Reduced APPL1 impairs osteogenic differentiation of mesenchymal stem cells by facilitating MGP expression to disrupt the BMP2 pathway in osteoporosis.

An imbalance of human mesenchymal stem cells (MSCs) adipogenic and osteogenic differentiation plays an important role in the pathogenesis of osteoporosis. Our previous study verified that Adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 (APPL1)/myoferlin deficiency promotes adipogenic differentiation of MSCs by blocking autophagic flux in osteoporosis. However, the function of APPL1 in the osteogenic differentiation of MSCs remains unclear. This study aimed to investigate the role of APPL1 in the osteogenic differentiation of MSCs in osteoporosis and the underlying regulatory mechanism. In this study, we demonstrated the downregulation of APPL1 expression in patients with osteoporosis and osteoporosis mice. The severity of clinical osteoporosis was negatively correlated with the expression of APPL1 in bone marrow MSCs. We found that APPL1 positively regulates the osteogenic differentiation of MSCs in vitro and in vivo. Moreover, RNA sequencing showed that the expression of MGP, an osteocalcin/matrix Gla family member, was significantly upregulated after APPL1 knockdown. Mechanistically, our study showed that reduced APPL1 impaired the osteogenic differentiation of mesenchymal stem cells by facilitating Matrix Gla protein expression to disrupt the BMP2 pathway in osteoporosis. We also evaluated the significance of APPL1 in promoting osteogenesis in a mouse model of osteoporosis. These results suggest that APPL1 may be an important target for the diagnosis and treatment of osteoporosis.

Simple modulation of Lissajous MEMS laser beam scanning with reconfigurable structured light patterns for 3D imaging.

Structured light 3D imaging systems commonly employ panel-based projectors or 1-axis MEMS mirrors with beam expander lens to project multi-frame barcodes or dot clouds, addressing challenges posed by objects with multi-scale feature sizes. However, these methods often result in large system volumes due to the required projection multi-lens modules, high hardware costs, or limited light pattern generation capabilities that hindering measurement precision enhancement. This paper introduces an innovative approach to reconfigurable spatial light pattern projection using a single bi-axial MEMS mirror with Lissajous scanning. In contrast to the pixel-by-pixel pre-defined image patterns encoding of conventional 2D laser beam scanning, the proposed method simply aligns the MEMS bi-axial resonance frequencies with laser pulse modulation, enabling the projection of diverse structured light patterns such as stripes, lines, dot matrices, and random dot clouds, which can adapt to different 3D imaging algorithms demands. It eliminates the need for multi-frame encoding and streamlines data caching, simplifies digital logic hardware. A prototype 3D imaging system was developed to demonstrate the mathematical model for laser modulation and the technical feasibility based on the proposed principle. Beyond its lens-free essence, the system supports focal-free optics and a compact projection form factor, which accommodates to a broad range of projection distances and field-of-views based on object's location. 3D depth map of polynomial surface and blocks objects are extracted through single-frame pattern projection with a relative high accuracy. The presented modulation theory for diverse structured light pattern generation opens avenues for versatile and compact 3D imaging applications of LiDAR and robotic 3D vision.

The efficacy and safety of PARP inhibitors in mCRPC with HRR mutation in second-line treatment: a systematic review and bayesian network meta-analysis.

