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OBJECTIVE: This study explored the mediating role of perceptions of discrimination and loneliness on the relationship between physical exercise and subjective well-being in rural left-behind children. METHODS: A package of surveys were administered to junior high school students and senior primary school students (n = 592) in the countryside, which including the scale of the Physical Activity Behavior Scale, Subjective Well-Being Scale, Perceived Discrimination Scale, and Loneliness Scale. Structural Equation Modeling and Bootstrap were used to analyze the data to investigate the chain mediating effect of perceived discrimination and loneliness. RESULTS: (1) There was a positive correlation between physical activity and subjective well-being, and the direct prediction of subjective well-being was significant. (2) Physical activity negatively predicted perceptions of discrimination, and perceptions of discrimination positively predicted loneliness and negatively predicted subjective well-being, and loneliness could negatively predict subjective well-being. (3) Perception of discrimination and loneliness significantly mediated the relationship between physical activity and subjective well-being. The mediating effect consisted of indirect effects generated by 2 paths, one was that physical exercise indirectly affected subjective well-being by affecting discrimination perception, and the other was that physical exercise further acted on subjective well-being through the chain mediating effect from discrimination perception to loneliness. CONCLUSION: Physical exercise can directly affect the subjective well-being of rural left-behind children. Physical exercise can indirectly affect left-behind children's subjective well-being through discrimination perceptions, and it can also indirectly affect left-behind children's subjective well-being through the chain mediating effect of discrimination perceptions and loneliness.
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Ejercicio Físico , Soledad , Población Rural , Humanos , Soledad/psicología , Masculino , Femenino , Niño , Ejercicio Físico/psicología , Adolescente , Estudiantes/psicología , Satisfacción Personal , China , Encuestas y CuestionariosRESUMEN
Proline is widely known as the only proteogenic amino acid with a secondary amine. In addition to its crucial role in protein structure, the secondary amino acid modulates neurotransmission and regulates the kinetics of signaling proteins. To understand the structural basis of proline import, we solved the structure of the proline transporter SIT1 in complex with the COVID-19 viral receptor ACE2 by cryo-electron microscopy. The structure of pipecolate-bound SIT1 reveals the specific sequence requirements for proline transport in the SLC6 family and how this protein excludes amino acids with extended side chains. By comparing apo and substrate-bound SIT1 states, we also identify the structural changes that link substrate release and opening of the cytoplasmic gate and provide an explanation for how a missense mutation in the transporter causes iminoglycinuria.
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Enzima Convertidora de Angiotensina 2 , Microscopía por Crioelectrón , Prolina , SARS-CoV-2 , Enzima Convertidora de Angiotensina 2/metabolismo , Enzima Convertidora de Angiotensina 2/química , Enzima Convertidora de Angiotensina 2/genética , Prolina/metabolismo , Humanos , SARS-CoV-2/metabolismo , SARS-CoV-2/genética , COVID-19/virología , COVID-19/metabolismo , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Sistemas de Transporte de Aminoácidos Neutros/genética , Sistemas de Transporte de Aminoácidos Neutros/química , Modelos MolecularesRESUMEN
BACKGROUND: Lumbar spondylolysis is a bone defect in the pars interarticularis of the lumbar vertebral, which is a common cause of low back pain in youth. Although non-surgical treatment is a mainstream option, surgery is necessary for patients with persistent symptoms. Buck technique is widely used as a classical direct repair technique, but it cannot achieve reduction of low-grade spondylolisthesis and reconstruction of lumbosacral sagittal balance. We have described a novel surgical procedure based on Buck technique with temporary intersegmental pedicle screw fixation, and report a series of clinical outcomes in 5 patients to provide a reference for the clinical treatment of young lumbar spondylolysis. METHODS: Five young patients with symptomatic lumbar spondylolysis with a mean age of 19.20 ± 5.41 years underwent surgical treatment after an average of 7.60 ± 1.52 months of failure to respond to