a notable correlation with diabetic wound healing. More specifically, hypoxic exosomes were transmitted to surrounding cells, which resulted in a significant increase in lncHAR1B level, thereby relieving the dysfunction of endothelial cells and promoting the switch from M1 to M2 macrophages under high glucose conditions. Mechanistically, lncHAR1B directly interacted with the transcription factor basic helix-loop-helix family member e23 (BHLHE23), which subsequently led to its binding to the KLF transcription factor 4 (KLF4) and promoted KLF4 expression. In our in vivo experiments, the use of hypoxic exosomes-loaded HGM-QCS hydrogels (Gel-H-Exos) resulted in rapid wound healing compared to that of normoxic exosomes-loaded HGM-QCS hydrogels (Gel-N-Exos) and diabetic groups. Consequently, our study provides potentially novel therapeutic approaches aimed at accelerating wound healing and developing a practical exosomes delivery platform.

Afterburning behind the detonation front of an aluminized explosive releases energy on the millisecond timescale, which prolong the release of detonation energy and the energy release at different stages also shows significant differences. However, at present, there are few effective methods for evaluating the energy release characteristics of the middle reaction stage of such explosives, which can have a duration of tens to hundreds of microseconds. The present work demonstrates an approach to assessing the mid-stage of an aluminized explosive detonation based on a water push test employing a high degree of confinement. In this method, the explosive is contained in a steel cylinder having one end closed that is installed at the bottom of a transparent water tank. Upon detonation, the gaseous products expand in one direction while forcing water ahead of them. The resulting underwater shock wave and the interface between the gas phase products and the water are tracked using an ultra-high-speed framing and streak camera. The shock wave velocity in water and the expansion work performed by the gaseous detonation products were calculated to assess the energy release characteristics of aluminized explosives such as CL-20 and RDX in the middle stage of the detonation reaction. During the middle stage of the detonation process of these aluminized explosives, the aluminum reaction reduced the attenuation of shock waves and increased the work performed by gas phase products. A higher aluminum content increased the energy output while the presence of oxidants slowed the energy release rate. This work demonstrates an effective means of evaluating the performance of aluminized explosives.

Abstract Emergent phenomena such as two-dimensional electron gas (2DEG) and interfacial superconductivity and ferromagnetism are generally built on the interface between insulating oxide thin films and substrates, e.g., LaAlO3/SrTiO3, where the 2D profiles of these electronic states are precisely confined at the interface of two insulators. Herein we report a high-mobility electron gas state with unusual symmetry at the interface of the Sr2CrMoO6/SrTiO3 (110) heterostructures, the fermiology of which follows the cubic crystallographic symmetry rather than the two-dimensional interface itself, resulting in the identical Shubnikov-de Haas oscillations with applied magnetic field along all the twelve equivalent [110] crystallographic directions of SrTiO3, distinctly different from the 2D nature of the electron gas reported previously. Neutron diffraction verifies the predicted ferrimagnetic ordering between Cr and Mo moments. This, together with the magnetic hysteresis loops and negative magnetoresistance in low-field region, suggests possible spin polarization of itinerant electrons. Therefore, a quasi-3D profile, high mobility (up to 104 cm2 V−1 s−1) and possibly spin polarized electronic state is observed in the double-perovskite-based oxide heterostructures. This finding of the electronic properties in Sr2CrMoO6/SrTiO3 (110) heterostructure expands the knowledge of interfacial physics, as well as shines light on oxide-based electronics and spintronics research.

Abstract Background Chronic inflammation, reflected by an increased blood C-reactive protein (CRP) level, is common in patients with chronic kidney disease (CKD) and is involved in the development of renal anemia. This systematic review aims to investigate the impacts of CRP on the efficacy of hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) in the treatment of renal anemia in patients with CKD. Methods We conducted a comprehensive search of electronic databases including Pubmed, Web of Science, Embase, Cochrane Library, CNKI, Wanfang, and the International Clinical Trials Registry Platform (ICTRP), from their inception to May 19, 2022. We systematically reviewed evidence from randomized controlled trials using HIF-PHIs for renal anemia treatment. The mean difference (MD) in changes in hemoglobin concentration (∆Hb) before and after treatment served as the meta-analysis outcome, utilizing a random-effects model. We compared groups with CRP levels greater than or equal to the upper limit of normal (ULN) and less than the ULN. Additionally, further analysis was conducted in the CRP ≥ ULN group comparing HIF-PHIs and erythropoiesis-stimulating agents (ESA). Results A total of 7 studies from 6 publications were included in the analysis. In the comparison between the CRP ≥ ULN group and the CRP

Objective To compare the efficacy and safety of high-intensity focused ultrasound (HIFU) and radical surgery for non-metastatic pancreatic cancer (PC).Materials and methods We retrospectively analyzed 89 stage I/II/III PC patients who underwent HIFU (n = 43) or surgery (n = 46) at the Third Xiangya Hospital from January 2020 to December 2021. Pain relief, Karnofsky Performance Scale (KPS), overall survival (OS), treatment-related complications and risk factors for OS were assessed.Results There was no significant difference in the pain relief rate at 30 days post-treatment between the two groups. However, compared with the surgery group, the HIFU group showed significantly lower post-treatment VAS scores (p = 0.019). In the surgery group, the KPS at 30 days post-treatment was lower than pretreatment KPS (70 vs 80; p = 0.015). This relationship was reversed in the HIFU group (80 vs 70; p = 0.024). Median OS favored surgery over HIFU (23 vs 10 months; p

Abstract T‐bet, encoded by TBX21, is extensively expressed across various immune cell types, and orchestrates critical functions in their development, survival, and physiological activities. However, the role of T‐bet in non‐immune compartments, notably the epithelial cells, remains obscure. Herein, a Tet‐O‐T‐bet transgenic mouse strain is generated for doxycycline‐inducible T‐bet expression in adult animals. Unexpectedly, ubiquitous T‐bet overexpression causes acute diarrhea, intestinal damage, and rapid mortality. Cell‐type‐specific analyses reveal that T‐bet‐driven pathology is not attributable to its overexpression in CD4+ T cells or myeloid lineages. Instead, inducible T‐bet overexpression in the intestinal epithelial cells is the critical determinant of the observed lethal phenotype. Mechanistically, T‐bet overexpression modulates ion channel and transporter profiles in gut epithelial cells, triggering profound fluid secretion and subsequent lethal dehydration. Furthermore, ectopic T‐bet expression enhances gut epithelial cell apoptosis and markedly suppresses colon cancer development in xenograft models. Collectively, the findings unveil a previously unrecognized role of T‐bet in intestinal epithelial cells for inducing apoptosis, diarrhea, and local inflammation, thus implicating its potential as a therapeutic target for the treatment of cancer and inflammatory diseases.