BACKGROUND: Poly (ADP- ribose) polymerase inhibitors (PARPi) has been increasingly adopted for metastatic castration-resistance prostate cancer (mCRPC) patients with homologous recombination repair deficiency (HRD). However, it is unclear which PARPi is optimal in mCRPC patients with HRD in 2nd -line setting. METHOD: We conducted a systematic review of trials regarding PARPi- based therapies on mCRPC in 2nd -line setting and performed a Bayesian network meta-analysis (NMA). Radiographic progression-free survival (rPFS) was assessed as primary outcome. PSA response and adverse events (AEs) were evaluated as secondary outcomes. Subgroup analyses were performed according to specific genetic mutation. RESULTS: Four RCTs comprised of 1024 patients (763 harbored homologous recombination repair (HRR) mutations) were identified for quantitative analysis. Regarding rPFS, olaparib monotherapy, rucaparib and cediranib plus olaparib showed significant improvement compared with ARAT. Olaparib plus cediranib had the highest surface under cumulative ranking curve (SUCRA) scores (87.5%) for rPFS, followed by rucaparib, olaparib and olaparib plus abiraterone acetate prednisone. For patients with BRCA 1/2 mutations, olaparib associated with the highest probability (98.1%) of improved rPFS. For patients with BRCA-2 mutations, olaparib and olaparib plus cediranib had similar efficacy. However, neither olaparib nor rucaparib showed significant superior effectiveness to androgen receptor-axis-targeted therapy (ARAT) in patients with ATM mutations. For safety, olaparib showed significantly lower ≥ 3 AE rate compared with cediranib plus olaparib (RR: 0.72, 95% CI: 0.51, 0.97), while olaparib plus cediranib was associated with the highest risk of all-grade AE. CONCLUSION: PARPi-based therapy showed considerable efficacy for mCRPC patients with HRD in 2nd -line setting. However, patients should be treated accordingly based on their genetic background as well as the efficacy and safety of the selected regimen. TRIAL REGISTRATION: CRD42023454079.

Human umbilical cord mesenchymal stem cells alleviate fatty liver ischemia-reperfusion injury by activating autophagy through upregulation of IFNγ.

Liver ischemia-reperfusion injury (IRI) is an important factor affecting the prognosis of liver transplantation, and extended criteria donors (e.g., steatosis donor livers) are considered to be more sensitive to ischemia-reperfusion injury in liver transplantation. Currently, the application of human umbilical cord mesenchymal stem cells (hMSCs) has great promise in the treatment of various injuries in the liver. This study aimed to investigate the therapeutic role and mechanism of hMSCs in fatty liver IRI. After more than 8 weeks of high-fat chow feeding, we constructed a fatty liver mouse model and established ischemic injury of about 70% of the liver. Six hours after IRI, liver injury was significantly alleviated in hMSCs-treated mice, and the expression levels of liver enzyme, inflammatory factor TNF-α, and apoptotic proteins were significantly lower than those of the control group, which were also significant in pathological sections. Transcriptomics analysis showed that IFNγ was significantly upregulated in the hMSCs group. Mechanistically, IFNγ, which activates the MAPK pathway, is a potent agonist that promotes the occurrence of autophagy in hepatocytes to exert a protective function, which was confirmed by in vitro experiments. In summary, hMSCs treatment could slow down IRI in fatty liver by activating autophagy through upregulation of IFNγ, and this effect was partly direct.

Role of soil nutrient elements transport on Camellia oleifera yield under different soil types.

BACKGROUND: Most of Camellia oleifera forests have low fruit yield and poor oil quality that are largely associated with soil fertility. Soil physical and chemical properties interact with each other affecting soil fertility and C. oleifera growing under different soil conditions produced different yield and oil composition. Three main soil types were studied, and redundancy, correlation, and double-screening stepwise regression analysis were used for exploring the relationships between C. oleifera nutrients uptake and soil physical and chemical properties, shedding light on the transport law of nutrient elements from root, leaves, and kernel, and affecting the regulation of fruit yield and oil composition. RESULTS: In the present study, available soil elements content of C. oleifera forest were mainly regulated by water content, pH value, and total N, P and Fe contents. Seven elements (N, P, K, Mg, Cu, Mn and C) were key for kernel's growth and development, with N, P, K, Cu and Mn contents determining 74.0% the yield traits. The transport characteristics of these nutrients from root, leaves to the kernel had synergistic and antagonistic effects. Increasing oil production and unsaturated fatty acid content can be accomplished in two ways: one through increasing N, P, Mg, and Zn contents of leaves by applying corresponding N, P, Mg, Zn foliar fertilizers, while the other through maintaining proper soil moisture content by applying Zn fertilizer in the surface layer and Mg and Ca fertilizer in deep gully. CONCLUSION: Soil type controlled nutrient absorption by soil pH, water content and total N, P and Fe content. There were synergistic and antagonistic effects on the inter-organ transport of nutrient elements, ultimately affecting N, P, K, Cu and Mn contents in kernel, which determined the yield and oil composition of C. oleifera.

Lissajous MEMS laser beam scanner with uniform and high fill-factor projection for augmented reality display.