conservative treatment, using a new surgical procedure based on Buck technique combined with temporary intersegmental pedicle screw fixation. RESULTS: Five patients were successfully operated without serious complications such as nerve and vascular injury. The average operation time was 109.00 ± 7.42 min, the interpretative average blood loss was 148.00 ± 31.14 ml, and the average fusion time was 11.20 ± 1.64 months. All patients were followed up for 2 years after surgery, and the visual analogue score (VAS) of low back pain and Oswestry disability index (ODI) scores were significantly improved compared with those before surgery, and the Henderson's evaluation were rated excellent or good. After the removal of the internal fixation, it was observed that temporary intersegmental fixation could repair the isthmus, reduce lumbar spondylolisthesis, and reconstruct the sagittal balance of the lumbosacral vertebrae while preserving lumbar motion and preventing intervertebral disc degeneration. Postoperative MRI indicated the Pfirrmann classification of the affected discs: 1 case from grade III to grade II, 3 cases from grade II to grade I, and 1 case remained grade II. CONCLUSIONS: Buck technique supplemented by temporary intersegmental pedicle screw fixation is a highly applicable and effective method for the treatment of adolescent lumbar spondylolysis. The isthmic fusion is accurate, and temporary intersegmental fixation can effectively prevent disc degeneration and reconstruct the sagittal balance of lumbosacral vertebra.
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Vértebras Lumbares , Tornillos Pediculares , Espondilólisis , Humanos , Espondilólisis/cirugía , Espondilólisis/diagnóstico por imagen , Vértebras Lumbares/cirugía , Vértebras Lumbares/diagnóstico por imagen , Adolescente , Masculino , Femenino , Adulto Joven , Adulto , Resultado del Tratamiento , Fusión Vertebral/métodos , Fusión Vertebral/instrumentación , Estudios de Seguimiento , Dolor de la Región Lumbar/cirugía , Dolor de la Región Lumbar/etiologíaRESUMEN
Two pore channels are lysosomal cation channels with crucial roles in tumor angiogenesis and viral release from endosomes. Inhibition of the two-pore channel 2 (TPC2) has emerged as potential therapeutic strategy for the treatment of cancers and viral infections, including Ebola and COVID-19. Here, we demonstrate that antagonist SG-094, a synthetic analog of the Chinese alkaloid medicine tetrandrine with increased potency and reduced toxicity, induces asymmetrical structural changes leading to a single binding pocket at only one intersubunit interface within the asymmetrical dimer. Supported by functional characterization of mutants by Ca2+ imaging and patch clamp experiments, we identify key residues in S1 and S4 involved in compound binding to the voltage sensing domain II. SG-094 arrests IIS4 in a downward shifted state which prevents pore opening via the IIS4/S5 linker, hence resembling gating modifiers of canonical VGICs. These findings may guide the rational development of new therapeutics antagonizing TPC2 activity.
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Canales de Calcio , Humanos , Canales de Calcio/metabolismo , Canales de Calcio/química , Sitios de Unión , Lisosomas/metabolismo , Células HEK293 , Unión Proteica , Calcio/metabolismo , Bloqueadores de los Canales de Calcio/farmacología , Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/metabolismo , Modelos Moleculares , Canales de Dos PorosRESUMEN
Smartphone location data provide the most direct field disaster distribution data with low cost and high coverage. The large-scale continuous sampling of mobile device location data provides a new way to estimate the distribution of disasters with high temporal-spatial resolution. On September 5, 2022, a magnitude 6.8 earthquake struck Luding County, Sichuan Province, China. We quantitatively analyzed the Ms 6.8 earthquake from both temporal and geographic dimensions by combining 1,806,100 smartphone location records and 4,856 spatial grid locations collected through communication big data with the smartphone data under 24-hour continuous positioning. In this study, the deviation of multidimensional mobile terminal location data is estimated, and a methodology to estimate the distribution of out-of-service communication base stations in the disaster area by excluding micro error data users is explored. Finally, the mathematical relationship between the seismic intensity and the corresponding out-of-service rate of communication base stations is established, which provides a new technical concept and means for the rapid assessment of post-earthquake disaster distribution.