IntroductionAlthough memory challenges in autistic individuals have been characterized recently, the functional connectivity of the hippocampus and ventral temporal lobe, two structures important for episodic and semantic memory functions, are poorly understood in autistic individuals. Moreover, age-related differences in the functional connectivity associated with these two memory networks are unrevealed.MethodsThe current study investigated age-related differences in intrinsic connectivity of the hippocampal and ventral temporal lobe (vTL) memory networks in well-matched ASD (n = 73; age range: 10.23–55.40 years old) and Non-ASD groups (n = 74; age range: 10.46–56.20 years old) from the open dataset ABIDE-I. Both theory-driven ROI-to-ROI approach and exploratory seed-based whole-brain approach were used.Results and discussionOur findings revealed reduced connectivity in ASD compared to Non-ASD peers, as well as an age-related reduction in the connectivity of hippocampal and vTL networks with triple networks, namely, the default mode network (DMN), the central executive network (CEN), and the salience network (SN), potentially underpinning their challenges in memory, language, and social functions. However, we did not observe reliable differences in age-related effects between the ASD and Non-ASD groups. Our study underscores the importance of understanding memory network dysfunctions in ASD across the lifespan to inform educational and clinical practices.

Abstract The clinical role and underlying mechanisms of valproic acid (VPA) on bone homeostasis remain controversial. Herein, we confirmed that VPA treatment was associated with decreased bone mass and bone mineral density (BMD) in both patients and mice. This effect was attributed to VPA-induced elevation in osteoclast formation and activity. Through RNA-sequencing, we observed a significant rise in precursor miR-6359 expression in VPA-treated osteoclast precursors in vitro, and further, a marked upregulation of mature miR-6359 (miR-6359) in vivo was demonstrated using quantitative real-time PCR (qRT-PCR) and miR-6359 fluorescent in situ hybridization (miR-6359-FISH). Specifically, the miR-6359 was predominantly increased in osteoclast precursors and macrophages but not in neutrophils, T lymphocytes, monocytes and bone marrow-derived mesenchymal stem cells (BMSCs) following VPA stimulation, which influenced osteoclast differentiation and bone-resorptive activity. Additionally, VPA-induced miR-6359 enrichment in osteoclast precursors enhanced reactive oxygen species (ROS) production by silencing the SIRT3 protein expression, followed by activation of the MAPK signaling pathway, which enhanced osteoclast formation and activity, thereby accelerating bone loss. Currently, there are no medications that can effectively treat VPA-induced bone loss. Therefore, we constructed engineered small extracellular vesicles (E-sEVs) targeting osteoclast precursors in bone and naturally carrying anti-miR-6359 by introducing of EXOmotif (CGGGAGC) in the 3’-end of the anti-miR-6359 sequence. We confirmed that the E-sEVs exhibited decent bone/osteoclast precursor targeting and exerted protective therapeutic effects on VPA-induced bone loss, but not on ovariectomy (OVX) and glucocorticoid-induced osteoporotic models, deepening our understanding of the underlying mechanism and treatment strategies for VPA-induced bone loss.

The diabetic wounds remain to be unsettled clinically, with chronic wounds characterized by drug-resistant bacterial infections, compromised angiogenesis and oxidative damage to the microenvironment. To ameliorate oxidative stress and applying antioxidant treatment in the wound site, we explore the function of folliculin-interacting protein 1 (FNIP1), a mitochondrial gatekeeper protein works to alter mitochondrial morphology, reduce oxidative phosphorylation and protect cells from unwarranted ROS accumulation. And our in vitro experiments showed the effects of FNIP1 in ameliorating oxidative stress and rescued impaired angiogenesis of HUVECs in high glucose environment. To realize the drug delivery and local regulation of FNIP1 in diabetic wound sites, a novel designed glucose-responsive HA-PBA-FA/EN106 hydrogel is introduced for improving diabetic wound healing. Due to the dynamic phenylboronate ester structure with a phenylboronic acid group between hyaluronic acid (HA) and phenylboronic acid (PBA), the hydrogel is able to realize a glucose-responsive release of drugs. Fulvic acid (FA) is added in the hydrogel, which not only severs as crosslinking agent but also provides antibacterial and anti-inflammatory abilities. Moreover, the release of FEM1b-FNIP1 axis inhibitor EN106 ameliorated oxidative stress and stimulated angiogenesis through FEM1b-FNIP1 axis regulation. These in vivo and in vitro results demonstrated that accelerated diabetic wounds repair with the use of the HA-PBA-FA/EN106 hydrogel, which may provide a promising strategy for chronic diabetic wound repair.

Optoelectronic integrated circuit (OEIC) technology has attracted considerable research attention. Studies have achieved numerous breakthroughs in the basic scientific problems, key technologies, demonstration applications, and industrial promotions of OEIC. This study details the technical process, development status, existing problems, and future research trends of the design, manufacturing, and packaging of OEIC to provide a systematic summary of OEIC technology.

Hepatic sparganosis (HS) is extremely rare and has not been previously reported in Eastern China. We report the diagnosis and treatment of a patient with HS from Xuzhou City, Jiangsu Province, China. The patient was admitted due to an acute biliary tract infection, and the symptoms improved after treatment at the Gastroenterology Department. During an ultrasound examination on admission, an abnormal echo was incidentally discovered at the junction of the left and right lobes of the liver. Thereafter, upper abdominal computed tomography (CT) and magnetic resonance imaging (MRI) non-contrast and contrast-enhanced examinations, and serum tumor biomarker examination were completed. After a multidisciplinary treatment (MDT) discussion at the Department of Hepatobiliary Surgery, the patient was diagnosed with intrahepatic mass-type cholangiocarcinoma (IMCC) and surgery was recommended. The patient underwent surgical treatment, and postoperative pathology revealed HS. No signs of intrahepatic recurrence were observed during the 1-year follow-up period.

