Protective effects of electroacupuncture on senile osteoporosis in rats.

OBJECTIVES: The objectives were to explore the protective effects of electroacupuncture (EA) on senile osteoporosis in aged rats and investigate the underlying mechanisms. METHODS: This study included aged (24-month-old; n = 16) and young (3-month-old; n = 8) male Sprague-Dawley rats. Aged rats were further randomized 1:1 to an aged control group (Aged; n = 8) and an EA treatment group (EA; n = 8). The 3-month-old rats served as young controls (Young). EA rats received EA at ST36, SP6, GB34 and SP10 bilaterally for 30 min a day, 5 days a week, for 8 weeks. RESULTS: EA significantly increased serum markers of bone formation in Aged rats. There were no significant differences in serum markers of bone resorption between EA and Aged rats. Deterioration of bone mineral density (BMD) and trabecular bone architecture was observed in the Aged group, while EA significantly increased BMD of the left femur and L5 vertebral body in aged rats. Aging-induced deterioration of trabecular bone architecture was partially reversed in EA rats. Runx2 and Osterix mRNA and protein levels were significantly increased and peroxisome proliferator-activated receptor (PPAR)γ was significantly decreased in bone marrow cells in EA compared with Aged groups. The mRNA and protein levels of core constituents of the Wnt/ß-catenin signaling pathway (Wnt3a, low-density lipoprotein receptor-related protein (LRP)5 and ß-catenin) were significantly increased and Dickkopf 1 was significantly decreased in bone marrow cells in EA compared with Aged groups. CONCLUSION: EA may prevent bone loss and deterioration in aged rats by promoting osteogenesis via a mechanism that may involve activation of the Wnt/ß-catenin signaling pathway. EA may represent a therapeutic option for senile osteoporosis.

Measuring health-related quality of life in a Chinese Mainland adolescent population: psychometric properties of the Mandarin Chinese self-reported KIDSCREEN-27 and KIDSCREEN-10 index.

BACKGROUND: The self-reported KIDSCREEN questionnaires are ideal for capturing children's and adolescents' health-related quality of life (HRQoL) and have gained worldwide popularity. Responding to demands for the concise nature of KIDSCREEN among Chinese Mainland researchers and practitioners, this study aimed to evaluate the psychometric properties of the Mandarin Chinese self-reported KIDSCREEN-27 (KS-27) and KIDSCREEN-10 index (KS-10), which are short versions of the self-reported KIDSCREEN-52 (KS-52). METHODS: This study reanalyzed the validation dataset of the Mandarin Chinese self-reported KS-52. The dataset originated from a cross-sectional survey conducted in Weifang City, the Chinese Mainland, from October to November 2016. Adolescents aged 11-17 years (N = 4385) were surveyed, and sub-samples (N = 841) were retested. Statistical analyses were conducted on the feasibility, item and dimension properties, reliability, and validity of the Mandarin Chinese self-reported KS-27 and KS-10. RESULTS: Indirect evidence from the Small Group Pilot Survey indicated that the Mandarin Chinese self-reported KS-27 and KS-10 can be completed on average in less than 12.33 mins. Their response rate exceeded 90% regardless of the unit- and item (dimension)-level. The psychometric properties of items and dimensions were likewise found to be satisfactory. Internal consistency was robust with inter-item and item-total correlations (0.173-0.873, 0.422-0.786), Cronbach's alpha (0.786-0.881), Guttman's lambda-2 and - 6 (0.807-0.889, 0.829-0.896), and McDonald's omega (0.725-0.886). Test-retest reliability at both item- and dimension-level was excellent, with intraclass correlation coefficients (ICCs) of (0.590-0.696, 0.785-0.842); standard error of measurements (SEMs) of (0.352-0.635, 0.949-1.949). Confirmatory factor analysis (CFA) confirmed their five- and one-dimensional structures, albeit with slight modifications. Moreover, the multi-group confirmatory factor analysis (MG-CFA) substantiated their configural and metric invariance across gender and grade groups. Convergent validity was robust, with stronger correlations observed with comparable dimensions of the Mandarin Chinese self-reported PedsQL™ 4.0, while discriminant validity was evident with low correlations observed with less comparable dimensions. The known-group validity was mainly supported by medium to large effect sizes concerning differences in socioeconomic status (η2 = 0.07-0.17, Cohen's d = 0.55-1.03) and mental health status (η2 = 0.09-0.40, Cohen's d = 0.73-1.83). The Mandarin Chinese self-reported KS-52 served as the criterion; the ICCs between the Mandarin Chinese self-reported KS-27 and KS-10 and their comparable dimensions were stronger, indicating robust criterion validity. CONCLUSIONS: The Mandarin Chinese self-reported KS-27 and KS-10 demonstrated excellent psychometric properties, indicating their good potential for measuring HRQoL for children and adolescents in the Chinese Mainland.