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Macrodatos , Terremotos , China , Humanos , Teléfono Inteligente , DesastresRESUMEN
Introduction: Acne detection is critical in dermatology, focusing on quality control of acne imagery, precise segmentation, and grading. Traditional research has been limited, typically concentrating on singular aspects of acne detection. Methods: We propose a multi-task acne detection method, employing a CenterNet-based training paradigm to develop an advanced detection system. This system collects acne images via smartphones and features multi-task capabilities for detecting image quality and identifying various acne types. It differentiates between noninflammatory acne, papules, pustules, nodules, and provides detailed delineation for cysts and post-acne scars. Results: The implementation of this multi-task learning-based framework in clinical diagnostics demonstrated an 83% accuracy in lesion categorization, surpassing ResNet18 models by 12%. Furthermore, it achieved a 76% precision in lesion stratification, outperforming dermatologists by 16%. Discussion: Our framework represents a advancement in acne detection, offering a comprehensive tool for classification, localization, counting, and precise segmentation. It not only enhances the accuracy of remote acne lesion identification by doctors but also clarifies grading logic and criteria, facilitating easier grading judgments.
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AIM: To investigate the protective effects, antioxidant potential, and anti-inflammatory mechanisms of eicosane on glutamate-induced cell damage and on N-methyl-D-aspartate (NMDA)-induced retinal ganglion cell (RGC) injury in a mouse model of glaucoma. METHODS: The protective effects of eicosane on the rat R28 retinal precursor cell line were assessed using cell counting kit-8 assays and Hoechst-propidium iodide staining. Intracellular reactive oxygen species (ROS) production was measured using the fluorescent probe 2'-7'-dichlorofluorescin diacetate and flow cytometry. The protective role of eicosane on NMDA-induced RGC injury in a mouse glaucoma model was determined by immunostaining of frozen sections of retina. The effects of eicosane on the metabolome of the retina in mice with NMDA-induced RGC damage were evaluated by liquid chromatography-mass spectroscopy (LC-MS) and untargeted metabolomics analyses. RESULTS: Eicosane treatment significantly attenuated glutamate-induced damage to R28 cells in vitro. Eicosane also protected RGCs against NMDA-induced injury in a mouse glaucoma model. Untargeted metabolomics analyses showed that eicosane increased multiple metabolites, including L-arginine and L-carnitine, in the retina. CONCLUSION: Eicosane has protective effects, antioxidant potential, and anti-inflammatory properties in an in vitro model of glutamate-induced cell damage and in an in vivo model of NMDA-induced RGC injury in mouse glaucoma through modulation of L-arginine and/or L-carnitine metabolism.
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The emergence and rapid development of human organoids have provided the possibility to replace animal models in treating human diseases. Intelligence studies help focus on research hotspots and address key mechanistic issues. Currently, few comprehensive studies describe the characteristics of human organoid research. In this study, we extracted 8,591 original articles on organoids from the Web of Science core collection database over the past two decades and conducted intelligence analysis using CiteSpace. The number of publications in this field has experienced rapid growth in the last ten years (almost 70-fold increase since 2009). The United States, China, Germany, Netherlands, and UK have strong collaborations in publishing articles. Clevers Hans, Van Der Laan, Jason R Spence, and Sato Toshiro have made significant contributions to advancing progress in this field. Clustering and burst analysis categorized research hotspots into tissue model and functional construction, intercellular signaling, immune mechanisms, and tumor metastasis. Organoid research in highly cited articles covers four major areas: basic research (38%), involving stem cell developmental processes and cell-cell interactions; biobanking (10%), with a focus on organoid cultivation; precision medicine (16%), emphasizing cell therapy and drug development; and disease modeling (36%), including pathogen analysis and screening for disease-related genetic variations. The main obstacles currently faced in organoid research include cost and technology, vascularization of cells, immune system establishment, international standard protocols, and limited availability of high-quality clinical trial data. Future research will focus on cost-saving measures, technology sharing, development of international standards, and conducting high-level clinical trials.