Tilapia skin peptides (TSP) possess a range of physiological activities. This study aimed to explore the effects of TSP on Dexamethasone (DEX)-induced muscle atrophy. In vitro, C2C12 myotube myotube diameter and expression levels of the muscle-specific E3 ubiquitin ligases F-box only protein 32 (Atrogin-1) and muscle ring finger protein 1 (MuRF1) challenged with DEX were reversed by TSP. In vivo, DEX was injected subcutaneously to build muscle atrophy model mice. TSP enhanced grip strength, running distance, body lean muscle content, cross-sectional area of the gastrocnemius and tibialis anterior muscles of DEX-induced mice. Moreover, TSP inhibited the expression levels of Atrogin-1 and MuRF1. Mechanically, TSP improved DEX-induced muscle atrophy by regulating the Protein Kinase B α (AKT)/Forkhead box O3 protein (FOXO3a), Sirtuin 1 (Sirt1)/peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) signaling pathway, and downstream factors such as nuclear respiratory factor (NRF)1/2 and mitochondrial transcription factor A (TFAM).

BackgroundAdolescent depression is a significant public health concern; however, access to effective mental health care is limited. Digital therapeutics (DTx) can improve access to evidence-based interventions; however, their efficacy in adolescents is sparsely documented. ObjectiveThis study aims to examine the efficacy of a mobile app DTx versus an active control as an adjunct treatment for adolescent depression symptoms. MethodsAn internet-based open-label randomized control trial was conducted nationwide with a partial crossover design, and 168 adolescents aged 13 to 21 years with symptoms of depression were recruited between November 2020 and September 2021. Participants were randomized (1:1) to the cognitive behavioral therapy–based treatment app (Spark) or to a psychoeducational control app (control), which they would use for a duration of 5 weeks. The primary outcome was a between-group (Spark vs control) difference in the change in depression symptoms from baseline to postintervention, as measured by the Patient Health Questionnaire-8 (PHQ-8) using a linear mixed-effects analysis. The PHQ-8 ranges from 0 to 24, with scores of 5 to 9 indicating mild depression symptoms, scores of 10 to 14 indicating moderate symptoms, scores of 15 to 19 indicating moderately severe symptoms, and scores of 20 to 24 indicating severe symptoms. A minimal clinically important difference (5-point reduction between baseline and postintervention) in the Spark arm and group differences in remission and treatment response rates based on the PHQ-8 at postintervention were also investigated. ResultsA total of 160 participants were randomized, 80 in the Spark arm (mean age 16.89, SD 2.5 y) and 80 in the control arm (mean age 16.79, SD 2.59 y). Data from 121 participants (Spark: n=63; control: n=58) with moderate to severe (PHQ-8≥10) symptoms at baseline were included in the primary analyses following a modified intention-to-treat principle. A linear mixed-effect analysis revealed a nonsignificant difference between the study arms in depression symptom change over the intervention period. The Spark arm met a minimal clinically important difference threshold (mean −5.08, 95% CI −6.72 to −3.42). The remission rate in the Spark arm was significantly higher than that in the control arm (11/63, 17% vs 2/58, 3%; χ21=6.2; P=.01; false discovery rate–adjusted P=.03). The treatment response rates were not significantly different between the study arms (P=.07; false discovery rate–adjusted P=.16). Post hoc analyses including participants with mild to severe (PHQ-8 score ≥5) symptoms at baseline revealed promising evidence that Spark is effective in those with mild to severe symptoms. ConclusionsThere is initial evidence that a self-guided, cognitive behavioral therapy–based DTx intervention may effectively treat mild to severe depression symptoms in adolescents. DTx may improve access to mental health care for adolescents or serve as an important adjunct to the standard of care. Trial RegistrationClinicalTrials.gov NCT04524598; https://clinicaltrials.gov/study/NCT04524598

The two-electron oxygen reduction reaction (2e− ORR) has emerged as an attractive alternative for H2O2 production. Developing efficient earth-abundant transition metal electrocatalysts and reaction mechanism exploration for H2O2 production are important but remain challenging. Herein, a nitrogen-doped carbon-coated NiSe2 (NiSe2@NC) electrocatalyst was prepared by successive annealing treatment. Benefiting from the synergistic effect between the NiSe2 nanoparticles and NC, the 2e− ORR activity, selectivity, and stability of NiSe2@NC in 0.1 M HClO4 was greatly enhanced, with the yield of H2O2 being 4.4 times that of the bare NiSe2 nanoparticles. The in situ Raman spectra and density functional theory (DFT) calculation revealed that the presence of NC was beneficial for regulating the electronic state of NiSe2 and optimizing the adsorption free energy of *OOH, which could enhance the adsorption of O2, stabilize the O-O bond, and boost the production of H2O2. This work provides an effective strategy to improve the performance of the transition metal chalcogenide for 2e− ORR to H2O2.

Abstract CuInP2S6 with robust room-temperature ferroelectricity has recently attracted much attention due to the spatial instability of its Cu cations and the van der Waals (vdW) layered structure. Herein, we report a significant enhancement of its remanent polarization by more than 50% from 4.06 to 6.36 µC cm−2 under a small pressure between 0.26 to 1.40 GPa. Comprehensive analysis suggests that even though the hydrostatic pressure suppresses the crystal distortion, it initially forces Cu cations to largely occupy the interlayer sites, causing the spontaneous polarization to increase. Under intermediate pressure, the condensation of Cu cations to the ground state and the polarization increase due cell volume reduction compensate each other, resulting in a constant polarization. Under high pressure, the migration of Cu cations to the center of the S octahedron dominates the polarization decrease. These findings improve our understanding of this fascinating vdW ferroelectric material, and suggest new ways to improve its properties.

