3D bioprinting of high-performance hydrogel with in-situ birth of stem cell spheroids.

Digital light processing (DLP)-based bioprinting technology holds immense promise for the advancement of hydrogel constructs in biomedical applications. However, creating high-performance hydrogel constructs with this method is still a challenge, as it requires balancing the physicochemical properties of the matrix while also retaining the cellular activity of the encapsulated cells. Herein, we propose a facile and practical strategy for the 3D bioprinting of high-performance hydrogel constructs through the in-situ birth of stem cell spheroids. The strategy is achieved by loading the cell/dextran microdroplets within gelatin methacryloyl (GelMA) emulsion, where dextran functions as a decoy to capture and aggregate the cells for bioprinting while GelMA enables the mechanical support without losing the structural complexity and fidelity. Post-bioprinting, the leaching of dextran results in a smooth curved surface that promotes in-situ birth of spheroids within hydrogel constructs. This process significant enhances differentiation potential of encapsulated stem cells. As a proof-of-concept, we encapsulate dental pulp stem cells (DPSCs) within hydrogel constructs, showcasing their regenerative capabilities in dentin and neovascular-like structures in vivo. The strategy in our study enables high-performance hydrogel tissue construct fabrication with DLP-based bioprinting, which is anticipated to pave a promising way for diverse biomedical applications.

Galangin Regulates Astrocyte Phenotypes to Ameliorate Cerebral Ischemia-reperfusion Injury by Inhibiting the RhoA/ROCK/LIMK Pathway.

PURPOSE: This study aimed to explore whether Galangin (Gal) could improve cerebral Ischemia- reperfusion (I/R) injury by regulating astrocytes, and clarify its potential molecular mechanism. METHODS: An I/R injury model of rats was established using the Middle Cerebral Artery Occlusion/Reperfusion (MCAO/R) method, followed by the administration of Gal (25, 50, 100 mg/kg) via gavage for 14 consecutive days. Besides, astrocytes were isolated from the rats to construct an Oxygen-Glucose Deprivation/Re-oxygenation (OGD/R) cell model, with treatments of Gal or the Ras homolog gene family member A (RhoA)/Rho-associated Coiled-coil containing protein Kinase (ROCK) inhibitor Y-27632. Subsequently, the severity of nerve injury was assessed using the modified Neurological Severity Score (mNSS) test; behavioral disorders in I/R rats were observed through the open field and ladder-climbing tests. Pathological damages and neuron survival in the peri-infarct zone were examined by hematoxylin and eosin staining and NeuN staining, respectively. Additionally, immunofluorescence staining was employed to determine astrocyte polarization and TUNEL staining was carried out to measure the level of cell apoptosis; also, western blot was performed to detect the expression of proteins related to the RhoA/ROCK/LIM domain Kinase (LIMK) pathway. RESULTS: Gal significantly ameliorated the neurological and motor dysfunctions caused by I/R in rats, reduced pathological damage in the peri-infarct zone, and promoted neuronal survival. Additionally, Gal increased the number of A2 astrocytes, while it decreased the number of A1 astrocytes. In vitro experiments revealed that the effect of Gal was consistent with that of Y-27632. Additionally, Gal significantly enhanced the survival of OGD/R cells, increased the number of A2 astrocytes, and inhibited the expression of proteins associated with the RhoA/ROCK pathway. CONCLUSION: Gal could reduce the level of apoptosis, promote the polarization of A2 astrocytes, and improve cerebral I/R injury, and its mechanism may be related to the inhibition of the RhoA/ROCK pathway.

Cascade contour-enhanced panoptic segmentation for robotic vision perception.