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Skin diseases pose significant challenges in China. Internet health forums offer a platform for millions of users to discuss skin diseases and share images for early intervention, leaving large amount of valuable dermatology images. However, data quality and annotation challenges limit the potential of these resources for developing diagnostic models. In this study, we proposed a deep-learning model that utilized unannotated dermatology images from diverse online sources. We adopted a contrastive learning approach to learn general representations from unlabeled images and fine-tuned the model on coarsely annotated images from Internet forums. Our model classified 22 common skin diseases. To improve annotation quality, we used a clustering method with a small set of standardized validation images. We tested the model on images collected by 33 experienced dermatologists from 15 tertiary hospitals and achieved a 45.05% top-1 accuracy, outperforming the published baseline model by 3%. Accuracy increased with additional validation images, reaching 49.64% with 50 images per category. Our model also demonstrated transferability to new tasks, such as detecting monkeypox, with a 61.76% top-1 accuracy using only 50 additional images in the training process. We also tested our model on benchmark datasets to show the generalization ability. Our findings highlight the potential of unannotated images from online forums for future dermatology applications and demonstrate the effectiveness of our model for early diagnosis and potential outbreak mitigation.
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Locoweed is a collective name for a variety of plants, such as Oxytropis and Astragalus L. When these plants are infected by some fungi or endophytes, they will produce an alkaloid (swainsonine) that is harmful to livestock. Chronic toxicity characterized by neurological disorders occurs in livestock overfed on locoweed, and swainsonine (SW) is considered a major toxic component. The mechanism of the SW synthesis of endophytic fungi from locoweed remains unknown. In order to further discover the possible synthetic pathway of SW, in this study, a mycotoxin (SW) producer, Alternaria oxytropis isolate, UA003, isolated from Locoweed plants, and its mutant were subjected to transcriptomic analyses to ascertain the genes involved in the synthesis of this toxin. Mutant strain A. oxytropis E02 was obtained by ethyl methanesulfonate (EMS) mutagenesis treatment, and the strains were sequenced with different culture times for transcriptomic analysis and screening of differentially expressed genes. The results show a highly significant (p < 0.01) increase in SW yield in the A. oxytropis E02 strain obtained by EMS mutagenesis treatment compared to A. oxytropis UA003. A total of 637 differentially expressed genes were screened by transcriptome sequencing analysis, including 11 genes potentially associated with SW biosynthesis. These genes were screened using GO and KEGG data annotation and analysis. Among the differential genes, evm.TU.Contig4.409, evm.TU.Contig19.10, and evm.TU.Contig50.48 were associated with L-lysine biosynthesis, the L-pipecolic acid pathway, and the α-aminoadipic acid synthesis pathway. This study provides new insights to elucidate the mechanism of SW synthesis of endophytic fungi in locoweed and provides data support for further exploration of A. oxytropis genomics studies.
