Permethrin as a Potential Furin Inhibitor through a Novel Non-Competitive Allosteric Inhibition.

Furin is a potential target protein associated with numerous diseases; especially closely related to tumors and multiple viral infections including SARS-CoV-2. Most of the existing efficient furin inhibitors adopt a substrate analogous structure, and other types of small molecule inhibitors need to be discovered urgently. In this study, a high-throughput screening combining virtual and physical screening of natural product libraries was performed, coupled with experimental validation and preliminary mechanistic assays at the molecular level, cellular level, and molecular simulation. A novel furin inhibitor, permethrin, which is a derivative from pyrethrin I generated by Pyrethrum cinerariifolium Trev. was identified, and this study confirmed that it binds to a novel allosteric pocket of furin through non-competitive inhibition. It exhibits a very favorable protease-selective inhibition and good cellular activity and specificity. In summary, permethrin shows a new parent nucleus with a new mode of inhibition. It could be used as a highly promising lead compound against furin for targeting related tumors and various resistant viral infections, including SARS-CoV-2.

Wen-Shen-Tong-Luo-Zhi-Tong Decoction regulates bone-fat balance in osteoporosis by adipocyte-derived exosomes.

CONTEXT: Wen-Shen-Tong-Luo-Zhi-Tong (WSTLZT) Decoction is a Chinese prescription with antiosteoporosis effects, especially in patients with abnormal lipid metabolism. OBJECTIVE: To explore the effect and mechanism of WSTLZT on osteoporosis (OP) through adipocyte-derived exosomes. MATERIALS AND METHODS: Adipocyte-derived exosomes with or without WSTLZT treated were identified by transmission electron microscopy, nanoparticle tracking analysis (NTA) and western blotting (WB). Co-culture experiments for bone marrow mesenchymal stem cells (BMSCs) and exosomes were performed to examine the uptake and effect of exosome in osteogenesis and adipogenic differentiation of BMSC. MicroRNA profiles, luciferase and IP were used for exploring specific mechanisms of exosome on BMSC. In vivo, 80 Balb/c mice were randomly divided into four groups: Sham, Ovx, Exo (30 µg exosomes), Exo-WSTLZT (30 µg WSTLZT-exosomes), tail vein injection every week. After 12 weeks, the bone microstructure and marrow fat distribution were analysed by micro-CT. RESULTS: ALP, Alizarin red and Oil red staining showed that WSTLZT-induced exosomes from adipocyte can regulate osteoblastic and adipogenic differentiation of BMSC. MicroRNA profiles observed that WSTLZT treatment resulted in 87 differentially expressed miRNAs (p < 0.05). MiR-122-5p with the greatest difference was screened by q-PCR (p < 0.01). The target relationship between miR-122-5p and SPRY2 was tested by luciferase and IP. MiR-122-5p negatively regulated SPRY2 and elevated the activity of MAPK signalling pathway, thereby regulating the osteoblastic and adipogenic differentiation of BMSC. In vivo, exosomes can not only improve bone microarchitecture but also significantly reduce accumulation of bone marrow adipose. CONCLUSIONS: WSTLZT can exert anti-OP effect through SPRY2 via the MAKP signalling by miR-122-5p carried by adipocyte-derived exosomes.

Analysis of the location and trajectory of the Kirschner wires in the fixation of extension-type supracondylar fracture of the humerus by 3D computational simulation.

BACKGROUND: Closed reduction and percutaneous pinning is still a preference for the treatment of supracondylar humerus fractures in children. However, no reports have shown the pin trajectory and the characteristics of the entry point so far. So we established a computational simulation model of the elbow to observe the trajectory of pinning for supracondylar humerus fractures. METHODS: We reconstructed an adult elbow computationally and simulated pin placement through lateral and medial pinning. Pin trajectories were traced after placement and after the addition of the skin profile; the relative entry points of the pins were determined. We used the center of the dorsal olecranon inflection as an anatomic reference for the entry points of lateral pinning. Four quadrants were established based on the center of the dorsal olecranon inflection: upper medial quadrant, upper lateral quadrant, lower medial quadrant, and lower lateral quadrant (LLQ). RESULTS: The maximum angle of pinning through the lateral column was 64° ± 3°. The minimum angles of pinning through the lateral column and middle column were 37° ± 3° and 20° ± 2°, respectively. The range of safe angle pinning through the medial column was between 18° ± 2° and 57° ± 3° to avoid penetration of the olecranon fossa and the cortex of the medial column. The entry points of lateral pinning were within the lateral half of the LLQ, and the lateral one-third of the LLQ contained all entry points of the pins through the lateral column and minor points of the pins through the middle column. The exit points of the medial pinning were within the lateral fringe of the metaphyseal-diaphyseal junction region; entering from the inferior two-thirds of the medial epicondyle could lead to the exit points in the proximal half of the metaphyseal-diaphyseal junction region laterally. DISCUSSION: For lateral pinning, the entry points would be within the lateral half of the LLQ. For the pins through the lateral column, the entry points should be within the lateral one-third of the LLQ. For medial pinning, entering from the inferior two-thirds of the medial epicondyle would lead to a more proximal exit.