Fracture nonunion remains a great challenge for orthopedic surgeons. Fracture repair comprises of three phases, the inflammatory, repair and remodeling stage. Extensive advancements have been made in the field of bone repair, including development of strategies to balance the M1/M2 macrophage populations, and to improve osteogenesis and angiogenesis. However, such developments focused on only one or the latter two phases, while ignoring the inflammatory phase during which cell recruitment occurs. In this study, we combined Stromal Cell-Derived Factor-1α (SDF-1α) and M2 macrophage derived exosomes (M2D-Exos) with a hyaluronic acid (HA)-based hydrogel precursor solution to synthesize an injectable, self-healing, adhesive HA@SDF-1α/M2D-Exos hydrogel. The HA hydrogel demonstrated good biocompatibility and hemostatic ability, with the 4% HA hydrogels displaying great antibacterial activity against gram-negative E. coli and gram-positive S. aureus and Methicillin-resistant Staphylococcus aureus (MRSA). Synchronously and sustainably released SDF-1α and M2D-Exos from the HA@SDF-1α/M2D-Exos hydrogel enhanced proliferation and migration of human bone marrow mesenchymal stem cell (HMSCs) and Human Umbilical Vein Endothelial Cells (HUVECs), promoting osteogenesis and angiogenesis both in vivo and in vitro. Overall, the developed HA@ SDF-1α/M2D-Exos hydrogel was compatible with the natural healing process of fractures and provides a new modality for accelerating bone repair by coupling osteogenesis, angiogenesis, and resisting infection at all stages.

Abstract Introduction Clinical trial findings may not be generalizable to routine practice. This study evaluated sarilumab effectiveness in patients with rheumatoid arthritis (RA) and tested the real-world applicability of a response prediction rule, derived from trial data using machine learning (based on C-reactive protein [CRP] > 12.3 mg/l and seropositivity [anticyclic citrullinated peptide antibodies, ACPA +]). Methods Sarilumab initiators from the ACR-RISE Registry, with ≥ 1 prescription on/after its FDA approval (2017–2020), were divided into three cohorts based on progressively restrictive criteria: Cohort A (had active disease), Cohort B (met eligibility criteria of a phase 3 trial in RA patients with inadequate response/intolerance to tumor necrosis factor inhibitors [TNFi]), and Cohort C (characteristics matched to the phase 3 trial baseline). Mean changes in Clinical Disease Activity Index (CDAI) and Routine Assessment of Patient Index Data 3 (RAPID3) were evaluated at 6 and 12 months. In a separate cohort, predictive rule was tested based on CRP levels and seropositive status (ACPA and/or rheumatoid factor); patients were categorized into rule-positive (seropositive with CRP > 12.3 mg/l) and rule-negative groups to compare the odds of achieving CDAI low disease activity (LDA)/remission and minimal clinically important difference (MCID) over 24 weeks. Results Among sarilumab initiators (N = 2949), treatment effectiveness was noted across cohorts, with greater improvement noted for Cohort C at 6 and 12 months. Among the predictive rule cohort (N = 205), rule-positive (vs. rule-negative) patients were more likely to reach LDA (odds ratio: 1.5 [0.7, 3.2]) and MCID (1.1 [0.5, 2.4]). Sensitivity analyses (CRP > 5 mg/l) showed better response to sarilumab in rule-positive patients. Conclusions In real-world setting, sarilumab demonstrated treatment effectiveness, with greater improvements in the most selective population, mirroring phase 3 TNFi-refractory and rule-positive RA patients. Seropositivity appeared a stronger driver for treatment response than CRP, although optimization of the rule in routine practice requires further data.

Objective: The purpose of this study was to establish a method for the isolation and purification of ellagic acid from Rosa roxburghii Tratt and to investigate the optimal acidification process condition for extraction of ellagic acid from Rosa roxburghii Tratt. Methods: Rosa roxburghii Tratt dried fruit was used as material, ellagic acid was obtained by acid hydrolyzed, and it was purified by methanol recrystallization. Its purity was determined by high performance liquid chromatography (HPLC), the structure of ellagic acid sample was confirmed by Nuclear magnetic resonance spectroscopy (NMR), infrared spectroscopy (IR), mass spectrometry (MS), high performance liquid chromatography (HPLC), ultraviolet spectroscopy (UV). In addition, with ellagic acid extraction yield as an indicator, acid concentration, extraction temperature, extraction time and liquid ratio as independent variables, based on the single-factor tests, a Box-Benhnken central composite and response surface methodology was designed to explore the optimum extraction conditions. Results: The ellagic acid extract was obtained from Rosa roxburghii Tratt, and its purification was 92% analyzed by HPLC, the maximum absorption wavelength of ellagic acid extract was 254 nm, the molecular ion peak m/z was 301.00, and the infrared absorption wavenumber was consistent with the standard, and its structure was determined by 1H-NMR and 13C-NMR, and the optimal extraction parameters of ellagic acid was obtained by response surface method: Acid concentration 5%, extraction temperature 127 ℃, liquid ratio 8:1 mL/g, extraction time 9.8 h. Under this condition, the highest yield of ellagic acid could reach 30.2%±2.3% (compared to predicted value P>0.05). Conclusion: In this study, a simple and efficient purification method of ellagic acid from Rosa roxburghii Tratt was established and its structure was confirmed, and the optimal process for the preparation of ellagic acid by acid hydrolysis was obtained, which would provide a reference for the development and utilization of Rosa roxburghii Tratt resources.

Objective Our objective was to evaluate the factors associated with regional variation of rheumatoid arthritis (RA) disease burden in the US. Methods In a retrospective cohort analysis of Rheumatology Informatics System for Effectiveness (RISE) registry data, seropositivity, RA disease activity (Clinical Disease Activity Index [CDAI], Routine Assessment of Patient Index Data–version 3 [RAPID3]), socioeconomic status (SES), geographic region, health insurance type, and comorbidity burden were recorded. An Area Deprivation Index score of more than 80 defined low SES. Median travel distance to practice sites’ zip codes was calculated. Linear regression was used to analyze associations between RA disease activity and comorbidity adjusting for age, sex, geographic region, race, and insurance type. Results Enrollment data for 184,722 patients with RA from 182 RISE sites were analyzed. Disease activity was higher in African American patients, in those from Southern regions, and in those with Medicaid or Medicare coverage. Greater comorbidity was prevalent in patients in the South and those with Medicare or Medicaid coverage. There was moderate correlation between comorbidity and disease activity (Pearson coefficient: RAPID3 0.28, CDAI 0.15). High‐deprivation areas were mainly in the South. Less than 10% of all participating practices cared for more than 50% of all Medicaid recipients. Patients living more than 200 miles away from specialist care were located mainly in Southern and Western regions. Conclusion A disproportionately large portion of socially deprived, high comorbidity, and Medicaid‐covered patients with RA were cared for by a minority of rheumatology practices. Studies are needed in high‐deprivation areas to establish more equitable distribution of specialty care for patients with RA.