Hydrogen attenuates ischaemia-reperfusion injury in skeletal muscles post-limb replantation by activating the NRF2/HO-1 signalling pathway to reduce BAX expression.

Background: Ischaemia-reperfusion injury (IRI) is a critical complication post-limb replantation. The oxidative stress and cellular apoptosis due to IRI considerably hinder the healing process. This study aimed to investigate the modulatory effects of pre-perfusion with hydrogen-rich heparin sodium on the nuclear factor erythroid 2-related factor 2 (NRF2)/haeme oxygenase-1 (HO-1) pathway and its potential mechanisms in mitigating skeletal muscle IRI post-limb replantation. Methods: Forty healthy Sprague-Dawley rats (250-300 g) were classified into five groups (n = 8 each): normal control, IRI + heparin sodium pre-perfusion (heparin group), IRI + hydrogen-rich heparin sodium pre-perfusion (hydrogen-rich heparin group), IRI + hydrogen-rich heparin sodium pre-perfusion + NRF2 inhibitor (hydrogen-rich heparin + all-trans retinoic acid [ATRA] group), and IRI + heparin sodium pre-perfusion + NRF2 inhibitor (heparin + ATRA group). The activation of the NRF2/HO-1 pathway in skeletal muscle IRI was evaluated based on HO-1 expression using western blotting and immunofluorescence. Furthermore, haematoxylin and eosin staining and transmission electron microscopy were employed to determine the histopathological characteristics. Additionally, superoxide dismutase and malondialdehyde levels in skeletal muscle tissue were measured to assess antioxidant capacity and the degree of oxidative stress damage. Tissue hypoxia was assessed based on hypoxia-inducible factor 1-alpha expression, whereas apoptosis markers BCL-2-associated X protein (BAX) and Caspase-3 in skeletal muscle tissues were analysed using western blotting with terminal deoxynucleotidyl transferase dUTP nick end labelling staining to quantify cell apoptosis. Results: Compared with the control group, the heparin group exhibited significant pathological changes, including inflammatory infiltration and cellular hypertrophy, with increased apoptosis and oxidative stress. Notably, NRF2 suppression aggravated these effects. However, hydrogen-rich heparin sodium prominently activated the NRF2/HO-1 pathway, enhancing antioxidant defence and reducing BAX/Caspase-3-mediated apoptosis, thereby mitigating IRI-induced damage. The use of an NRF2 inhibitor to inhibit NRF2 excitation by hydrogen-rich heparin sodium notably weakened NRF2 activation and the antioxidant response, resulting in a substantial increase in cellular apoptosis. Conclusion: Pre-perfusion with hydrogen-rich heparin sodium markedly diminishes the BAX/Caspase-3-mediated apoptotic pathway in skeletal muscle tissues with IRI through the excitation of the NRF2/HO-1 pathway.

Effects of understory intercropping with salt-tolerant legumes on soil organic carbon pool in coastal saline-alkali land.