TRIM47 promotes malignant progression of renal cell carcinoma by degrading P53 through ubiquitination.

BACKGROUND: Renal cell carcinoma (RCC) is one of the most common malignant tumors originating from the renal parenchymal urinary epithelial system. Tripartite motif 47 (TRIM47) is a member of the TRIM family proteins, which has E3 ligase activity and has been demonstrated to be involved in the occurrence and prognosis of many tumors. The main purpose of this study is to explore the role and potential mechanism of TRIM47 in promoting malignant biological behavior of RCC. MATERIALS AND METHODS: TRIM47 mRNA and protein levels in human renal cancer and paired normal adjacent tissues were detected by qRT-PCR and Western blot. The effects of TRIM47 knockdown and overexpression in renal cell carcinoma cells on cell proliferation, invasion and xenograft tumor growth in nude mice were analyzed. The molecular mechanism was explored by mass spectrometric exploration,Western blot and immunoprecipitation assays. RESULTS: TRIM47 promoted RCC cell proliferation in vitro and in vivo as an oncogene. Mechanistically, TRIM47 exerted an E3 ligase activity by interacting with P53 protein to increase its ubiquitination and degradation, which further promoted the malignant biological behavior of RCC. CONCLUSIONS: Our study demonstrated that the TRIM47-P53 axis played a functional role in RCC progression and suggested a potential therapeutic target for RCC.

EWS-FLI1-mediated tenascin-C expression promotes tumour progression by targeting MALAT1 through integrin α5ß1-mediated YAP activation in Ewing sarcoma.

BACKGROUND: The extracellular matrix has been critically associated with the tumorigenesis and progression of Ewing sarcoma (ES). However, the regulatory and prognostic roles of tenascin-C (TNC) in ES remain unclear. METHODS: TNC expression was examined in specimens by immunohistochemistry, and the association of TNC expression with ES patient survival was also analysed. TNC-knockout cell lines were constructed using CRISPR/Cas9 methods. In vitro experiments and in vivo bioluminescent imaging using BALB/c nude mice were conducted to evaluate the effect of TNC on ES tumour progression. RNA sequencing was performed, and the underlying mechanism of TNC was further explored. RESULTS: TNC was overexpressed in ES tissue and cell lines, and TNC overexpression was associated with poor survival in ES patients. TNC enhanced cell proliferation, migration and angiogenesis in vitro and promoted ES metastasis in vivo. The oncoprotein EWS-FLI1 profoundly increased TNC expression by directly binding to the TNC promoter region. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) upregulation induced by Yes-associated protein (YAP) activation was responsible for TNC-regulated ES tumour progression. Activated integrin α5ß1 signalling might be correlated with YAP dephosphorylation and nuclear translocation. CONCLUSIONS: TNC may promote ES tumour progression by targeting MALAT1 through integrin α5ß1-mediated YAP activation.

[Advanced progress in classic genomic and non-genomic regulating mechanism mediated by retinoic acids in anti-cancer treatments].

Retinoic acid, an active metabolite of vitamin A, exerts multiple effects on regulating embryonic development and inducing differentiation, proliferation, apoptosis as well as resistance in various cancer cells. Apart from the classic genomic action (binding to the nuclear receptors to regulate the expression of its downstream target genes), retinoic acids also play important roles in anti-cancer effect through non-genomic pathways (via extranuclear and non-transcriptional effects).

Ataxin-3 promotes testicular cancer cell proliferation by inhibiting anti-oncogene PTEN.