Bone fracture: faster healing after traumatic brain injury Extracellular vesicles enriched with a particular microRNA released following traumatic brain injury (TBI) help fractures heal faster and could inform treatments for skeletal disorders. Patients with TBI and associated fractures experience shorter fracture recovery times than patients with fractures only, but precisely why is unclear. Ze Lin at Huazhong University of Science and Technology, Wuhan, China, and co-workers examined molecules released during recovery in samples taken from patients with TBI and fractures, those with fractures only, and mouse models with femur fractures. They found that exosomes (extracellular vesicles that transport metabolites including microRNA) released following TBI are enriched with miRNA-21-5 p, which enhances differentiation of bone-forming cells and bone repair. No miRNA-21-5 p enrichment occurred in patients with fractures only. Knocking out exosomal miRNA-21-5 p impaired bone repair in mice, while injecting exosomes from TBI patients boosted bone formation.

To investigate the impact of Al and Nb elements on the formation of a protective oxide layer on the surface of Fe-35Ni-20Cr-xAl-yNb (x = 0, 2, 4, 6 wt.%; y = 0, 1, 2 wt.%) alloys, their oxidation behavior was examined at 1000 °C, 10−17 atm. and 10−25 atm. oxygen pressure, and the oxidation mechanism was analyzed by Factsage and Pandat calculations. Enhancing the Al content at 10−17 atm. inhibited the generation of FeCr2O4 on the alloy surface and increased the Al content in the M2O3 layer. When the Al content exceeded 6 wt.%, the oxide film partially peeled off. It was found that the addition of Nb increased the activity of Cr and Al and decreased the activity of Ni and Fe and promoted the formation of Al2O3, and the appearance of Nb2O5 in the subsurface layer increased the density of the oxide film. In addition, under an oxygen pressure of 10−25 atm., the only protective layer on the surface of the alloy comprised of Al2O3. The experimental results demonstrated that the Fe-35Ni-20Cr-4Al-2Nb alloy generated a continuous and dense Al2O3 protective film, and the reduction in oxygen pressure and the addition of Nb elements were favorable for selective external oxidation of Al2O3.

Abstract The origin of insulating ferromagnetism in epitaxial LaCoO3 films under tensile strain remains elusive despite extensive research efforts are devoted. Surprisingly, the spin state of its Co ions, the main parameter of its ferromagnetism, is still to be determined. Here, the spin state in epitaxial LaCoO3 thin films is systematically investigated to clarify the mechanism of strain‐induced ferromagnetism using element‐specific X‐ray absorption spectroscopy and dichroism. Combining with the configuration interaction cluster calculations, it is unambiguously demonstrated that Co3+ in LaCoO3 films under compressive strain (on LaAlO3 substrate) is practically a low‐spin state, whereas Co3+ in LaCoO3 films under tensile strain (on SrTiO3 substrate) have mixed high‐spin and low‐spin states with a ratio close to 1:3. From the identification of this spin state ratio, it is inferred that the dark strips observed by high‐resolution scanning transmission electron microscopy indicate the position of Co3+ high‐spin state, i.e., an observation of a spin state disproportionation in tensile‐strained LaCoO3 films. This consequently explains the nature of ferromagnetism in LaCoO3 films. The study highlights the importance of spin state degrees of freedom, along with thin‐film strain engineering, in creating new physical properties that do not exist in bulk materials.

Children with autism spectrum disorders (ASDs) often display atypical learning styles; however, little is known regarding learning-related brain plasticity and its relation to clinical phenotypic features. Here, we investigate cognitive learning and neural plasticity using functional brain imaging and a novel numerical problem-solving training protocol. Children with ASD showed comparable learning relative to typically developing children but were less likely to shift from rule-based to memory-based strategy. While learning gains in typically developing children were associated with greater plasticity of neural representations in the medial temporal lobe and intraparietal sulcus, learning in children with ASD was associated with more stable neural representations. Crucially, the relation between learning and plasticity of neural representations was moderated by insistence on sameness, a core phenotypic feature of ASD. Our study uncovers atypical cognitive and neural mechanisms underlying learning in children with ASD, and informs pedagogical strategies for nurturing cognitive abilities in childhood autism.

Chronic hepatitis B virus (HBV) infection is a leading cause of hepatocellular carcinoma. However, the function and mechanism of the effect of HBV on host protein ubiquitination remain largely unknown. We aimed at characterizing whether and how HBV promotes self-replication by affecting host protein ubiquitination. In this study, we identified UBXN7, a novel inhibitor for nuclear factor kappa B (NF-κB) signaling, was degraded via interaction with HBV X protein (HBx) to activate NF-κB signaling and autophagy, thereby affecting HBV replication. The expression of UBXN7 was analyzed by Western blot and quantitative reverse transcription polymerase chain reaction in HBV-transfected hepatoma cells and HBV-infected primary human hepatocytes (PHHs). The effects of UBXN7 on HBV replication were analyzed by using in vitro and in vivo assays, including stable isotope labeling by amino acids in cell culture (SILAC) analysis. Changes in HBV replication and the associated molecular mechanisms were analyzed in hepatoma cell lines. SILAC analyses showed that the ubiquitination of UBXN7 was significantly increased in HepG2.2.15 cells compared with control cells. After HBV infection, HBx protein interacted with UBXN7 to promote K48-linked ubiquitination of UBXN7 at K99, leading to UBXN7 degradation. On the other hand, UBXN7 interacted with the ULK domain of IκB kinase β through its ubiquitin-associating domain to facilitate its degradation. This in turn reduced NF-κB signaling, leading to reduced autophagy and consequently decreased HBV replication.