Phytoremediation through understory intercropping with salt-tolerant legumes (forest-green manure composite patterns) efficiently and sustainably enhances saline-alkali soils, while significantly improving the stability of monoculture forest ecosystems and the efficacy of soil upgrades. However, exactly how forest-green manure patterns regulate the dynamics of the soil organic carbon (SOC) pool and related mechanisms remain unclear. For this study, a pure forest was used as the control, and three leguminous herbaceous plants (M. sativa, S. cannabina, and C. pallida) were intercropped under two forest stand types (T. hybrid 'Zhongshanshan' and C. illinoensis). The variable characteristics and control factors of SOC and its components under different patterns were elucidated by analyzing the soil physical and chemical properties, enzyme activities, and microbial communities. The results revealed that the composite pattern improved soil salinization and increased the activities of ß-1,4-glucosidase, polyphenol oxidase, peroxidase (PER), invertase (INV), and urease, as well as the carbon pool management index and the proportion of active organic carbon. At the T. hybrid 'Zhongshanshan' experimental site, planting M. sativa effectively increased the total carbon (TC) content. The ammonium nitrogen, soil moisture content, total phosphorus, alkaline phosphatase, PER, and polyphenol oxidase were the primary driving factors that affected the SOC pool. At the C. illinoensis experimental site, S. cannabina planting was observed to increase the TC content, with the TC, exchangeable Na+, ß-1,4-N-acetylglucosaminidase, and INV being the main driving factors that impacted the SOC pool. The composite pattern can indirectly influence the SOC pool by altering the soil properties to regulate the microbial community. Further, it was found that soil inorganic carbon (SIC) was the main contributor to increasing the soil carbon pool following the short-term planting of legumes; thus, there may have been a transfer process that occurred from the SOC to SIC. Our study suggests that the forest-green manure pattern has more positive effects on improving soil quality and the carbon pool in saline-alkali land.

Identification of concurrent infection with Jaagsiekte sheep retrovirus and maedi-visna virus in China.

IMPORTANCE: Ovine pulmonary adenomatosis (OPA) and maedi-visna disease (MVD) are chronic and progressive infectious diseases in sheep caused by Jaagsiekte sheep retrovirus (JSRV) and maedi-visna virus (MVV), respectively. OBJECTIVE: To investigate the pathological changes and conduct viral gene analysis of OPA and MVD co-occurrence in Inner Mongolia, China. METHODS: Using gross pathology, histopathology, immunohistochemistry, ultrastructural pathology, PCR, and sequence analysis, we investigated the concurrent infection of JSRV and MVV in 319 Dorper rams slaughtered in a private slaughterhouse in Inner Mongolia, in 2022. RESULTS: Of the 319 rams included, 3 showed concurrent JSRV and MVV infection. Gross lung pathology showed diffuse enlargement, consolidation, and greyish-white miliary nodules on the lung surface; the trachea was filled with a white foamy fluid; hilar and mediastinal lymph nodes were significantly enlarged. Histopathology results revealed typical OPA and MVD lesions in the lung tissue. Immunohistochemical results were positive for JSRV envelope protein (Env) in the tumor cells and MVV CA in alveolar macrophages. Transmission electron microscopy showed several virions and autophagosomes in the lung tissue, severely damaged mitochondria, and the induced mitophagy. Nucleotide sequences obtained for JSRV env and MVV gag showed the highest homology with the Inner Mongolian strains of JSRV env (JQ837489) and MVV gag (MW248464). CONCLUSIONS AND RELEVANCE: Our study confirmed that OPA and MVD co-occurrence and identified the pathological changes in Inner Mongolia, China, thereby providing references for the identification of concurrent JSRV and MVV infections.

A compact, versatile drug-induced splicing switch system with minimal background expression.

Gene-switch techniques hold promising applications in contemporary genetics research, particularly in disease treatment and genetic engineering. Here, we developed a compact drug-induced splicing system that maintains low background using a human ubiquitin C (hUBC) promoter and optimized drug (LMI070) binding sequences based on the Xon switch system. To ensure precise subcellular localization of the protein of interest (POI), we inserted a 2A self-cleaving peptide between the extra N-terminal peptide and POI. This streamlined and optimized switch system, named miniXon2G, effectively regulated POIs in different subcellular localizations both in vitro and in vivo. Furthermore, miniXon2G could be integrated into endogenous gene loci, resulting in precise, reversible regulation of target genes by both endogenous regulators and drugs. Overall, these findings highlight the performance of miniXon2G in controlling protein expression with great potential for general applicability to diverse biological scenarios requiring precise and delicate regulation.

Generation of human induced pluripotent stem cells carrying albumin-sfGFP reporter.

Current methodologies for hepatocyte induction from human induced pluripotent stem cells (hiPSCs) have limited efficacy due to lack of a functional hepatocyte reporter. To address this, we developed an endogenous albumin (ALB)-sfGFP reporter system in hiPSCs using homologous directed recombination (HDR)-mediated knock-in. The hiPSCs maintained the characteristic morphology, pluripotency, and normal karyotype while demonstrating successful differentiation into all three germ layers both in vitro and in vivo. Co-expression of EGFP and ALB was observed in the derived hepatocyte-like cells (HLCs). This reporter system holds promise for functional hepatocyte induction.