Panoptic segmentation plays a crucial role in enabling robots to comprehend their surroundings, providing fine-grained scene understanding information for robots' intelligent tasks. Although existing methods have made some progress, they are prone to fail in areas with weak textures, small objects, etc. Inspired by biological vision research, we propose a cascaded contour-enhanced panoptic segmentation network called CCPSNet, attempting to enhance the discriminability of instances through structural knowledge. To acquire the scene structure, a cascade contour detection stream is designed, which extracts comprehensive scene contours using channel regulation structural perception module and coarse-to-fine cascade strategy. Furthermore, the contour-guided multi-scale feature enhancement stream is developed to boost the discrimination ability for small objects and weak textures. The stream integrates contour information and multi-scale context features through structural-aware feature modulation module and inverse aggregation technique. Experimental results show that our method improves accuracy on the Cityscapes (61.2 PQ) and COCO (43.5 PQ) datasets while also demonstrating robustness in challenging simulated real-world complex scenarios faced by robots, such as dirty cameras and rainy conditions. The proposed network promises to help the robot perceive the real scene. In future work, an unsupervised training strategy for the network could be explored to reduce the training cost.

Low pelvic incidence as a risk factor for vertebral recollapse after percutaneous vertebroplasty in the thoracolumbar region.

BACKGROUND CONTEXT: Percutaneous vertebroplasty (PVP) is an effective procedure for treatment of osteoporotic vertebral compression fractures (OVCFs). Recollapse of the cemented vertebrae is not unusual and the thoracolumbar junction is the most common region. Nevertheless, not all patients suffering from OVCFs in this region develop recollapse after PVP. PURPOSE: The aim of this study was to investigate possible risk factors related to recollapse of the cemented vertebrae in the thoracolumbar region. STUDY DESIGN/SETTING: Retrospective study. PATIENT SAMPLE: A total of 161 patients undergoing PVP. OUTCOME MEASURES: Clinical outcomes were assessed using Visual Analog Scale (VAS) scores. Radiographic parameters included pelvic incidence (PI), thoracolumbar kyphosis (TLK), kyphotic angle, compression rate, reduction rate, and occurrence of intravertebral cleft (IVC). METHODS: Patients were divided into the recollapse group and control group. Patient characteristics, clinical and radiographic parameters were compared between the two groups. Univariate and multivariate logistic regression were used to evaluate the potential risk factors for recollapse. The correlations between the variables were examined. A receiver operating characteristic curve of PI was constructed to discriminate between patients with and without recollapse. RESULTS: There were no significant differences in patient characteristics between the two groups except for bone mineral density (BMD). Occurrence rate of IVC was significantly higher in the recollapse group. VAS scores were significantly decreased after PVP. At last follow-up, they were increased in the recollapse group and maintained in the control group. PI was significantly lower in the recollapse group than in the control group. The univariate logistic regression found four possible risk factors for recollapse, including low PI, IVC, low BMD, and high TLK. Further multivariate logistic regression eliminated high TLK from them. The collinear analysis showed low tolerance and high variance inflation factor for preoperative and postoperative TLK, but not for PI, IVC and BMD. PI was a good predictor of recollapse, and the optimal cut-off value was 43°. The magnitude of preoperative and postoperative TLK was significantly correlated with the value of PI. CONCLUSIONS: Recollapse of the cemented vertebrae in the thoracolumbar region was related to low PI, IVC and low BMD. PI less than 43° was a good predictor of recollapse. TLK was dependent on PI and not a risk factor for recollapse. In addition to PVP, patients with low PI, IVC and low BMD may require personalized interventions such as combined internal fixation and trunk orthoses.

High-Order Topological Pumping on a Superconducting Quantum Processor.

High-order topological phases of matter refer to the systems of n-dimensional bulk with the topology of m-th order, exhibiting (n-m)-dimensional boundary modes and can be characterized by topological pumping. Here, we experimentally demonstrate two types of second-order topological pumps, forming four 0-dimensional corner localized states on a 4×4 square lattice array of 16 superconducting qubits. The initial ground state of the system at half-filling, as a product of four identical entangled 4-qubit states, is prepared using an adiabatic scheme. During the pumping procedure, we adiabatically modulate the superlattice Bose-Hubbard Hamiltonian by precisely controlling both the hopping strengths and on-site potentials. At the half pumping period, the system evolves to a corner-localized state in a quadrupole configuration. The robustness of the second-order topological pump is also investigated by introducing different on-site disorder. Our Letter studies the topological properties of high-order topological phases from the dynamical transport picture using superconducting qubits, which would inspire further research on high-order topological phases.