Human Ataxin-3 protein was first identified as a transcript from patients with Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3). Recent studies have demonstrated that Ataxin-3 is involved in gastric cancer and lung cancer. However, the role of Ataxin-3 in testicular cancer (TC) remains poorly understood. This study aims to explore the significance of Ataxin-3 expression in TC. Firstly, we investigated 53 paired TC and para-tumor tissues and found that Ataxin-3 was overexpressed in TC tissues, and this overexpression of Ataxin-3 was correlated with tumor stages. Functionally, Ataxin-3 overexpression promoted cell proliferation, and Ataxin-3 knockdown inhibited cell proliferation. In addition, up-regulation of Ataxin-3 inhibited the expression of PTEN and activated the AKT/mTOR pathway. Conversely, inhibition of Ataxin-3 suppressed the expression of p-AKT and p-mTOR, and increased the expression of p-4EBP1. These findings may provide a better understanding about the mechanism of TC and suggest that Ataxin-3 may be a potential prognostic biomarker and therapeutic target for TC.

B-cell lymphoma 2 ovarian killer suppresses testicular cancer cell malignant behavior, but plays a role in platinum resistance.

Testicular cancer (TC) is the most common malignancy in men. Although the 5-year survival rate of TC patients exceeds 95%, the prognosis of patients with platinum-resistant tumors remains poor because of limited therapeutic options. Overcoming chemoresistance is the key to improving survival in poor-prognosis patients. However, the mechanism remains poorly understood. B-cell lymphoma 2 ovarian killer (BOK) is a proapoptotic protein and functions as a tumor suppressor in malignancy tumors. In this study, we found that BOK was frequently downregulated in TC tissues compared with paratumor tissues. BOK overexpression inhibited TC cell proliferation and invasion. In contrast, BOK knockdown promoted TC cell proliferation and invasion. Surprisingly, either BOK overexpression or knockdown rendered TC cells resistant to Cisplatin (DDP). In conclusion, BOK downregulation may be associated with tumorigenesis of TC. BOK had the potency to suppress TC cell proliferation and invasion, and may function as a tumor suppressor in TC. However, BOK also contributes to Cisplatin resistance. These data may provide a wider perspective on TC research and treatment.

Surgical management of spinal liposarcoma: a case series of 7 patients and literature review.

PURPOSE: Liposarcoma, one of the most common soft tissue sarcomas originates from primitive mesenchymal cells. But spinal involvement of either primary or metastatic liposarcoma is rare. Here we present our experience of seven consecutive patients with spinal liposarcoma. METHOD: We retrospectively reviewed our patients who have spinal liposarcoma from January 2009 to December 2013. All patients were surgically treated at least once at our spine tumor center and be confirmed as liposarcoma after surgery. All patients' information and follow-up data were collected afterwards. RESULTS: A total of six male and one female patients have been included. Five of them had mobile spinal involvement while the others had sacral involvement. Six piecemeal and one en-bloc resections were successfully performed. Patients' Frankel scores were upgraded with one level or at least preserved postoperatively. The average time of follow-up was 24.6 ± 13.9 months. Three patients died 13, 15 and 24 months after surgical treatment, respectively while the other four patients were still alive and one of them alive with disease at the end of follow-up. CONCLUSION: The outcome and prognosis of spinal liposarcoma is poor, and surgical resections should be considered when diagnosis is confirmed. For those whose tumors were too large to resect and/or with multiple metastases, effective treatment options are currently limited. Therefore, multidisciplinary treatment should be adopted, intraoperative chemotherapy, systemic chemotherapy and radiotherapy for instance.

MicroRNA-146a Induced by Hypoxia Promotes Chondrocyte Autophagy through Bcl-2.