Clarifying the Direct Generation of •OH Radicals in Photocatalytic O2 Reduction: Theoretical Prediction Combined with Experimental Validation.

This work systematically studied thermocatalytic and photocatalytic pathways of formaldehyde degradation and H-assisted O2 reduction over a Pt13/anatase-TiO2(101) composite via DFT calculations together with constrained molecular dynamics (MD) simulations. We show that photocatalytic O2 reduction on Pt/TiO2 can directly generate •OH radicals (*O2 → *OOH → •OH) via two hydrogenation steps with small barriers, and the product selectivity (*H2O2 or •OH) is decided by the relative position between catalyst Fermi level and •OH/*H2O2 redox potential (theoretical determination of 0.07 V referencing to the SHE). Such a novel reaction channel was furthermore validated at the liquid-solid interface via constrained MD simulations and experimental electron paramagnetic resonance detections, and a wide range of H resources, e.g., *HCHO, *HCO, *H (H+ + e-), can always drive the direct •OH generation. The additional portion of e--triggered •OH radicals are prone to diffuse into solution or the TiO2 surface and furthermore cooperate with the conventional h+-driven photooxidations.

Efficacy of the tetravalent protein COVID-19 vaccine, SCTV01E: a phase 3 double-blind, randomized, placebo-controlled trial.

Evolution of SARS-CoV-2 variants emphasizes the need for multivalent vaccines capable of simultaneously targeting multiple strains. SCTV01E is a tetravalent COVID-19 vaccine derived from the spike protein of SARS-CoV-2 variants Alpha, Beta, Delta, and Omicron BA.1. In this double-blinded placebo-controlled pivotal efficacy trial (NCT05308576), the primary endpoint was vaccine efficacy (VE) against COVID-19 seven days post-vaccination in individuals without recent infection. Other endpoints included evaluating safety, immunogenicity, and the VE against all SARS-CoV-2 infections in individuals meeting the study criteria. Between December 26, 2022, and January 15, 2023, 9,223 individuals were randomized at a 1:1 ratio to receive SCTV01E or a placebo. SCTV01E showed a VE of 69.4% (95% CI: 50.6, 81.0) 7 days post-vaccination, with 75 cases in the placebo group and 23 in the SCTV01E group for the primary endpoint. VEs were 79.7% (95% CI: 51.0, 91.6) and 82.4% (95% CI: 57.9, 92.6), respectively, for preventing symptomatic infection and all SARS-CoV-2 infections 14 days post-vaccination. SCTV01E elicited a 25.0-fold higher neutralizing antibody response against Omicron BA.5 28 days post-vaccination compared to placebo. Reactogenicity was generally mild and transient, with no reported vaccine-related SAE, adverse events of special interest (AESI), or deaths. The trial aligned with the shift from dominant variants BA.5 and BF.7 to XBB, suggesting SCTV01E as a potential vaccine alternative effective against present and future variants.

Case report: A rare case of hereditary hemochromatosis caused by a mutation in the HAMP gene in Fuyang, China.

Hemochromatosis, also known as siderosis, is a disease caused by excessive iron deposition in human organs and tissues, resulting from iron metabolism disorders. It is clinically characterized by skin pigmentation (bronze color), liver cirrhosis, diabetes, weakness, and fatigue. Additional symptoms may include arthritis, hypothyroidism, heart failure, and sexual hypofunction. Clinical manifestations can vary from person to person, with a few patients showing no clinical manifestations, which makes the diagnosis difficult for clinicians. In this case report, we described hereditary hemochromatosis related to a mutation in the HAMP gene in Fuyang City, China, as a reference for clinicians. Hereditary hemochromatosis is rarely reported in China. Clinicians in China have relatively insufficient knowledge of this disease, which leads to frequent misdiagnosis. In this case report, we describe hereditary hemochromatosis related to HAMP gene mutation in Fuyang City, China, for the clinician's reference.

A modified glycosylase base editor without predictable DNA off-target effects.