Clinical application values of a novel synthetic training simulator for bulbar urethral anastomosis.

Purpose: This study aimed to report a newly developed, high-fidelity synthetic simulator to simulate excision and primary anastomotic (EPA) bulbar urethroplasty and its clinical use for new practitioners in shortening the learning curve. Material and Methods: The bulbar urethral anastomosis simulator consists of several standardized components created according to the actual size of the male patient. Interns, novice residents, and fellows inexperienced with urethral reconstruction (n = 10, 5, 5) from different medical centres were invited to participate in the training programme. Two reconstructive urology experts monitored each practice. Following the training, three kinds of validity testing were used to assess the simulator: face, content, and construct. In the intern group, the task performance in the first five training sessions and the last five training ones were compared using a self-control approach. In the resident and fellow group, the real surgical data, including estimated blood loss, operative duration, and 6-month post-operative success rate of trainees after training, are plotted, which are compared with that of reconstructive urology experts (n = 5) included retrospectively to study the effectiveness of the simulator in shortening the learning curve. Results: The overall mean satisfaction rate for the simulators was inspiring and evaluated by experts. In the intern group, significant improvement can be achieved through 10 training sessions (p < 0.05). In clinical practice, the intraoperative indicators and surgical success rate of both the training groups showed the tendency to close or even better than those in the expert group. In terms of the learning curve, training groups performed better compared with experts in the early stages of their careers. Conclusions: In conclusion, this synthetic training simulator for bulbar urethral anastomosis is novel, effective, and convenient for beginners of different groups. The training course can bridge the gap between preclinical use and actual surgery via this simulator.

LncRNA PCBP1-AS1 suppresses cell growth in oral squamous cell carcinoma by targeting miR-34c-5p/ZFP36 axis.

Oral squamous cell carcinoma (OSCC) is the most frequently diagnosed oral malignancy and poses a great threat to public health. According to bioinformatics analysis, long noncoding RNA PCBP1-AS1 is downregulated in OSCC. In this work, the functions and mechanism of PCBP1-AS1 in OSCC were further investigated. PCBP1-AS1 expression in OSCC cells was measured by quantitative polymerase chain reaction. Cell viability and proliferation were detected using CCK-8 assays and colony-forming assays. TUNEL assays as well as flow cytometry analyses were carried out to detect OSCC cell apoptosis. Binding relationship between PCBP1-AS1 and miR-34c-5p or that between miR-34c-5p and ZFP36 in OSCC cells was identified using RNA immunoprecipitation assays, RNA pulldown assays, and luciferase reporter assays. Experimental results revealed that PCBP1-AS1 was downregulated in OSCC cells. PCBP1-AS1 overexpression hampered cell proliferation and enhanced cell apoptosis in OSCC. PCBP1-AS1 interacted with miR-34c-5p in OSCC and negatively regulated miR-34c-5p. ZFP36 3'untranslated region was targeted by miR-34c-5p. PCBP1-AS1 positively regulated ZFP36 expression. ZFP36 silencing abrogated the suppressive impact of PCBP1-AS1 on OSCC cell growth. In summary, PCBP1-AS1 suppresses cell growth in OSCC by upregulating ZFP36 through interaction with miR-34c-5p.

Clinical value of a radiomics model based on machine learning for the prediction of prostate cancer.