BACKGROUND/AIMS: There have been many studies on the etiology of osteoarthritis (OA) with regard to the function of inflammatory cytokines, the process of cartilage degradation, the function of miR-146a, hypoxia stimulation and autophagy in OA chondrocytes, but there have been no reports on the relationship between miR-146a and autophagy in cartilage, especially under hypoxia. This study aimed to confirm the relationship of miR-146a and autophagy in cartilage under hypoxia. METHODS: Chondrocytes were treated by hypoxia gradients, and the main factors including HIF-1α, HIF-2α, miR-146a and Bcl-2 and autophagy markers ULK-1, ATG-5 were detected by quantitative PCR (Q-PCR) and western blotting. The autophagy marker LC-3 was detected by immunofluorescence. The reciprocal effects between miR-146a and Bcl-2 were confirmed by several combinations of shRNAs and adenovirus-gene systems followed by Q-PCR and western blot detection. RESULTS: Hypoxia maintained the chondrocytes phenotype and promoted autophagy and miR-146a expression via HIF-1α, but not HIF-2α, while miR-146a did not reversely affect HIF-1α. The autophagy induced by hypoxia through HIF-1α, miR-146a and Bcl-2. Simply, hypoxia induced HIF-1α, and HIF-1α increased miR-146a, but miR-146a suppressed Bcl-2, an autophagy inhibitor. While Bcl-2 affected neither HIF-1α nor miR-146a. The absence of both HIF-1α and miR-146a or Bcl-2 over-expression inhibited hypoxia-induced autophagy. CONCLUSION: HIF-1α, miR-146a and Bcl-2 play crucial roles during hypoxia-induced autophagy, Hypoxia, HIF-1α and miR-146a promote chondrocytes autophagy via depressing Bcl-2. We conclude that miR-146a may serve as a novel therapeutic target for protecting cartilage from degeneration in OA.

XCR1 promotes cell growth and migration and is correlated with bone metastasis in non-small cell lung cancer.

Bone metastasis occurs in approximately 30-40% patients with advanced non-small cell lung cancer (NSCLC), but the mechanism underlying this bone metastasis remains poorly understood. The chemokine super family is believed to play an important role in tumor metastasis in lung cancer. The chemokine receptor XCR1 has been identified to promote cell proliferation and migration in oral cancer and ovarian carcinoma, but the role of XCR1 in lung cancer has not been reported. In this study, we demonstrated for the first time that XCR1 was overexpressed in lung cancer bone metastasis as compared with that in patients with primary lung cancer. In addition, the XCR1 ligand XCL1 promoted the proliferation and migration of lung cancer cells markedly, and knockdown of XCR1 by siRNA abolished the effect of XCL1 in cell proliferation and migration. Furthermore, we identified JAK2/STAT3 as a novel downstream pathway of XCR1, while XCL1/XCR1 increased the mRNA level of the downstream of JAK2/STAT3 including PIM1, JunB, TTP, MMP2 and MMP9. These results indicate that XCR1 is a new potential therapeutic target for the treatment of lung cancer bone metastasis.

[Expression of proteins related neurodegeneration in autopsy brains of the aged].

OBJECTIVE: To recognize relationship of protein related neurodegeneration abnormal aggregation in the aged brains with their cognitive and motor functions. METHODS: Brain tissues from the consecutive autopsy cases of the aged from January 2005 to December 2006 in PLA General Hospital were carried out for immunohistochemical staining with beta amyloid, tau, α-synuclein and ubiquitin antibodies. The consortium to establish a registry for Alzheimer's disease (CERAD) was used to semi-quantitatively analyze Aß positive core plaques density and Braak staging for tau positive neurofibrillary tangles (NFTs) and α-synuclein positive Lewy bodies. In addition, Aß positive cerebral amyloid angiopathy (CAA), neuritic plaques and various ubiquitin positive structures were also observed. The relationship of these protein abnormal depositions in the aged brains with cognitive and motor functions were analyzed. RESULTS: In brain tissues of 16 consecutive autopsy cases of the aged from 78 to 95 years, there were 13 cases with Aß positive core plaques, their density was 2 cases with sparse, 2 cases with moderate and 9 cases with frequent, respectively, according to CREAD.Eight cases with Aß positive CAA were found, including 6 cases of mild CAA and 2 cases of severe CAA. There were 12 cases with tau positive NFTs, including 6 cases with Braak stageI-II, 4 cases with stage III-IV and 2 cases with stage V-VI. There were 5 cases with frequent Aß core plaques, meanwhile existing numerous tau/ubiquitin positive neuritic plaques and Braak stage IV-VI of tau positive NFTs, all of them presented cognitive dysfunction. Among 4 other cases with frequent Aß core plaques, only one case coexisted α-synuclein positive Lewy bodies showed moderate cognitive impairment, remaining 3 cases did not present cognitive dysfunction. There were 4 cases with α-synuclein positive Lewy bodies in the brainstem, and all of these cases presented parkinsonian motor dysfunction. 13 cases with ubiquitin positive structures were found. CONCLUSIONS: Beta amyloid protein positive deposit in the aged brain is an important marker of normal brain aging and cognitive impairment; frequent Aß core plaques in the neocortex plus Braak IV and above tau positive NFTs are closely related to cognitive dysfunction of Alzheimer's disease; α-synuclein positive Lewy bodies in the brainstem is one of the important pathological markers of parkinsonian motor disorders; ubiquitin deposition involves the development of some characteristic structures of several neurodegenerative diseases.