Major traumatic tissue defects are common clinical problems often complicated by infection and local vascular dysfunction, processes which hinder the healing process. Although local application of growth factors or stem cells through various tissue engineering techniques are promising methods for the repair of tissue defects, limitations in their clinical application exist. Herein, we synthesized multifaceted nanohybrids composed of Quaternized chitosan (QCS), Graphene oxide (GO), and Polydopamine (PDA; QCS-GO-PDA). Covalent grafting of QCS and GO at a mass ratio of 5:1 (5QCS-1GO) displayed excellent biocompatibility and enhanced osteogenic ability, while addition of PDA (5QCS-1GO-PDA) reduced the level of reactive oxygen species (ROS). 5QCS-1GO-PDA was able to achieve wound tissue regeneration by reducing the inflammatory response and enhancing angiogenesis. Furthermore, Polylactic acid/hydroxyapatite (PLA/HA) composite scaffolds were printed using Selective Laser Sintering (SLS) and the hybrid nanomaterial (5QCS-1GO-PDA) was used to coat the PLA/HA scaffold (5QCS-1GO-PDA@PLA/HA) to be used for rapid bone regeneration. 5QCS-1GO-PDA not only improved angiogenesis and osteogenic differentiation, but also induced M2-type polarization of macrophages and promoted bone regeneration via the BMP2/BMPRs/Smads/Runx2 signaling pathway. The bidirectional enhanced healing ability of the multifaceted nanohybrids 5QCS-1GO-PDA provides a promising method of effectively treating tissue defects.

Abstract Bone, cartilage, and soft tissue regeneration is a complex spatiotemporal process recruiting a variety of cell types, whose activity and interplay must be precisely mediated for effective healing post-injury. Although extensive strides have been made in the understanding of the immune microenvironment processes governing bone, cartilage, and soft tissue regeneration, effective clinical translation of these mechanisms remains a challenge. Regulation of the immune microenvironment is increasingly becoming a favorable target for bone, cartilage, and soft tissue regeneration; therefore, an in-depth understanding of the communication between immune cells and functional tissue cells would be valuable. Herein, we review the regulatory role of the immune microenvironment in the promotion and maintenance of stem cell states in the context of bone, cartilage, and soft tissue repair and regeneration. We discuss the roles of various immune cell subsets in bone, cartilage, and soft tissue repair and regeneration processes and introduce novel strategies, for example, biomaterial-targeting of immune cell activity, aimed at regulating healing. Understanding the mechanisms of the crosstalk between the immune microenvironment and regeneration pathways may shed light on new therapeutic opportunities for enhancing bone, cartilage, and soft tissue regeneration through regulation of the immune microenvironment.

Abstract Growth mindset, the belief that one’s abilities can improve through cognitive effort, is an important psychological construct with broad implications for enabling children to reach their highest potential. However, surprisingly little is known about malleability of growth mindset in response to cognitive interventions in children and its neurobiological underpinnings. Here we address critical gaps in our knowledge by investigating behavioral and brain changes in growth mindset associated with a four-week training program designed to enhance foundational, academically relevant, cognitive skills in 7–10-year-old children. Cognitive training significantly enhanced children’s growth mindset. Cross-lagged panel analysis of longitudinal pre- and post-training data revealed that growth mindset prior to training predicted cognitive abilities after training, providing support for the positive role of growth mindset in fostering academic achievement. We then examined training-induced changes in brain response and connectivity associated with problem solving in relation to changes in growth mindset. Children’s gains in growth mindset were associated with increased neural response and functional connectivity of the dorsal anterior cingulate cortex, striatum, and hippocampus, brain regions crucial for cognitive control, motivation, and memory. Plasticity of cortico-striatal circuitry emerged as the strongest predictor of growth mindset gains. Taken together, our study demonstrates that children’s growth mindset can be enhanced by cognitive training, and elucidates the potential neurobiological mechanisms underlying its malleability. Findings provide important insights into effective interventions that simultaneously promote growth mindset and learning during the early stages of cognitive development.

Abstract Background Postmenopausal bone loss, mainly caused by excessive bone resorption mediated by osteoclasts, has become a global public health burden. Metformin, a hypoglycemic drug, has been reported to have beneficial effects on maintaining bone health. However, the role and underlying mechanism of metformin in ovariectomized (OVX)-induced bone loss is still vague. Results In this study, we demonstrated for the first time that metformin administration alleviated bone loss in postmenopausal women and ovariectomized mice, based on reduced bone resorption markers, increased bone mineral density (BMD) and improvement of bone microstructure. Then, osteoclast precursors administered metformin in vitro and in vivo were collected to examine the differentiation potential and autophagical level. The mechanism was investigated by infection with lentivirus-mediated BNIP3 or E2F1 overexpression. We observed a dramatical inhibition of autophagosome synthesis and osteoclast formation and activity. Treatment with RAPA, an autophagy activator, abrogated the metformin-mediated autophagy downregulation and inhibition of osteoclastogenesis. Additionally, overexpression of E2F1 demonstrated that reduction of OVX-upregulated autophagy mediated by metformin was E2F1 dependent. Mechanistically, metformin-mediated downregulation of E2F1 in ovariectomized mice could downregulate BECN1 and BNIP3 levels, which subsequently perturbed the binding of BECN1 to BCL2. Furthermore, the disconnect between BECN1 and BCL2 was shown by BNIP3 overexpression. Conclusion In summary, we demonstrated the effect and underlying mechanism of metformin on OVX-induced bone loss, which could be, at least in part, ascribed to its role in downregulating autophagy during osteoclastogenesis via E2F1-dependent BECN1 and BCL2 downregulation, suggesting that metformin or E2F1 inhibitor is a potential agent against postmenopausal bone loss. Video abstract