OBJECTIVE: Radiomics models have demonstrated good performance for the diagnosis and evaluation of prostate cancer (PCa). However, there are currently no validated imaging models that can predict PCa or clinically significant prostate cancer (csPCa). Therefore, we aimed to identify the best such models for the prediction of PCa and csPCa. METHODS: We performed a retrospective study of 942 patients with suspected PCa before they underwent prostate biopsy. MRI data were collected to manually segment suspicious regions of the tumor layer-by-layer. We then constructed models using the extracted imaging features. Finally, the clinical value of the models was evaluated. RESULTS: A diffusion-weighted imaging (DWI) plus apparent diffusion coefficient (ADC) random-forest model and a T2-weighted imaging plus ADC and DWI multilayer perceptron model were the best models for the prediction of PCa and csPCa, respectively. Areas under the curve (AUCs) of 0.942 and 0.999, respectively, were obtained for a training set. Internal validation yielded AUCs of 0.894 and 0.605, and external validation yielded AUCs of 0.732 and 0.623. CONCLUSION: Models based on machine learning comprising radiomic features and clinical indicators showed good predictive efficiency for PCa and csPCa. These findings demonstrate the utility of radiomic models for clinical decision-making.

Impact of butyric acid modification on the structural and functional properties of rice starch.

Rice is a food with a high starch content, comprising over 75% of its composition. However, prolonged and excessive consumption of this cereal may lead to elevated blood glucose levels, which can increase the risk of obesity, type 2 diabetes, and cardiovascular disease. Butyric acid (BA), the primary energy source for colonic epithelial cells, exhibits the highest utilization rate among short-chain fatty acids, underscoring its importance for human health. In this study, rice starch butyrate (RSB) samples were synthesized using the aqueous phase process, with broken rice starch (RS) and butyric anhydride serving as the substrate. RSB samples with different degrees of substitution (DS) were produced by modulating the addition amount of butyric anhydride. The crystal structures, morphology of starch granules, pasting properties, thermal stability, and in vitro digestibilities of the RSB were investigated and compared with those of native rice starch. Fourier transform infrared (FTIR) spectroscopy confirmed the successful incorporation of butyryl into the starch molecules. With the increase in DS, the roughness of the RSB material's surface gradually increased, leading to the deterioration of the smooth structure on certain surfaces, which resulted in the appearance of cracks and collapses. Additionally, the crystallinity diminished from 24.77% to 7.41% with increasing DS. Concurrently, in vitro digestive characterisation revealed that the percentage of resistant starch increased from 24.33% to 47.72%. Thus, this study can provide a theoretical basis for the development of novel products of amyl butyrate.

A Novel Hypersonic Target Trajectory Estimation Method Based on Long Short-Term Memory and a Multi-Head Attention Mechanism.

To address the complex maneuvering characteristics of hypersonic targets in adjacent space, this paper proposes an LSTM trajectory estimation method combined with the attention mechanism and optimizes the model from the information-theoretic perspective. The method captures the target dynamics by using the temporal processing capability of LSTM, and at the same time improves the efficiency of information utilization through the attention mechanism to achieve accurate prediction. First, a target dynamics model is constructed to clarify the motion behavior parameters. Subsequently, an LSTM model incorporating the attention mechanism is designed, which enables the model to automatically focus on key information fragments in the historical trajectory. In model training, information redundancy is reduced, and information validity is improved through feature selection and data preprocessing. Eventually, the model achieves accurate prediction of hypersonic target trajectories with limited computational resources. The experimental results show that the method performs well in complex dynamic environments with improved prediction accuracy and robustness, reflecting the potential of information theory principles in optimizing the trajectory prediction model.

Optimizing CLM4.5 simulations of the active layer: The role of gravel in Tibetan Plateau permafrost.

Gravel is widely distributed in soils of the Tibetan Plateau (TP), where permafrost also occurs over approximately half of the total area. Gravel has different thermal and hydrological properties to those of fine-grained soils, which may have a considerable impact on hydrothermal transport within TP soils. However, few land models consider gravel. Here, we incorporated the thermal and hydraulic properties of gravel into the Community Land Model and explored the effect of differing gravel contents on land surface processes. We found that all parameters affecting soil hydrothermal transport were sensitive to gravel content. Soil thermal and hydraulic conductivities increased with increasing gravel content, ultimately leading to variations in soil temperature, soil water content, and radiation fluxes with changing gravel content. Soil containing gravel exhibited higher infiltration and greater total water storage capacities. We also compared different model schemes in an attempt to improve the simulation of active layers in permafrost regions with high gravel content on the TP. The scheme in which both gravel and freeze-thaw parameterizations were applied (i.e., SP3) improved both the latent heat flux and ground heat flux transfer. The SP3 scheme performed best in terms of soil temperature and soil moisture simulations at both the Nagqu and Madoi field stations, demonstrating a particular ability to better characterize soil moisture processes as a function of temperature during soil freezing and thawing.