MEMS Laser beam scanning (LBS) has been identified as a key advancement for augmented reality (AR) displays due to its ability to create compact optical systems that generate bright, high-contrast images with minimal heat dissipation. This innovation can be attributed to the focus-free, efficient light-on-demand pixel projection mechanisms integral to LBS. The LBS, specifically in Lissajous-mode, outperforms the raster-mode in terms of larger scan angles and stability to external vibrations, by leveraging a MEMS mirror operating at bi-axial resonance. However, it tends to be hampered by small mirror aperture, low fill-factor, and inconsistent uniformity of image projection. In this research, a unique gimbal-less Lissajous MEMS scanner was proposed. It employs a bi-axial high frequency of 12,255 Hz and 7,182 Hz to achieve a resolution of 640 × 360 pixels and a video refresh rate of 57 Hz, all while maintaining a high image fill factor of 85.11%. The robust structure of the mirror is proven to sustain stable scanning under broad spectrum of external vibration disturbance up to 2,000 Hz. Furthermore, the large mirror diameter of 2 mm improves refined pixel projection and increased optical etendue for exit pupil. Mathematic model of Lissajous pixel-cells and image reconstruction simulation were established to validate the LBS's ability to generate a uniform and densely pixelated visual effect that fits for typical AR head-up display (AR-HUD). In a pioneering move, performance metric of figure-of-merit was defined to evaluate AR light-engines using varied picture-generation techniques, laying a foundation for guiding future AR system development.

Impairment of APPL1/Myoferlin facilitates adipogenic differentiation of mesenchymal stem cells by blocking autophagy flux in osteoporosis.

An imbalance of human mesenchymal stem cells (hMSCs) adipogenic and osteogenic differentiation is crucial in the pathogenesis of osteoporosis, and elucidation of the underlying mechanism is urgently needed. APPL1, an adaptor protein of the adiponectin receptor, was recently shown to be closely related to bone mass. However, the role of APPL1 in the imbalance of hMSC differentiation in osteoporosis is unclear. Therefore, we aimed to explore the mechanisms by which APPL1 alters hMSCs adipogenic differentiation in osteoporosis. Here, we found that APPL1 expression was downregulated in elderly patients with osteoporosis and in mouse osteoporosis model. APPL1 negatively regulated hMSC adipogenic differentiation in vivo and in vitro. Mechanistically, by enhancing ubiquitination-mediated Myoferlin degradation, downregulated APPL1 expression increased the risk of lysosome dysfunction during hMSCs adipogenic differentiation. Lysosomal dysfunction inhibited autophagy flux by suppressing autophagosome degradation and promoted hMSC differentiation towards the adipocyte lineage. Our findings suggest that APPL1/Myoferlin downregulation promoted hMSCs adipogenic differentiation by inhibiting autophagy flux, further impairing the balance of hMSCs adipogenic and osteogenic differentiation in osteoporosis; the APPL1/ Myoferlin axis may be a promising diagnostic and therapeutic target for osteoporosis.

Ultrafast 3D histological imaging based on a minutes-time scale tissue clearing and multidirectional selective plane illumination microscopy.

Conventional histopathological examinations are time-consuming and labor-intensive, and are insufficient to depict 3D pathological features intuitively. Here we report an ultrafast 3D histological imaging scheme based on optimized selective plane illumination microscopy (mSPIM), a minutes-time scale clearing method (FOCM), and a deep learning-based image enhancement algorithm (SRACNet) to realize histological preparation and imaging of clinical tissues. Our scheme enables 1-minute clearing and fast imaging (up to 900 mm2/min) of 200 µm-thick mouse kidney slices at micron-level resolution. With hematoxylin and eosin analog, we demonstrated the detailed 3D morphological connections between glomeruli and the surrounding tubules, which is difficult to identify in conventional 2D histology. Further, by the preliminary verification on human kidney tissues, this study will provide new, to the best of our knowledge, feasible histological solutions and inspirations in future 3D digital pathology.

Blockchain-Enabled Asynchronous Federated Learning in Edge Computing.