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BACKGROUND: Traumatic coronoid deficiency with persistent elbow instability is a challenging condition. Autologous bone graft reconstruction is often associated with a range of additional clinical problems and the outcome is often unpredictable. The purpose of this study was to design a prosthetic device that can reconstruct coronoid deficiency of any height and to evaluate its mechanical properties using finite element analysis. MATERIALS AND METHODS: A customized coronoid prosthesis was designed based on image registration, automatic measurement, and computer-aided design. After pilot study and sample size calculation, image data collected from 6 patients who underwent bilateral complete upper extremity CT scans were reconstructed. The test was divided into 3 groups: coronoid intact, prosthesis and autograft. Regan-Morrey type II and autologous olecranon osteotomy models were established. The prosthesis and autogenous olecranon were assembled to the coronoid base. Stress was applied axially along the proximal humeral diaphysis and implant micromotion and contact mechanics of the humeroulnar joint were measured at 30°, 45°, 60° and 90° of joint flexion respectively. RESULTS: At all flexion angles, the maximum stress on the coronoid articular surface was significantly reduced in the prosthesis and autograft groups, with the reduction being more significant in the latter (P < .001). With increasing flexion, the maximum stress at the coronoid articular surface increased significantly after autograft reconstruction (7.2 to 68 MPa, P < .001), whereas the humeroulnar joint obtained a similar contact mechanics pattern to that of the control group after prosthetic reconstruction. As the flexion angle increased, the relative micromotion of both the prosthesis and autograft increased significantly (0.5-1.6 vs. 0.2-1.2, Pmeasure time < 0.001, Pgroups < 0.001). Contact pressure and center-of-force paths of the humeroulnar joint experience abrupt stress changes at approximately 60° of flexion. CONCLUSION: The contact stress pattern in the humeroulnar joint is similar in prosthesis and intact coronoid groups. Autograft reconstruction increases contact stresses at the articular surface and alters the joint center-of-force path. The "stress surge phenomenon" in the humeroulnar joint surface before and after 60° of flexion may be one of the mechanisms of traumatic elbow degeneration.
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Articulación del Codo , Inestabilidad de la Articulación , Humanos , Articulación del Codo/diagnóstico por imagen , Articulación del Codo/cirugía , Inestabilidad de la Articulación/diagnóstico por imagen , Inestabilidad de la Articulación/etiología , Inestabilidad de la Articulación/cirugía , Análisis de Elementos Finitos , Proyectos Piloto , Prótesis e Implantes , Rango del Movimiento ArticularRESUMEN
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by persistent deficits in social communication and stereotyped behaviors. Although major advances in basic research on autism have been achieved in the past decade, and behavioral interventions can mitigate the difficulties that individuals with autism experience, little is known about the many fundamental issues of the interventions, and no specific medication has demonstrated efficiency for the core symptoms of ASD. Intermittent hypobaric hypoxia (IHH) is characterized by repeated exposure to lowered atmospheric pressure and oxygen levels, which triggers multiple physiological adaptations in the body. Here, using two mouse models of ASD, male Shank3B -/- and Fmr1 -/y mice, we found that IHH training at an altitude of 5,000â m for 4â h per day, for 14 consecutive days, ameliorated autistic-like behaviors. Moreover, IHH training enhanced hypoxia inducible factor (HIF) 1α in the dorsal raphe nucleus (DRN) and activated the DRN serotonergic neurons. Infusion of cobalt chloride into the DRN, to mimic IHH in increasing HIF1α expression or genetically knockdown PHD2 to upregulate HIF1α expression in the DRN serotonergic neurons, alleviated autistic-like behaviors in Shank3B -/- mice. In contrast, downregulation of HIF1α in DRN serotonergic neurons induced compulsive behaviors. Furthermore, upregulating HIF1α in DRN serotonergic neurons increased the firing rates of these neurons, whereas downregulation of HIF1α in DRN serotonergic neurons decreased their firing rates. These findings suggest that IHH activated DRN serotonergic neurons via upregulation of HIF1α, and thus ameliorated autistic-like phenotypes, providing a novel therapeutic option for ASD.