Comparative Transcriptomic Analysis Reveals Domestication and Improvement Patterns of Broomcorn Millet (Panicum miliaceum L.).

Broomcorn millet (Panicum miliaceum L.) is one of the earliest crops, domesticated nearly 8000 years ago in northern China. It gradually spread across the entire Eurasian continent, as well as to America and Africa, with recent improvement in various reproductive and vegetative traits. To identify the genes that were selected during the domestication and improvement processes, we performed a comparative transcriptome analysis based on wild types, landraces, and improved cultivars of broomcorn millet at both seeding and filling stages. The variations in gene expression patterns between wild types and landraces and between landraces and improved cultivars were further evaluated to explore the molecular mechanisms underlying the domestication and improvement of broomcorn millet. A total of 2155 and 3033 candidate genes involved in domestication and a total of 84 and 180 candidate genes related to improvement were identified at seedling and filling stages of broomcorn millet, respectively. The annotation results suggested that the genes related to metabolites, stress resistance, and plant hormones were widely selected during both domestication and improvement processes, while some genes were exclusively selected in either domestication or improvement stages, with higher selection pressure detected in the domestication process. Furthermore, some domestication- and improvement-related genes involved in stress resistance either lost their functions or reduced their expression levels due to the trade-offs between stress resistance and productivity. This study provided novel genetic materials for further molecular breeding of broomcorn millet varieties with improved agronomic traits.

Exosomes derived from mucoperiosteum Krt14+Ctsk+ cells promote bone regeneration by coupling enhanced osteogenesis and angiogenesis.

Repair of large bone defects is a sophisticated physiological process involving the meticulous orchestration of cell activation, proliferation, and differentiation. Cellular interactions between different cell types are paramount for successful bone regeneration, making it a challenging yet fascinating area of research and clinical practice. With increasing evidence underscoring the essential role of exosomes in facilitating intercellular and cell-microenvironment communication, they have emerged as an encouraging therapeutic strategy to promote bone repair due to their non-immunogenicity, diverse sources, and potent bioactivity. In this study, we characterized a distinctive population of Krt14+Ctsk+ cells from the orbital mucoperiosteum. In vitro experiments confirmed that exosomes from Krt14+Ctsk+ cells dramatically boosted the capacities of human umbilical vein endothelial cells (HUVECs) to proliferate, migrate, and induce angiogenesis. Additionally, the exosomes notably elevated the expression of osteogenic markers, thereby indicating their potential to augment osteogenic capabilities. Furthermore, in vivo experiments utilizing a rat calvarial defect model verified that exosome-loaded sodium alginate (SA) hydrogels accelerated local vascularized bone regeneration within the defective regions. Collectively, these findings suggest that exosomes secreted by Krt14+Ctsk+ cells offer an innovative method to accelerate bone repair via coupling enhanced osteogenesis and angiogenesis, highlighting the therapeutic potential in bone repair.

Identification of a novel intronic variant in COL4A2 gene associated with fetal severe cerebral encephalomalacia and subdural hemorrhage.