The fast proliferation of edge computing devices brings an increasing growth of data, which directly promotes machine learning (ML) technology development. However, privacy issues during data collection for ML tasks raise extensive concerns. To solve this issue, synchronous federated learning (FL) is proposed, which enables the central servers and end devices to maintain the same ML models by only exchanging model parameters. However, the diversity of computing power and data sizes leads to a significant difference in local training data consumption, and thereby causes the inefficiency of FL. Besides, the centralized processing of FL is vulnerable to single-point failure and poisoning attacks. Motivated by this, we propose an innovative method, federated learning with asynchronous convergence (FedAC) considering a staleness coefficient, while using a blockchain network instead of the classic central server to aggregate the global model. It avoids real-world issues such as interruption by abnormal local device training failure, dedicated attacks, etc. By comparing with the baseline models, we implement the proposed method on a real-world dataset, MNIST, and achieve accuracy rates of 98.96% and 95.84% in both horizontal and vertical FL modes, respectively. Extensive evaluation results show that FedAC outperforms most existing models.

Novel [1,2,3]triazolo[4,5-d]pyrimidine derivatives containing hydrazone fragment as potent and selective anticancer agents.

In this paper, based on molecular hybridization, a series of [1,2,3]triazolo[4,5-d]pyrimidine derivatives containing hydrazine was synthesized and their antiproliferative activities against 5 cancer cell lines (MGC-803, PC3, PC9, EC9706 and SMMC-7721) were evaluated. We found that most of them exhibited obvious growth inhibition effects on these tested cancer cells, especially compound 34 on PC3 cells (IC50 = 26.25 ± 0.28 nM). Meanwhile, compound 34 displayed best selectivity on PC3, compared with the other cancer cell lines, as well as excellent selectivity towards normal cell lines (Het-1A, L02 and GES-1). Further investigations demonstrated that 34 could significantly inhibit PC3 cells' colony formation, increase cellular ROS content, suppress EGFR expression and induce apoptosis. Our findings indicate that 34 may serve as a novel lead compound for the discovery of more triazolopyrimidine derivatives with improved anticancer potency and selectivity.

Association Between Vitamin D Level and Clinical Outcomes of Assisted Reproductive Treatment: A Systematic Review and Dose-Response Meta-Analysis.

The investigation about association between vitamin D level and clinical outcomes of assisted reproductive treatment showed various outcomes. This study aimed to review the correlation between vitamin D and outcomes of assisted reproductive treatment. The search was registered on the PROSPERO database (CRD42023458040). PubMed, Embase, Medline, ClinicalTrials.gov, and Cochrane databases were searched up to July 2023. Twenty-three observational studies were selected for meta-analysis. Comparing groups with deficient and 'insufficient + sufficient' vitamin D level, meta-analysis showed positive correlation between clinical pregnancy rate and vitamin D (OR 0.81, 95%CI: 0.70, 0.95, P = 0.0001). Comparing groups with 'deficient + insufficient' and sufficient vitamin D level, meta-analysis showed positive correlation between vitamin D and clinical pregnancy rate (OR 0.71, 95%CI: 0.55, 0.91, P = 0.006), vitamin D and live birth rate (OR 0.69, 95%CI: 0.54, 0.89, P = 0.003). Subgroup analysis did not show the source of high heterogeneity. No correlation was found in biochemical pregnancy rate, ongoing pregnancy rate, miscarriage rate and implantation rate. In dose-response meta-analysis, a nonlinear association was found between vitamin D levels and outcomes when levels are below approximately 24 ng/L. The study shows that vitamin D level is associated with clinical pregnancy rate and live birth rate. Low vitamin D level does not influence biochemical pregnancy rate, ongoing pregnancy rate, miscarriage rate and implantation rate. Furthermore, 24 ng/L may be a possible threshold of vitamin D concentration in assisted reproduction therapy.

Nano-Titanium Oxide-Coated Carbon Nanotubes for Photothermal Therapy in the Treatment of Colorectal Cancer.