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Trastorno del Espectro Autista , Trastorno Autístico , Ratones , Masculino , Animales , Trastorno Autístico/genética , Trastorno Autístico/terapia , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/terapia , Núcleo Dorsal del Rafe , Neuronas Serotoninérgicas/fisiología , Hipoxia , Fenotipo , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X FrágilRESUMEN
Major depressive disorder (MDD) is a devastating condition. Although progress has been made in the past seven decades, patients with MDD continue to receive an inadequate treatment, primarily due to the late onset of first-line antidepressant drugs and to their acute withdrawal symptoms. Resilience is the ability to rebound from adversity in a healthy manner and many people have psychological resilience. Revealing the mechanisms and identifying methods promoting resilience will hopefully lead to more effective prevention strategies and treatments for depression. In this study, we found that intermittent hypobaric hypoxia training (IHHT), a method for training pilots and mountaineers, enhanced psychological resilience in adult mice. IHHT produced a sustained antidepressant-like effect in mouse models of depression by inducing long-term (up to 3 months after this treatment) overexpression of hypoxia-inducible factor (HIF)-1α in the dorsal raphe nucleus (DRN) of adult mice. Moreover, DRN-infusion of cobalt chloride, which mimics hypoxia increasing HIF-1α expression, triggered a rapid and long-lasting antidepressant-like effect. Down-regulation of HIF-1α in the DRN serotonergic (DRN5-HT) neurons attenuated the effects of IHHT. HIF-1α translationally regulated the expression of P2X2, and conditionally knocking out P2rx2 (encodes P2X2 receptors) in DRN5-HT neurons, in turn, attenuated the sustained antidepressant-like effect of IHHT, but not its acute effect. In line with these results, a single sub-anesthetic dose of ketamine enhanced HIF-1α-P2X2 signaling, which is essential for its rapid and long-lasting antidepressant-like effect. Notably, we found that P2X2 protein levels were significantly lower in the DRN of patients with MDD than that of control subjects. Together, these findings elucidate the molecular mechanism underlying IHHT promoting psychological resilience and highlight enhancing HIF-1α-P2X2 signaling in DRN5-HT neurons as a potential avenue for screening novel therapeutic treatments for MDD.
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Trastorno Depresivo Mayor , Resiliencia Psicológica , Humanos , Ratones , Animales , Núcleo Dorsal del Rafe/metabolismo , Neuronas Serotoninérgicas/metabolismo , Serotonina/metabolismo , Serotonina/farmacología , Antidepresivos/farmacología , Hipoxia , Receptores Purinérgicos P2X2/metabolismoRESUMEN
IMPORTANCE: In this study, we successfully established a new One-Pot method, named TB One-Pot, for detecting Mtb in sputum by combining CRISPR-cas12b-mediated trans-cleavage with cross-priming amplification (CPA). Our study evaluated the diagnostic performance of TB One-Pot in clinical sputum samples for tuberculosis. The findings provide evidence for the potential of TB One-Pot as a diagnostic tool for tuberculosis.
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Mycobacterium tuberculosis , Tuberculosis , Humanos , Mycobacterium tuberculosis/genética , Esputo/microbiología , Reactividad Cruzada , Sistemas CRISPR-Cas , Sensibilidad y Especificidad , Técnicas de Amplificación de Ácido Nucleico/métodos , Tuberculosis/diagnóstico , Tuberculosis/microbiologíaRESUMEN
Background: Due to the lower reliability of laboratory tests, skin diseases are more suitable for diagnosis with AI models. There are limited AI dermatology diagnostic models combining images and text; few of these are for Asian populations, and few cover the most common types of diseases. Methods: Leveraging a dataset sourced from Asia comprising over 200,000 images and 220,000 medical records, we explored a deep learning-based system for Dual-channel images and extracted text for the diagnosis of skin diseases model DIET-AI to diagnose 31 skin diseases, which covers the majority of common skin diseases. From 1 September to 1 December 2021, we prospectively collected images from 6,043 cases and medical records from 15 hospitals in seven provinces in China. Then the performance of DIET-AI was compared with that of six doctors of different seniorities in the clinical dataset. Results: The average performance of DIET-AI in 31 diseases was not less than that of all the doctors of different seniorities. By comparing the area under the curve, sensitivity, and specificity, we demonstrate that the DIET-AI model is effective in clinical scenarios. In addition, medical records affect the performance of DIET-AI and physicians to varying degrees. Conclusion: This is the largest dermatological dataset for the Chinese demographic. For the first time, we built a Dual-channel image classification model on a non-cancer dermatitis dataset with both images and medical records and achieved comparable diagnostic performance to senior doctors about common skin diseases. It provides references for exploring the feasibility and performance evaluation of DIET-AI in clinical use afterward.