Discrete residual diffusion model for high-resolution prostate MRI synthesis.

Objective.High-resolution magnetic resonance imaging (HR MRI) is an effective tool for diagnosing PCa, but it requires patients to remain immobile for extended periods, increasing chances of image distortion due to motion. One solution is to utilize super-resolution (SR) techniques to process low-resolution (LR) images and create a higher-resolution version. However, existing medical SR models suffer from issues such as excessive smoothness and mode collapse. In this paper, we propose a novel generative model avoiding the problems of existing models, called discrete residual diffusion model (DR-DM).Approach.First, the forward process of DR-DM gradually disrupts the input via a fixed Markov chain, producing a sequence of latent variables with increasing noise. The backward process learns the conditional transit distribution and gradually match the target data distribution. By optimizing a variant of the variational lower bound, training diffusion models effectively address the issue of mode collapse. Second, to focus DR-DM on recovering high-frequency details, we synthesize residual images instead of synthesizing HR MRI directly. The residual image represents the difference between the HR and LR up-sampled MR image, and we convert residual image into discrete image tokens with a shorter sequence length by a vector quantized variational autoencoder (VQ-VAE), which reduced the computational complexity. Third, transformer architecture is integrated to model the relationship between LR MRI and residual image, which can capture the long-range dependencies between LR MRI and the synthesized imaging and improve the fidelity of reconstructed images.Main results.Extensive experimental validations have been performed on two popular yet challenging magnetic resonance image super-resolution tasks and compared to five state-of-the-art methods.Significance.Our experiments on the Prostate-Diagnosis and PROSTATEx datasets demonstrate that the DR-DM model significantly improves the signal-to-noise ratio of MRI for prostate cancer, resulting in greater clarity and improved diagnostic accuracy for patients.

Arbitrary scale super-resolution diffusion model for brain MRI images.

Given the constraints posed by hardware capacity, scan duration, and patient cooperation, the reconstruction of magnetic resonance imaging (MRI) images emerges as a pivotal aspect of medical imaging research. Currently, deep learning-based super-resolution (SR) methods have been widely discussed in medical image processing due to their ability to reconstruct high-quality, high resolution (HR) images from low resolution (LR) inputs. However, most existing MRI SR methods are designed for specific magnifications and cannot generate MRI images at arbitrary scales, which hinders the radiologists from fully visualizing the lesions. Moreover, current arbitrary scale SR methods often suffer from issues like excessive smoothing and artifacts. In this paper, we propose an Arbitrary Scale Super-Resolution Diffusion Model (ASSRDM), which combines implicit neural representation with the denoising diffusion probabilistic model to achieve arbitrary-scale, high-fidelity medical images SR. Moreover, we formulate a continuous resolution regulation mechanism, comprising a multi-scale LR guidance network and a scaling factor. The scaling factor finely adjusts the resolution and dynamically influences the weighting of LR details and synthesized features in the final output. This capability allows the model to seamlessly adapt to the requirements of continuous resolution adjustments. Additionally, the multi-scale LR guidance network provides the denoising block with multi-resolution LR features to enrich texture information and restore high-frequency details. Extensive experiments conducted on the IXI and fastMRI datasets demonstrate that our ASSRDM exhibits superior performance compared to existing techniques and has tremendous potential in clinical practice.

Pt/Al2O3@Ce/ZrO2-S bifunctional catalysts prepared by mechanically milling for selective catalytic oxidation of high-concentration ammonia.