Glycosylase base editor (GBE) can induce C-to-G transversion in mammalian cells, showing great promise for the treatment of human genetic disorders. However, the limited efficiency of transversion and the possibility of off-target effects caused by Cas9 restrict its potential clinical applications. In our recent study, we have successfully developed TaC9-CBE and TaC9-ABE by separating nCas9 and deaminase, which eliminates the Cas9-dependent DNA off-target effects without compromising editing efficiency. We developed a novel GBE called TaC9-GBEYE1, which utilizes the deaminase and UNG-nCas9 guided by TALE and sgRNA, respectively. TaC9-GBEYE1 showed comparable levels of on-target editing efficiency to traditional GBE at 19 target sites, without any off-target effects caused by Cas9 or TALE. The TaC9-GBEYE1 is a safe tool for gene therapy.

Nuclear Receptor Subfamily 4 Group A Member 1 (NR4A1) Promotes the Adipogenesis of Intramuscular Preadipocytes through PI3K/AKT Pathway in Goats.

As a transcription factor, Nuclear Receptor Subfamily 4 Group A Member 1 (NR4A1) binds to downstream target genes to participate in cell proliferation and cell differentiation. We found that the NR4A1 reached the highest expression at 60 h after the differentiation of goat intramuscular preadipocytes. Overexpression of goat NR4A1 increased the number of intracellular lipid droplets and up-regulated the expression of adipocyte-differentiation-related marker genes including AP2, SREBP1, ACC, GPAM, and DGAT2, while the relative expression levels of Pref-1 and HSL were significantly decreased. On the contrary, after NR4A1 was knocked down by siRNA, the number of intracellular lipid droplets and the relative expression levels of LPL, CEBPα, CEBPß, ACC, and DGAT2 were significantly decreased, and the relative expression levels of Pref-1 and HSL were significantly up-regulated. These results suggest that NR4A1 promotes the differentiation of goat intramuscular preadipocytes. Transcriptome sequencing was carried out after overexpression of goat NR4A1, and the KEGG enrichment analysis result showed that the most differentially expressed genes were related to adipocyte differentiation and were enriched in the PI3K-Akt signaling pathway. LY249002, an inhibitor of the PI3K-Akt signaling pathway, was introduced and decreased the number of intracellular lipid droplets, and the relative expression levels of C/EBPα, SREBP1, AP2, C/EBPß, GPAM, ACC, DGAT1, DGAT2, and ATGL were decreased accordingly. The above results indicate that overexpression of goat NR4A1 may promote the differentiation of intramuscular preadipocytes through the PI3K-Akt signaling pathway.

Improved Precision and Safety of Supra-Tentorial Intracranial Hematoma Puncture Using C-Arm CT Four-Dimensional Navigation.

BACKGROUND Spontaneous intracerebral hemorrhage has a high fatality rate within the initial month after onset. This study determined the safety and therapeutic efficacy of minimally invasive puncture for supra-tentorial intracranial hematoma under C-arm computed tomography (CT) 4-dimensional navigation. MATERIAL AND METHODS We retrospectively analyzed 64 patients with supra-tentorial cerebral hemorrhage from June 2020 to May 2023; 31 patients were assigned to the study group (C-arm CT navigation puncture) and 33 patients were in the control group (conventional CT-guided puncture). The analysis focused on assessment of puncture error, postoperative complication rate, and the Glasgow Outcome Scale (GOS) and National Institute of Health Stroke Scale (NIHSS) scores 30 and 90 days after surgery. RESULTS C-arm CT navigation puncture had improved precision, with significantly reduced transverse (3.17±1.75 mm) and longitudinal (1.83±1.21 mm) deviations, compared with the control group (7.88±1.74 mm and 5.50±1.84 mm, respectively; P<0.05). The overall postoperative complication rate was significantly lower in the study group than in the control group (12.90% vs 36.36%, P<0.05). The mean GOS score was higher in the study group than in the control group 30 and 90 days postoperatively (3.42±0.96 and 3.97±0.95 vs 2.94±0.79 and 3.46±0.90, respectively; P<0.05), while the mean NIHSS score was lower in the study group than in the control group 30 and 90 days postoperatively (10.58±6.52 and 5.97±4.55 vs 14.42±8.13 and 9.55±8.31, respectively; P<0.05). CONCLUSIONS Supra-tentorial intracranial hematoma puncture under C-arm CT 4-dimensional navigation is accurate, safe, and beneficial.

Targeted pH-responsive biomimetic nanoparticle-mediated starvation-enhanced chemodynamic therapy combined with chemotherapy for ovarian cancer treatment.