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Solute carriers (SLCs) are membrane transporters that import and export a range of endogenous and exogenous substrates, including ions, nutrients, metabolites, neurotransmitters, and pharmaceuticals. Despite having emerged as attractive therapeutic targets and markers of disease, this group of proteins is still relatively underdrugged by current pharmaceuticals. Drug discovery projects for these transporters are impeded by limited structural, functional, and physiological knowledge, ultimately due to the difficulties in the expression and purification of this class of membrane-embedded proteins. Here, we demonstrate methods to obtain high-purity, milligram quantities of human SLC transporter proteins using codon-optimized gene sequences. In conjunction with a systematic exploration of construct design and high-throughput expression, these protocols ensure the preservation of the structural integrity and biochemical activity of the target proteins. We also highlight critical steps in the eukaryotic cell expression, affinity purification, and size-exclusion chromatography of these proteins. Ultimately, this workflow yields pure, functionally active, and stable protein preparations suitable for high-resolution structure determination, transport studies, small-molecule engagement assays, and high-throughput in vitro screening.
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Proteínas de Transporte de Membrana , Proteínas Transportadoras de Solutos , Humanos , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Proteínas Transportadoras de Solutos/química , Proteínas Transportadoras de Solutos/metabolismo , Descubrimiento de Drogas/métodos , Ensayos Analíticos de Alto Rendimiento , Proteínas de la Membrana/metabolismo , Preparaciones FarmacéuticasRESUMEN
BACKGROUND: Both modular and monoblock tapered fluted titanium (TFT) stems are increasingly being used for revision total hip arthroplasty (rTHA). However, the differences between the two designs in clinical outcomes and complications are not yet clear. Here, we intend to compare the efficacy and safety of modular versus monoblock TFT stems in rTHA. METHODS: PubMed, Embase, Web of Science, and Cochrane Library databases were searched to include studies comparing modular and monoblock implants in rTHA. Data on the survivorship of stems, postoperative hip function, and complications were extracted following inclusion criteria. Inverse variance and Mantel-Haenszel methods in Review Manager (version 5.3 from Cochrane Collaboration) were used to evaluate differences between the two groups. RESULTS: Ten studies with a total of 2188 hips (1430 modular and 758 monoblock stems) were finally included. The main reason for the revision was aseptic loosening. Paprosky type III was the most common type in both groups. Both stems showed similar re-revision rates (modular vs monoblock: 10.3% vs 9.5%, P = 0.80) and Harris Hip Scores (WMD = 0.43, P = 0.46) for hip function. The intraoperative fracture rate was 11.6% and 5.0% (P = 0.0004) for modular and monoblock stems, respectively. The rate of subsidence > 10 mm was significantly higher in the monoblock group (4.5% vs 1.0%, P = 0.003). The application of extended trochanteric osteotomy was more popular in monoblock stems (22.7% vs 17.5%, P = 0.003). The incidence of postoperative complications such as periprosthetic femoral fracture and dislocation was similar between both stems. CONCLUSIONS: No significant difference was found between modular and monoblock tapered stems as regards postoperative hip function, re-revision rates, and complications. Severe subsidence was more frequent in monoblock stems while modular ones were at higher risk of intraoperative fracture. LEVEL OF EVIDENCE: Level III, systematic review of randomized control and non-randomized studies. TRIAL REGISTRATION: We registered our study in the international prospective register of systematic reviews (PROSPERO) (CRD42020213642).