The selective catalytic oxidation (SCO) is an effective method for removing slipped high-concentration ammonia from NH3-fueled engine exhaust gas. Herein a novel bifunctional catalyst was synthesized by mechanically mixing sulfated Ce/ZrO2 (Ce/ZrO2-S) with a small fraction of Pt/Al2O3 (Pt 0.1 wt.%) for SCO of NH3. As expected, the introduction of a small amount of Pt/Al2O3 significantly improved NH3 conversion ability of Ce/ZrO2-S catalysts toward low-temperature direction. When the mass ratio of Pt/Al2O3 to Ce/ZrO2-S was 7.5% (the corresponding mixed catalyst was denoted as P@CZS-7.5), T90 temperature was 312 °C. More importantly, P@CZS-7.5 catalyst exhibited a much better N2 selectivity (> 96%) in a wide temperature range (320 ~ 450 °C). H2-TPR results revealed that the addition of a trace amount of Pt/Al2O3 significantly led to a distinct shift of reduction temperature peak toward low-temperature direction, thereby greatly improved the low-temperature redox performance of mixed catalysts. Furthermore, NH3-TPD and BET results showed that P@CZS-7.5 catalyst exhibited a similar NH3 adsorption capacity to Ce/ZrO2-S catalyst, while the former had a relatively higher specific surface area than the latter. It was considered as a crucial factor for P@CZS-7.5 catalyst maintaining superior N2 selectivity in high-concentration NH3 (5000 ppm) removal processes. In situ DRIFTS results indicated that P@CZS-7.5 catalyst followed the internal selective catalytic reduction (i-SCR) mechanism in NH3-SCO reactions.

A multifunctional biomimetic nanoplatform for image-guideded photothermal-ferroptotic synergistic osteosarcoma therapy.

Much effort has been devoted to improving treatment efficiency for osteosarcoma (OS). However, most current approaches result in poor therapeutic responses, thus indicating the need for the development of other therapeutic options. This study developed a multifunctional nanoparticle, PDA-MOF-E-M, an aggregation of OS targeting, programmed death targeting, and near-infrared (NIR)-aided targeting. At the same time, a multifunctional nanoparticle that utilises Fe-MOFs to create a cellular iron-rich environment and erastin as a ferroptosis inducer while ensuring targeted delivery to OS cells through cell membrane encapsulation is presented. The combination of PDA-MOF-E-M and PTT increased intracellular ROS and LPO levels and induced ferroptosis-related protein expression. A PDA-based PTT combined with erastin showed significant synergistic therapeutic improvement in the anti-tumour efficiency of the nanoparticle in vitro and vivo. The multifunctional nanoparticle efficiently prevents the osteoclasia progression of OS xenograft bone tumors in vivo. Finally, this study provides guidance and a point of reference for clinical approaches to treating OS.

Senktide blocks aberrant RTN3 interactome to retard memory decline and tau pathology in social isolated Alzheimer's disease mice.

Sporadic or late-onset Alzheimer's disease (LOAD) accounts for more than 95% of Alzheimer's disease (AD) cases without any family history. Although genome-wide association studies have identified associated risk genes and loci for LOAD, numerous studies suggest that many adverse environmental factors, such as social isolation, are associated with an increased risk of dementia. However, the underlying mechanisms of social isolation in AD progression remain elusive. In the current study, we found that 7 days of social isolation could trigger pattern separation impairments and presynaptic abnormalities of the mossy fibre-CA3 circuit in AD mice. We also revealed that social isolation disrupted histone acetylation and resulted in the downregulation of 2 dentate gyrus (DG)-enriched miRNAs, which simultaneously target reticulon 3 (RTN3), an endoplasmic reticulum protein that aggregates in presynaptic regions to disturb the formation of functional mossy fibre boutons (MFBs) by recruiting multiple mitochondrial and vesicle-related proteins. Interestingly, the aggregation of RTN3 also recruits the PP2A B subunits to suppress PP2A activity and induce tau hyperphosphorylation, which, in turn, further elevates RTN3 and forms a vicious cycle. Finally, using an artificial intelligence-assisted molecular docking approach, we determined that senktide, a selective agonist of neurokinin3 receptors (NK3R), could reduce the binding of RTN3 with its partners. Moreover, application of senktide in vivo effectively restored DG circuit disorders in socially isolated AD mice. Taken together, our findings not only demonstrate the epigenetic regulatory mechanism underlying mossy fibre synaptic disorders orchestrated by social isolation and tau pathology but also reveal a novel potential therapeutic strategy for AD.

Remarkable N2 selectivity enhancement of NH3-SCO reactions over V0.5/Pt0.04/TiO2 catalyst through Cu-Er co-modification.