BACKGROUND: Genetic variants in COL4A2 are less common than those of COL4A1 and their fetal clinical phenotype has not been well described to date. We present a fetus from China with an intronic variant in COL4A2 associated with a prenatal diagnosis of severe cerebral encephalomalacia and subdural hemorrhage. METHODS: Whole exome sequencing (WES) was applied to screen potential genetic causes. Bioinformatic analysis was performed to predict the pathogenicity of the variant. In in vitro experiment, the minigene assays were performed to assess the variant's effect. RESULTS: In this proband, we observed ventriculomegaly, subdural hemorrhage, and extensive encephalomalacia that initially suggested cerebral hypoxic-ischemic and/or hemorrhagic lesions. WES identified a de novo heterozygous variant c.549 + 5G > A in COL4A2 gene. This novel variant leads to the skipping of exon 8, which induces the loss of 24 native amino acids, resulting in a shortened COL4A2 protein (p.Pro161_Gly184del). CONCLUSION: Our study demonstrated that c.549 + 5G > A in COL4A2 gene is a disease-causing variant by aberrant splicing. This finding enriches the variant spectrum of COL4A2 gene, which not only improves the understanding of the fetal neurological disorders associated with hypoxic-ischemic and hemorrhagic lesions from a clinical perspective but also provides guidance on genetic diagnosis and counseling.

An integrative pan-cancer analysis of MASP1 and the potential clinical implications for the tumor immune microenvironment.

Mannose-binding lectin-associated serine protease 1 (MASP1) plays a crucial role in the complement lectin pathway and the mediation of immune responses. However, comprehensive research on MASP1 across various cancer types has not been performed to date. This study aimed to evaluate the significance of MASP1 in pan-cancer. The Cancer Genome Atlas (TCGA), UCSC Xena and Genotype Tissue Expression (GTEx) databases were used to evaluate the expression profiles, genomic features, prognostic relevance, and immune microenvironment associations of MASP1 across 33 cancer types. We observed significant dysregulation of MASP1 expression in multiple cancers, with strong associations between MASP1 expression levels and diagnostic value as well as patient prognosis. Mechanistic insights revealed significant correlations between MASP1 levels and various immunological and genomic factors, including tumor-infiltrating immune cells (TIICs), immune-related genes, mismatch repair (MMR), tumor mutation burden (TMB), and microsatellite instability (MSI), highlighting a critical regulatory function of MASP1 within the tumor immune microenvironment (TIME). In vitro and in vivo experiments demonstrated that MASP1 expression was markedly decreased in liver hepatocellular carcinoma (LIHC). Moreover, the overexpression of MASP1 in hepatocellular carcinoma (HCC) cell lines significantly inhibited their proliferation, invasion and migration. In conclusion, MASP1 exhibits differential expression in the pan-cancer analyses and might play an important role in TIME. MASP1 is a promising prognostic biomarker and a potential target for immunological research, particularly in LIHC.

Genetic diseases are not necessarily inherited: suggestion on its Chinese translation.

From Mendel's discovery of the basic laws of genetics in 1865 to the widespread application of genomics in medicine today, medical genetics has made enormous progress, and the concept of genetic diseases has also been evolved. In 1972, the World Health Organization (WHO) expert group began to use "Genetic Disease" to define hereditary diseases, while early Chinese genetics textbooks used "inferior inheritance", and later introduced terms such as "Genetic Disease" and "Inherited Disease". In the early days, it was generally believed that genetic diseases were inherited from ancestors. However, research in recent years has found that genetic diseases are not necessarily inherited, and some diseases are actually caused by de novo mutations in the offspring. Although the occurrence of this type of genetic disease is related to genetic factors, it is not inherited from ancestors. If we still use "Inherited Disease" or "Hereditary Disease" to describe it, it is not accurate enough. In order to further standardize the translation and use of the concept of "Genetic Disease", this article briefly reviews its development process in both English and Chinese literature, discusses the difference between different Chinese translations, and provides guidance and suggestions for scientifically and accurately describing genetic diseases in Chinese, with a view to promote efficient exchange and cooperation in the field of medical genetics.

Characterization of Vortex Vein Drainage System in Healthy Individuals Imaged by Ultra-Widefield Optical Coherence Tomography Angiography.