Background: Primary central nervous system lymphoma (PCNSL) is a rare extranodal non-Hodgkin’s lymphoma that occurs in the central nervous system. Although sensitive to chemotherapy, 35–60% of PCNSL patients still relapse within 2 years after the initial treatment. High-dose methotrexate (HD-MTX) rechallenge is generally used in recurrent PCNSL, especially for patients who have achieved a response after initial methotrexate (MTX) treatment. However, the overall remission rate (ORR) of HD-MTX rechallenge is about 70–80%. Additionally, the side effects of HD-MTX treatment endanger the health of patients and affect their quality of life. Methods: This is a retrospective study of patients with first relapse PCNSL at Huashan Hospital, Fudan University between January 2000 and November 2020. By comparing the clinical characteristics and radiological manifestations of first relapsed PCNSL patients with remission and non-remission after receiving HD-MTX rechallenge, we screened out the key factors associated with HD-MTX rechallenge treatment response, to provide some help for the selection of salvage treatment strategies for patients with recurrent PCNSL. Additionally, patients with remission after HD-MTX rechallenge were followed up to identify the factors related to progression-free survival of the second time (PFS2) (time from the first relapse to second relapse/last follow-up). The Kruskal–Wallis and Pearson chi-square tests were performed to examine the univariate association. Further, multivariable logistic regression analysis was used to study the simultaneous effect of different variables. Results: A total of 207 patients were enrolled in the study based on the inclusion criteria, including 114 patients in the remission group (RG) and 81 patients in the non-remission group (nRG), and 12 patients were judged as having a stable disease. In Kruskal–Wallis and Pearson chi-square tests, progression-free survival rates for first time (PFS1) and whether the initial treatment was combined with consolidated whole brain radiotherapy (WBRT) were related to the response to HD-MTX rechallenge treatment, which was further validated in regression analysis. Further, after univariate analysis and regression analysis, KPS was related to PFS2. Conclusions: For PCNSL patients in their first relapse, HD-MTX rechallenge may be an effective salvage treatment. PFS1 and whether initial treatment was combined with consolidation WBRT were associated with HD-MTX rechallenge treatment response. In addition, patients with higher KPS at the time of the first relapse had a longer PFS2 after HD-MTX rechallenge treatment.

Methane (CH4) is the main pollutant in oil and gas production. The detection and accounting of CH4 is an important issue in the process of greenhouse gas control and emission reduction in oil and gas industry. In this study, a portable CH4 detector based on tunable diode laser absorption spectroscopy (TDLAS) technology was deployed. The three-dimensional distribution of CH4 in a natural gas purification plant in Sichuan was obtained through vertical unmanned aerial vehicle (UAV) flight observations and ground mobile observations. According to the mass balance method, the emission of CH4 on 30 m above ground level (AGL) and 60 m AGL in this site was about 0.012 kg/s (±42% at 1σ) and 0.034 kg/s (±47% at 1σ), respectively, in one day. The vertical distribution showed that the CH4 concentration reached the maximum (2.75 ± 0.19 ppm) with height of 0 to 100 m AGL. The CH4 concentration from 100 to 300 m AGL showed a downward trend with height. Atmospheric instability at high altitude and high wind speed promoted the diffusion of CH4. The CH4 concentrations of horizontal distribution on 30 m AGL and 60 m AGL were 2.48 ± 0.11 ppm and 2.76 ± 0.34 ppm. In the observation of mobile campaigns, the connecting equipment of natural gas treatment facilities was prone to leakage, such as in valves and flanges. CH4 leakage was also detected at the torch mouth, especially when there was an open flame at the torch mouth. During the mobile movement investigation, the downwind measurement (OTM-33A) was applied to determine the overall CH4 emission rate shortly after patrolling the site. This work plays a vital role in optimizing the operation and maintenance of natural gas production stations pipe network, ensuring human safety and minimizing greenhouse gas emissions.

A moderate inflammatory response at the early stages of fracture healing is necessary for callus formation. Over-active and continuous inflammation, however, impairs fracture healing and leads to excessive tissue damage. Adequate fracture healing could be promoted through suppression of local over-active immune cells in the fracture site. In the present study, we achieved an enriched concentration of PD-L1 from exosomes (Exos) of a genetically engineered Human Umbilical Vein Endothelial Cell (HUVECs), and demonstrated that exosomes overexpressing PD-L1 specifically bind to PD-1 on the T cell surface, suppressing the activation of T cells. Furthermore, exosomal PD-L1 induced Mesenchymal Stem Cells (MSCs) towards osteogenic differentiation when pre-cultured with T cells. Moreover, embedding of Exos into an injectable hydrogel allowed Exos delivery to the surrounding microenvironment in a time-released manner. Additionally, exosomal PD-L1, embedded in a hydrogel, markedly promoted callus formation and fracture healing in a murine model at the early over-active inflammation phase. Importantly, our results suggested that activation of T cells in the peripheral lymphatic tissues was inhibited after local administration of PD-L1-enriched Exos to the fracture sites, while T cells in distant immune organs such as the spleen were not affected. In summary, this study provides the first example of using PD-L1-enriched Exos for bone fracture repair, and highlights the potential of Hydrogel@Exos systems for bone fracture therapy through immune inhibitory effects.

A deep understanding of explosive sensitivities and their factors is important for safe and reliable applications. However, quantitative prediction of the sensitivities is difficult. Here, reactive molecular dynamics simulation models for high-speed piston impacts on explosive supercells were established. Simulations were also performed to investigate shock-induced reactions of various high-energy explosives. The fraction of reacted explosive molecules in an initial supercell changed linearly with the propagation distance of the shock-wave front. The corresponding slope could be used as a reaction rate for a specific shock-loading velocity. Reaction rates that varied with the shock-loading pressure exhibited two-stage linearities with different slopes. The two inflection points corresponded to the initial and accelerated reactions, which respectively correlated to the thresholds of shock-induced ignition and detonation. Therefore, the ignition and detonation critical pressures could be determined. The sensitivity could then be a quantitative prediction of the critical pressure. The accuracies of the quantitative shock sensitivity predictions were verified by comparing the impact and shock sensitivities of common explosives and the characteristics of anisotropic shock-induced reactions. Molecular dynamics simulations quantitatively predict and rank shock sensitivities by using only crystal structures of the explosives. Overall, this method will enable the design and safe use of explosives.

ObjectivesStereotactic radiosurgery (SRS), a therapy that uses radiation to treat brain tumors, has become a significant treatment procedure for patients with brain metastasis (BM). However, a proportion of patients have been found to be at risk of local failure (LF) after treatment. Hence, accurately identifying patients with LF risk after SRS treatment is critical to the development of successful treatment plans and the prognoses of patients. To accurately predict BM patients with the occurrence of LF after SRS therapy, we develop and validate a machine learning (ML) model based on pre-treatment multimodal magnetic resonance imaging (MRI) radiomics and clinical risk factors.Patients and methodsIn this study, 337 BM patients were included (247, 60, and 30 in the training set, internal validation set, and external validation set, respectively). Four clinical features and 223 radiomics features were selected using least absolute shrinkage and selection operator (LASSO) and Max-Relevance and Min-Redundancy (mRMR) filters. We establish the ML model using the selected features and the support vector machine (SVM) classifier to predict the treatment response of BM patients to SRS therapy.ResultsIn the training set, the SVM classifier that uses a combination of clinical and radiomics features demonstrates outstanding discriminative performance (AUC=0.95, 95% CI: 0.93-0.97). Moreover, this model also achieves satisfactory results in the validation sets (AUC=0.95 in the internal validation set and AUC=0.93 in the external validation set), demonstrating excellent generalizability.ConclusionsThis ML model enables a non-invasive prediction of the treatment response of BM patients receiving SRS therapy, which can in turn assist neurologist and radiation oncologists in the development of more precise and individualized treatment plans for BM patients.