In recent years, the use of arsenic trioxide (ATO) in the context of ovarian cancer chemotherapy has attracted significant attention. However, ATO's limited biocompatibility and the occurrence of severe toxic side effects hinder its clinical application. A nanoparticle (NP) drug delivery system using ATO as a therapeutic agent is reported in this study. Achieving a synergistic effect by combining starvation therapy, chemodynamic therapy, and chemotherapy for the treatment of ovarian cancer was the ultimate goal of this system. This nanotechnology-based drug delivery system (NDDS) introduced arsenic-manganese complexes into cancer cells, leading to the subsequent release of lethal arsenic ions (As3+) and manganese ions (Mn2+). The acidic microenvironment of the tumor facilitated this process, and MR imaging offered real-time monitoring of the ATO dose distribution. Simultaneously, to produce reactive oxygen species that induced cell death through a Fenton-like reaction, Mn2+ exploited the surplus of hydrogen peroxide (H2O2) within tumor cells. Glucose oxidase-based starvation therapy further supported this mechanism, which restored H2O2 and lowered the cellular acidity. Consequently, this approach achieved self-enhanced chemodynamic therapy. Homologous targeting of the NPs was facilitated through the use of SKOV3 cell membranes that encapsulated the NPs. Hence, the use of a multimodal NDDS that integrated ATO delivery, therapy, and monitoring exhibited superior efficacy and biocompatibility compared with the nonspecific administration of ATO. This approach presents a novel concept for the diagnosis and treatment of ovarian cancer.

Development of radiofluorinated MLN-4760 derivatives for PET imaging of the SARS-CoV-2 entry receptor ACE2.

PURPOSE: The angiotensin converting enzyme 2 (ACE2) plays a regulatory role in the cardiovascular system and serves SARS-CoV-2 as an entry receptor. The aim of this study was to synthesize and evaluate radiofluorinated derivatives of the ACE2 inhibitor MLN-4760. [18F]F-MLN-4760 and [18F]F-Aza-MLN-4760 were demonstrated to be suitable for non-invasive imaging of ACE2, potentially enabling a better understanding of its expression dynamics. METHODS: Computational molecular modeling, based on the structures of human ACE2 (hACE2) and mouse ACE2 (mACE2), revealed that the ACE2-binding modes of F-MLN-4760 and F-Aza-MLN-4760 were similar to that of MLN-4760. Co-crystallization of the hACE2/F-MLN-4760 protein complex was performed for confirmation. Displacement experiments using [3H]MLN-4760 enabled the determination of the binding affinities of the synthesized F-MLN-4760 and F-Aza-MLN-4760 to hACE2 expressed in HEK-ACE2 cells. Aryl trimethylstannane-based and pyridine-based radiofluorination precursors were synthesized and used for the preparation of the respective radiotracers. [18F]F-MLN-4760 and [18F]F-Aza-MLN-4760 were evaluated with regard to the uptake in HEK-ACE2 and HEK-ACE cells and in vitro binding to tissue sections of HEK-ACE2 xenografts and normal organs of mice. Biodistribution and PET/CT imaging studies of [18F]F-MLN-4760 and [18F]F-Aza-MLN-4760 were performed using HEK-ACE2 and HEK-ACE xenografted nude mice. RESULTS: Crystallography data revealed an equal hACE2-binding mode for F-MLN-4760 as previously found for MLN-4760. Moreover, computer-based modeling indicated that similar binding to hACE2 and mACE2 holds true for both, F-MLN-4760 and F-Aza-MLN-4760, as is the case for MLN-4760. The IC50 values were three-fold and seven-fold higher for F-MLN-4760 and F-Aza-MLN-4760, respectively, than for MLN-4760. [18F]F-MLN-4760 and [18F]F-Aza-MLN-4760 were obtained in 1.4 ± 0.3 GBq and 0.5 ± 0.1 GBq activity with > 99% radiochemical purity in a 5.3% and 1.2% radiochemical yield, respectively. Uptake in HEK-ACE2 cells was higher for [18F]F-MLN-4760 (67 ± 9%) than for [18F]F-Aza-MLN-4760 (37 ± 8%) after 3-h incubation while negligible uptake was seen in HEK-ACE cells (< 0.3%). [18F]F-MLN-4760 and [18F]F-Aza-MLN-4760 accumulated specifically in HEK-ACE2 xenografts of mice (13 ± 2% IA/g and 15 ± 2% IA/g at 1 h p.i.) with almost no uptake observed in HEK-ACE xenografts (< 0.3% IA/g). This was confirmed by PET/CT imaging, which also visualized unspecific accumulation in the gall bladder and intestinal tract. CONCLUSION: Both radiotracers showed specific and selective binding to ACE2 in vitro and in vivo. [18F]F-MLN-4760 was, however, obtained in higher yields and the ACE2-binding affinity was superior over that of [18F]F-Aza-MLN-4760. [18F]F-MLN-4760 would, thus, be the candidate of choice for further development in view of its use for PET imaging of ACE2.