Recent studies have shown that carbon nanotubes display good potential in tumor photothermal therapy. In this study, we aimed to investigate the therapeutic potential of nano-titanium oxide-coated multi-walled carbon nanotubes (MCNTs) against colorectal cancer (CRC). Firstly, we modified TiO2 nanosheets on the surface of MCNTs to obtain nano-TiO2-coated MCNTs. Next, we conducted cell compatibility validation on nano-TiO2-coated MCNTs, and found that nano-TiO2-coated MCNTs were safe within a certain concentration range (0∼200 µg/ml). Interestingly, nano-TiO2-coated MCNTs displayed a good killing effect in CRC cells under NIR laser irradiation. Subsequently, nano-TiO2-coated MCNTs markedly promoted the proapoptotic effects of NIR laser irradiation, and significantly inhibited the expression of cell cycle proteins CCNA1 and CCND1 in CRC cells under NIR laser irradiation, which indicated that nano-TiO2-coated MCNTs exerted anti-CRC effects under NIR laser irradiation by regulating cell apoptosis and cell cycle. Furthermore, nano-TiO2-coated MCNTs accelerated inhibitory effects on the AKT signaling pathway under NIR laser irradiation. Finally, a cell line-derived xenograft model was established, and the results showed that nano-TiO2-coated MCNTs significantly exhibited superior tumor-killing ability under NIR laser irradiation in vivo. Collectively, our results demonstrate that nano-TiO2-coated MCNTs with NIR laser irradiation may serve as an effective strategy for the treatment of CRC. This article is protected by copyright. All rights reserved.

Impact of preoperative infection on the outcomes of liver transplant recipients: a national propensity score-matched retrospective cohort study in China.

BACKGROUND: Impact of preoperative infection on liver transplantation (LT) needs further investigation. MATERIALS AND METHODS: From 1 January 2015 to 31 December 2022, 24 122 eligible patients receiving LT were enrolled from the China Liver Transplant Registry database. The outcomes of LT were compared after using the propensity score-matched analysis. RESULTS: Compared to the noninfection group, patients in the infection group were more likely to have postoperative effusion, infection, abdominal bleeding, and biliary complications (all P <0.01), and they had shorter 30-day, 90-day survival, and overall survival (all P <0.01). Cox proportional hazards regression analysis revealed that MELD score and cold ischemia time were risk factors for the overall survival in the infection group (both P <0.05). Besides, compared to the nonpulmonary group, patients in the pulmonary group were more likely to have postoperative effusion and infection (both P <0.0001), and less likely to have postoperative abscess and early allograft dysfunction (both P <0.05). Patients in the nonabdominal group also had a higher proportion of postoperative infection than those in the abdominal group ( P <0.05). Furthermore, compared to the number=1 group, patients in the number ≥2 group were more prone to postoperative effusion and infection (both P <0.01), and they also had shorter 30-day and 90-day survival (both P <0.05). CONCLUSION: Preoperative infection can result in a higher incidence of early postoperative complications and shorter survival in liver transplant recipients. The types and number of infection sites will also influence the prognosis of liver transplant recipients.

Trends in research related to fetal therapy from 2012 to 2022: a bibliometric analysis.

Background: The development of prenatal diagnosis technology allows prompt detection of severe fetal diseases. To address adverse factors that threaten fetal survival, fetal therapy came into existence, which aims to preserve the function after birth to a higher degree and improve the quality of life. Objective: To conduct a comprehensive bibliometric analysis of studies on fetal therapy in the past decade and explore the research trends and hotspots in this field. Methods: We conducted a systematic search on the Web of Science Core Collection to retrieve studies related to fetal therapy published from 2012 to 2022. VOSviewer and CiteSpace were used to analyze the key features of studies, including annual output, countries/regions, institutions, authors, references, research hotspots, and frontiers. Results: A total of 9,715 articles were included after eliminating duplicates. The annual distribution of the number of articles showed that the number of articles published in fetal therapy had increased in the past decade. Countries and institutions showed that fetal therapy is more mature in the United States. Author analysis showed the core investigators in the field. Keyword analysis showed the clustering and emergence frequency, which helped summarize the research results and frontier hotspots in this field. The cocited references were sorted out to determine the literature with a high ranking of fetal therapy in recent years, and the research trend in recent years was analyzed. Conclusions: This study reveals that countries, institutions, and researchers should promote wider cooperation and establish multicenter research cooperation in fetal therapy research. Moreover, fetal therapy has been gradually explored from traditional surgical treatment to gene therapy and stem cell therapy. In recent years, fetoscopic laser surgery, guideline, and magnetic resonance imaging have become the research hotspots in the field.

Epidemiology, site-specific characteristics and survival of carcinosarcoma: a retrospective study based on SEER database.