Pt-V bimetallic catalysts maybe promising substitutes to precious metal catalysts for selective catalytic oxidation (SCO) of NH3. But it remains a major challenge for Pt-V bimetallic catalysts to pursue high NH3 conversion rate and N2 selectivity simultaneously. In this work, both Cu and Er were adopted to modify V0.5/Pt0.04/TiO2 catalyst (denoted as V/PT), and the influences of Cu and Er doping amounts on NH3-SCO performance of V/PT catalysts were investigated systematically. The results indicated that the co-modification of Cu and Er imposed little influence on NH3 conversion efficiency, but significantly boosted N2 selectivity. Compared with other Cu-Er-modified V/PT catalysts, CEV/PT-4 catalyst exhibited outstanding NH3-SCO performance, which attained completely 100% NH3 conversion efficiency and > 90% N2 selectivity in the temperature range of 225-450 °C. It was significantly superior to the NH3-SCO performance of most previously reported catalysts. The characterization results indicated that the adequate doping amounts of Cu and Er resulted in an obvious enhancement on redox property and surface acidity of CEV/PT-4 catalyst. It also led to abundant Pt0 and surface chemisorbed oxygen species on catalyst surface, which facilitated the oxidation of NH3 to NOx and enhanced i-SCR reactions. In situ DRIFTS results showed that -NH2 species on the surface of CEV/PT-4 catalyst could actively react with nitrate species to generate N2 and H2O.

Assessment of Instant Loss of Elbow Flexion in Children with Untreated Gartland IIA Humeral Supracondylar Fractures-A Simulation Study with Lateral Elbow Radiographs.

OBJECTIVE: The suitability of in situ cast fixation for treating Gartland IIA humeral supracondylar fractures has remained controversial due to concerns regarding loss of elbow flexion. This study aimed to assess the instant loss of elbow flexion after Gartland IIA humeral supracondylar fractures based on the relationship between the anterior marginal line of the humerus and capitellum in the lateral view. METHODS: This simulation study was conducted with normal radiographs using Adobe Photoshop 14.0, followed by verification using clinical cases. Standard lateral views of normal elbows of children were collected from January 2008 to February 2020. Adobe Photoshop was used to simulate Gartland IIA supracondylar fractures with different degrees of angulation in the sagittal plane. A formula was deduced to assess flexion loss, and this method was verified in three cases. The data were grouped by age, and the relationship between elbow flexion loss and age, as well as the angulation of the fracture, was analyzed using a one-way or multivariate ANOVA. RESULTS: There was a flexion loss of 19° (11-30°) when the anterior margin line of the humerus was tangential to the capitellum. This loss increased with age at injury (r = 0.731, P = 0.000). Moreover, the difference in angulation in the sagittal plane also influenced the extent of elbow flexion loss (r = -0.739, P = 0.000). The more horizontal the fracture line in the lateral view, the greater the loss of elbow flexion. CONCLUSION: Instant elbow flexion loss after Gartland IIA humeral supracondylar fractures increases with age at the time of injury and decreases with angulation in the sagittal plane. When the anterior margin of the humerus is tangential to the capitellum, there will be an average loss of 19° in elbow flexion. These findings provide a quantitative reference for clinical decision-making in the treatment of Gartland IIA supracondylar fractures.

BARX1 promotes osteosarcoma cell proliferation and invasion by regulating HSPA6 expression.

Osteosarcoma (OS) is a bone tumour affecting adolescents. Dysregulation of Barx homeobox 1 (BARX1) expression is involved in various cancers, but its function and mechanism in the process of OS are undefined. This study revealed that BARX1 expression is higher in OS tissue than in adjacent normal tissue. Downregulation of BARX1 in OS cells significantly suppressed their proliferation and migration, whereas enforced expression of exogenous BARX1 exerted the opposite effects on OS cells. Subsequently, heat shock 70-kDa protein 6 (HSPA6) expression was clearly increased after BARX1 overexpression in OS cells, as confirmed by RNA sequencing. The dual-luciferase reporter assay confirmed that HSPA6 expression is directly regulated by BARX1. The in vitro assay indicated that silencing HSPA6 expression attenuated OS proliferation and migration induced by BARX1. A dual immunofluorescence labelling assay provided further evidence that BARX1 was overexpressed and associated with HSPA6 overexpression in OS tumour tissue. In conclusion, BARX1 promotes OS cell proliferation and migration by inducing the expression of HSPA6, which plays an oncogenic role in OS. BARX1 and HSPA6 can potentially act as novel therapeutic targets for OS.