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Artroplastia de Reemplazo de Cadera , Fracturas del Fémur , Fracturas Periprotésicas , Humanos , Reoperación , Bases de Datos Factuales , FémurRESUMEN
Solute carrier spinster homolog 2 (SPNS2), one of only four known major facilitator superfamily (MFS) lysolipid transporters in humans, exports sphingosine-1-phosphate (S1P) across cell membranes. Here, we explore the synergistic effects of lipid binding and conformational dynamics on SPNS2's transport mechanism. Using mass spectrometry, we discovered that SPNS2 interacts preferentially with PI(4,5)P2. Together with functional studies and molecular dynamics (MD) simulations, we identified potential PI(4,5)P2 binding sites. Mutagenesis of proposed lipid binding sites and inhibition of PI(4,5)P2 synthesis reduce S1P transport, whereas the absence of the N terminus renders the transporter essentially inactive. Probing the conformational dynamics of SPNS2, we show how synergistic binding of PI(4,5)P2 and S1P facilitates transport, increases dynamics of the extracellular gate, and stabilizes the intracellular gate. Given that SPNS2 transports a key signaling lipid, our results have implications for therapeutic targeting and also illustrate a regulatory mechanism for MFS transporters.
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Lisofosfolípidos , Esfingosina , Humanos , Proteínas de Transporte de Anión/genética , Proteínas de Transporte de Anión/metabolismoRESUMEN
Changes in the cerebral microenvironment caused by acute ischemic stroke-reperfusion are the main obstacle to the recovery of neurological function and an important cause of stroke recurrence after thrombolytic therapy. The intracerebral microenvironment after ischemia-reperfusion reduces the neuroplasticity of the penumbra and ultimately leads to permanent neurological damage. To overcome this challenge, we developed a triple-targeted self-assembled nanodelivery system, which combines the neuroprotective drug rutin with hyaluronic acid through esterification to form a conjugate, and then connected SS-31, a small peptide that can penetrate the blood brain barrier and target mitochondria. Brain targeting, CD44-mediated endocytosis, hyaluronidase 1-mediated degradation, and the acidic environment synergistically promoted the enrichment of nanoparticles and drug release in the injured area. Results demonstrate that rutin has a high affinity for ACE2 receptors on the cell membrane and can directly activate ACE2/Ang1-7 signaling, maintain neuroinflammation, and promote penumbra angiogenesis and normal neovascularization. Importantly, this delivery system enhanced the overall plasticity of the injured area and significantly reduced neurological damage after stroke. The relevant mechanism was expounded from the aspects of behavior, histology, and molecular cytology. All results suggest that our delivery system may be an effective and safe strategy for the treatment of acute ischemic stroke-reperfusion injury.
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BACKGROUND: New immunotherapeutic strategies based on predictors are urgently needed. Toll-like receptor adaptor interacting with SLC15A4 on the lysosome (TASL) was recently confirmed to fulfill an important role in the innate immune response. However, whether TASL is involved in tumor development and immunotherapy response prediction has not been reported. METHODS: TCGA and GTEx were used to yield transcriptional, genetic, and epigenetic levels of TASL in 33 cancer types. CIBERSORT was used to explore the correlation between TASL expression and multiple immune-related signatures and tumor-infiltrating immune cell content in different cancer types. The ability of TASL to predict tumor immunotherapy response was analyzed in seven datasets. Finally, we tested TASL expression in human glioma cell lines and tissue samples and analyzed its correlation with clinicopathological parameters. RESULTS: TASL is widely heterogeneous at the transcriptional, genetic, and epigenetic levels. High TASL expression is an independent poor prognostic factor for immune "cold" tumor Low-Grade Glioma (LGG) but an opposite factor for "hot" tumors Lung Adenocarcinoma (LUAD) and Skin Cutaneous Melanoma (SKCM). TASL may affect tumor immune infiltration by mediating tumor-infiltrating lymphocytes and tumor-associated macrophages. It may differentially affect the prognosis of the three cancers by regulating the immunosuppressive microenvironment in LGG and the immunostimulatory microenvironment in LUAD and SKCM. High TASL expression is a potential biomarker for the positive response to immunotherapy in cancers such as SKCM and was also experimentally confirmed to be positively associated with adverse clinicopathological features of gliomas. CONCLUSION: TASL expression is an independent prognostic factor for LGG, LUAD, and SKCM. High TASL expression is a potential biomarker for the positive response to immunotherapy in certain cancer types such as SKCM. Further basic studies focusing on TASL expression and tumor immunotherapy are urgently needed.