OBJECTIVES: Carcinosarcoma (CS) is a rare and biphasic malignancy characterised by a highly invasive biological nature and poor prognosis. This study explored the epidemiology, site-specific characteristics and survival outcome of CS. DESIGN: We conducted a retrospective study in the Surveillance, Epidemiology and End Results (SEER) database (1975-2018) for primary CS. SETTING AND PARTICIPANTS: SEER database includes publicly available information from regional and state cancer registries in the US centres. A total of 5042 CS patients were identified. We selected the top five anatomic CS (uterus, double adnexa, lung, bladder and breast) patients for further analysis. PRIMARY OUTCOME MEASURES: Incidence was estimated by geographical region, age, sex, race, stage and primary site. Trends were calculated using joinpoint regression. The cancer-specific survival (CSS) rate and initial treatment were summarised. RESULTS: Nearly 80% of CS occurred in the uterus and double adnexa, followed by lung, bladder and breast. The elderly and black population presented the highest age-adjusted rate of CS. The rates of distant metastasis in CS progressively increased from 1989 to 2018. Atlanta was the area with the highest incidence at 0.7 per 100 000. Pulmonary and bladder CS more frequently occurred in men and were diagnosed with regional stage. Distant metastasis was mostly found in ovary/fallopian tube CS. Radiotherapy was more commonly applied in uterine CS, while adnexa CS cases were more likely to receive chemotherapy. Multiple treatments were more used in breast CS. Pulmonary CS seemed to suffer worse CSS (median: 9.92 months), for which radiotherapy might not provide survival benefits (HR 0.60, 95% CI 0.42 to 0.86). Compared with the common histological types in each site, CS had the shortest survival. CONCLUSIONS: CS has unique clinical features in each primary site. Substantial prognosis variances exist based on tumour locations. The aggressive course is the common feature in CS at all sites.

Development of phenyltriazole thiol-based derivatives as highly potent inhibitors of DCN1-UBC12 interaction.

Defective in cullin neddylation 1(DCN1) is a co-E3 ligase that is important for cullin neddylation. Dysregulation of DCN1 highly correlates with the development of various cancers. Herein, from the initial high-throughput screening, a novel hit compound 5a containing a phenyltriazole thiol core (IC50 value of 0.95 µM for DCN1-UBC12 interaction) was discovered. Further structure-based optimization leads to the development of SK-464 (IC50 value of 26 nM). We found that SK-464 not only directly bound to DCN1 in vitro, but also engaged cellular DCN1, suppressed the neddylation of cullin3, and hindered the migration and invasion of two DCN1-overexpressed squamous carcinoma cell lines (KYSE70 and H2170). These findings indicate that SK-464 may be a novel lead compound targeting DCN1-UBC12 interaction.

Correction: Construction of PtSe2/Ge heterostructure-based short-wavelength infrared photodetector array for image sensing and optical communication applications.

Correction for 'Construction of PtSe2/Ge heterostructure-based short-wavelength infrared photodetector array for image sensing and optical communication applications' by Yu Lu et al., Nanoscale, 2021, 13, 7606-7612, DOI: 10.1039/D1NR00333J.

Construction of PtSe2/Ge heterostructure-based short-wavelength infrared photodetector array for image sensing and optical communication applications.

In this work, we present the construction of a multilayered PtSe2/Ge heterostructure-based photodetector array comprising 1 × 10 device units operating in the short-wavelength infrared (SWIR) spectrum region. The as-fabricated heterostructures show an obvious photovoltaic effect, providing the devices with the ability to work as self-driven photodetectors. Upon 1550 nm illumination, a typical photodetector exhibits prominent photoresponse performance with the current on/off ratio, responsivity, external quantum efficiency and specific detectivity reaching 1.08 × 103, 766 mA W-1, 61.3% and 1.1 × 1011 Jones, respectively. The device also has a fast response speed with rise/fall times of 54.9 µs/56.6 µs. Thanks to the respectable homogeneity in device performance, the photodetector array can reliably record an image of a "diode symbol" produced by SWIR irradiation. What is more, the photodetector is successfully integrated into a SWIR optical communication system serving as an optical receiver to transmit a text signal. The above results imply a huge possibility of the present heterostructure-based photodetector array for some optoelectronic purposes such as SWIR image sensing and optical communication applications.