BackgroundPrimary breast angiosarcoma (PBA) is a rare sarcoma, accounting for only 0.04% of all breast malignancies, with a difficult diagnosis and a poor prognosis. Mastectomy is the standard treatment, and the role of adjuvant treatment (chemotherapy and/or radiotherapy following surgery) remains uncertain with very few studies.Case PresentationWe report the case of a 17-year-old female patient who presented with a right breast lump that had rapidly increased in size and was hemorrhaging. She was diagnosed with breast angiosarcoma by needle biopsy and pathological evaluation. However, the mass showed a quick tendency to bleed during biopsies. After that, we performed angiography and tumor vascular embolization. The patient underwent a mastectomy followed by adjuvant chemotherapy.ConclusionTumor vascular embolization reduced the surgical risk of PBA with hemorrhage complications. Postoperative therapeutic roles still need further exploration and verification.

The Coronavirus Disease 2019 (COVID-19) pandemic has been estimated to have claimed more than 6 million lives, and most deaths have been attributed to complications non-specific to the virus. Therefore, understanding and treating these complications are imperative. In this meta-analysis, we reviewed 181 studies published in early stages of the COVID-19 pandemic. We presented that the complications with high incidence among all COVID-19 cases were acute respiratory distress syndrome (ARDS, 18.52%), respiratory failure (16.54%), liver injury (14.13%) and multiple-organ dysfunction syndrome (MODS, 13.62%). Among patients who died, the most common complications were ARDS (84.10%), respiratory failure (78.75%) and respiratory injury (75.72%). Subsequently, we analyzed the risk factors for complications, and reviewed the currently available therapies according to complications and prognosis. To decrease the prevalence of COVID-19 complications and mortality, healthcare workers and patients should pay greater attention to the complications identified herein, particularly those occurring preclinically.

Objective This study’s objective was to test whether an online video intervention discussing appropriate treatment escalation improves willingness to change treatment in people living with rheumatoid arthritis (RA). Methods We conducted a controlled, randomized trial among patients with RA enrolled in ArthritisPower, a United States patient registry. We recruited participants by email and surveyed their assessment of disease activity (patient global), satisfaction with disease control (patient acceptable symptom state), attitudes about RA medications, decisional conflict (decisional conflict scale), and willingness to modify RA treatment (choice predisposition scale, higher scores are better) if or when recommended by their rheumatologist. Intervention groups watched educational videos relevant to a treat‐to‐target (T2T) strategy, whereas control groups viewed vaccination‐related videos as an “attention control.” We compared the between‐group difference in patients’ willingness to modify RA treatment (primary outcome) and difference in decisional conflict about changing RA treatment (secondary outcome) after watching the videos using t tests. Results Participants with self‐reported RA (n = 208) were 90% White and 90% women, with a mean (standard deviation) age of 50 (11) years, and 52% reported familiarity with the RA T2T strategy. We found a significant improvement in between‐group difference in willingness to change RA treatment among intervention versus control participants (0.49 [95% confidence interval 0.09‐0.88], P = 0.02). The effect size (Glass’s delta) for the intervention was 0.48. Decisional conflict about treatment change decreased, but the between‐group difference was not significant. Conclusion This novel educational patient‐directed intervention discussing appropriate treatment escalation was associated with improved willingness to change RA treatment if or when recommended by a rheumatologist. Further studies should evaluate whether this change in patients’ predisposition translates into actual treatment escalation.

Bcl-2 mainly executes anti-apoptotic function in the Bcl-2 family. Nuclear orphan receptor Nur77 can be translocated from nucleus to mitochondria, then interact with Bcl-2 to reverse the function of Bcl-2 from a cell protector to a cell killer, thereby inducing cell apoptosis. The function of Bcl-2 is regulated by post-translational modification, such as the phosphorylation of T69 in the intrinsically disordered loop between BH3 and BH4 motifs. However, due to the lack of structural information of the full-length protein, the effect of phosphorylation modification of T69 in the loop region on the interaction of the two proteins is still unclear, and there is a lack of related research at the atomic level. Therefore, we constructed a full-length intracellular Bcl-2 containing loop region and T69E mutant to mimic stable phosphorylation modification, and investigated the interactions by combining circular dichroism (CD), Western blot and nuclear magnetic resonance (NMR) methods. It was observed that the full-length Bcl-2 had a stronger interaction with Nur77 compared to the Bcl-2/xl chimera, and the phosphorylation modification mimicked by T69E weakened the interaction between Bcl-2 and Nur77. The results will promote future research based on Bcl-2 and Nur77 signal transduction pathways and the apoptosis targeting cancer cells.

Bone mesenchymal stem cells (BMSCs) play an important role in maintaining the dynamic balance of bone metabolism. Recent studies have reported that a decrease in the osteogenic function of MSCs is strongly associated with osteoporosis. Melatonin is a neuroendocrine hormone produced in the pineal gland and is essential in the physiological regulation. This study is aimed at exploring the effect of melatonin on MSCs osteoblastic differentiation and elucidate the underlying mechanisms. We isolated BMSCs from rat bone marrow and demonstrated that melatonin improved osteogenic differentiation of BMSCs by the alizarin red staining and ALP staining. We then showed that melatonin enhanced osteogenic gene expression in BMSCs, including ALP, Col 1, OCN, OPN, and RUNX2. We further revealed that melatonin inhibited the inflammatory response of BMSCs by suppressing the NF-κB signaling pathways. In light of this, we found that the NF-κB pathway-specific activator TNF-α activated the NF-κB pathway, inhibited osteogenic differentiation, and induced inflammatory response in BMSCs. Melatonin was found to reverse the inhibitory effect of TNF-α on osteogenic differentiation and inflammation in BMSCs. Taken together, these findings indicated that melatonin may have therapeutic potential to be used for the treatment of osteoporosis.