Improvement of TaC9-ABE mediated correction of human SMN2 gene.

Spinal muscular atrophy (SMA) is a devastating neuromuscular disease caused by mutations in the survival motor neuron 1 (SMN1) gene. Gene editing technology repairs the conversion of the 6th base T to C in exon 7 of the paralogous SMN2 gene, compensating for the SMN protein expression and promoting the survival and function of motor neurons. However, low editing efficiency and unintended off-target effects limit the application of this technology. Here, we optimized a TaC9-adenine base editor (ABE) system by combining Cas9 nickase with the transcription activator-like effector (TALE)-adenosine deaminase fusion protein to effectively and precisely edit SMN2 without detectable Cas9 dependent off-target effects in human cell lines. We also generated human SMA-induced pluripotent stem cells (SMA-iPSCs) through the mutation of the splice acceptor or deletion of the exon 7 of SMN1. TaC9-R10 induced 45% SMN2 T6 > C conversion in the SMA-iPSCs. The SMN2 T6 > C splice-corrected SMA-iPSCs were directionally differentiated into motor neurons, exhibiting SMN protein recovery and antiapoptosis ability. Therefore, the TaC9-ABE system with dual guides from the combination of Cas9 with TALE could be a potential therapeutic strategy for SMA with high efficacy and safety.

The dynamics and control of a multi-lingual rumor propagation model with non-smooth inhibition mechanism.

In this paper, the dynamic behaviors and control strategies of a rumor propagation model are studied in multi-lingual environment. First, an S2E2I2R rumor propagation model is proposed, which incorporates a non-smooth inhibition mechanism. Meanwhile, the existence and stability of the equilibrium are analyzed, grounded in the spreader threshold of the government intervention. Finally, the optimal control and the event-triggered impulsive control strategies are proposed to mitigate the spread of rumors, and the comparison of their effectiveness is further presented by the numerical simulation and a practical case.

Predicting Osteoporosis and Osteopenia by Fusing Deep Transfer Learning Features and Classical Radiomics Features Based on Single-Source Dual-energy CT Imaging.

RATIONALE AND OBJECTIVES: To develop and validate a predictive model for osteoporosis and osteopenia prediction by fusing deep transfer learning (DTL) features and classical radiomics features based on single-source dual-energy computed tomography (CT) virtual monochromatic imaging. METHODS: A total of 606 lumbar vertebrae with dual-energy CT imaging and quantitative CT (QCT) evaluation were included in the retrospective study and randomly divided into the training (n = 424) and validation (n = 182) cohorts. Radiomics features and DTL features were extracted from 70-keV monochromatic CT images, followed by feature selection and model construction, radiomics and DTL features models were established. Then, we integrated the selected two types of features into a features fusion model. We developed a two-level classifier for the hierarchical pairwise classification of each vertebra. All the vertebrae were first classified into osteoporosis and non-osteoporosis groups, then non-osteoporosis group was classified into osteopenia and normal groups. QCT was used as reference. The predictive performance and clinical usefulness of three models were evaluated and compared. RESULTS: The area under the curve (AUC) of the features fusion, radiomics and DTL models for the classification between osteoporosis and non-osteoporosis were 0.981, 0.999, 0.997 in the training cohort and 0.979, 0.943, 0.848 in the validation cohort. Furthermore, the AUCs of the previously mentioned models for the differentiation between osteopenia and normal were 0.994, 0.971, 0.996 in the training cohort and 0.990, 0.968, 0.908 in the validation cohort. The overall accuracy of the previously mentioned models for two-level classifications was 0.979, 0.955, 0.908 in the training cohort and 0.918, 0.885, 0.841 in the validation cohort. Decision curve analysis showed that all models had high clinical value. CONCLUSION: The feature fusion model can be used for osteoporosis and osteopenia prediction with improved predictive ability over a radiomics model or a DTL model alone.