Purpose: The purpose of this study was to investigate the choroidal characteristics of vortex vein (VV) drainage systems in healthy individuals using ultra-widefield optical coherence tomography angiography. Methods: The mean choroidal thickness (ChT) and choroidal vascularity index (CVI) of each VV quadrant (24 × 20 mm2 scan mode; superotemporal [ST], superonasal [SN], inferonasal [IN], and inferotemporal [IT] quadrants) were calculated. Furthermore, intervortex venous anastomosis (IVA) was classified into temporal, superior, inferior, and nasal types. Results: A total of 207 healthy eyes were analyzed to find that the ST quadrant had the thickest choroidal layer and highest CVI (all P < 0.05). Among the four VV drainage quadrants, the mean ChT and CVI decreased in the sequence of ST, SN, IT, and IN (all P < 0.05). Moreover, men had a higher CVI than women in all VV quadrants (all P < 0.05). IVA was observed in all VV quadrants of 91 eyes (43.96%), and in the macular region of 33 eyes (15.94%). Conclusions: The ST drainage system was identified as the preferred VV drainage route in healthy eyes. Among the four VV drainage quadrants, the drainage system adhered to the ST-SN-IT-IN order of descending perfusion. Furthermore, age- and sex-related differences were noted in the choroidal VV drainage systems of healthy eyes. Additionally, almost half of the healthy eyes had IVA in their choroidal vessel networks. Translational Relevance: The VV drainage system may be considered a novel imaging biomarker for ocular diseases.

The efficacy and safety of laparoscopic common bile duct exploration with primary duct closure for cholecystolithiasis combined with choledocholithiasis.

Cholecystolithiasis combined with choledocholithiasis represents a prevalent disease. At present, regarding the management of the common bile duct (CBD), T-tube drainage (TTD) and primary duct closure (PDC) emerge as two prominent approaches for biliary tract repair after laparoscopic CBD exploration (LCBDE). Here, retrospective analysis was conducted on the clinical records of 157 patients who underwent LCBDE at our hospital between January 2019 and January 2022. All patients were categorized into the PDC group or the TTD group based on the chosen CBD treatment approach. A comparative assessment was made across demographic factors, preoperative conditions, surgical particulars, and postoperative complications. The results showed that PDC is recommended for patients with a limited number of small stones, particularly when the CBD is in the 10-15 mm diameter range.

Tilorone mitigates the propagation of α-synucleinopathy in a midbrain-like organoid model.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative condition characterized by the loss of dopaminergic neurons and the accumulation of Lewy-body protein aggregates containing misfolded α-synuclein (α-syn) in a phosphorylated form. The lack of effective models for drug screens has hindered drug development studies for PD. However, the recent development of in vitro brain-like organoids provides a new opportunity for evaluating therapeutic agents to slow the progression of this chronic disease. METHODS: In this study, we used a 3D brain-like organoid model to investigate the potential of repurposing Tilorone, an anti-viral drug, for impeding the propagation of α-synucleinopathy. We assessed the effect of Tilorone on the uptake of fluorescently labeled α-syn preformed fibrils (sPFF) and sPFF-induced apoptosis using confocal microscopy. We also examined Tilorone's impact on the phosphorylation of endogenous α-syn induced by pathogenic sPFF by immunoblotting midbrain-like organoid extracts. Additionally, quantitative RT-PCR and proteomic profiling of sPFF-treated organoids were conducted to evaluate the global impact of Tilorone treatment on tissue homeostasis in the 3D organoid model. RESULTS: Tilorone inhibits the uptake of sPFF in both mouse primary neurons and human midbrain-like organoids. Tilorone also reduces the phosphorylation of endogenous α-syn induced by pathogenic α-syn fibrils and mitigates α-syn fibril-induced apoptosis in midbrain-like organoids. Proteomic profiling of fibril-treated organoids reveals substantial alterations in lipid homeostasis by α-syn fibrils, which are reversed by Tilorone treatment. Given its safety profile in clinics, Tilorone may be further developed as a therapeutic intervention to alleviate the propagation of synucleinopathy in PD patients.