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Background: In past studies, non-medical factors in the social-healthcare-patient triad associated with the prevalence of COVID-19 have led to delays in the presentation of patients with acute appendicitis and an increase in complications. However, as research progresses, there is increasing evidence of a clinical association between COVID-19 and the development of acute appendicitis. Methods: The effect of COVID-19 prevalence and associated factors on acute appendicitis in the control (2016-2019) and exposed (2020-2023) groups was derived from a retrospective study of 3070 patients with acute appendicitis from 2016 to 2023. Results: After the implementation of the restrictions, the rate of acute appendicitis visits in the exposed group compared to the control group dropped sharply in the initial period (P = 0.047) and recovered gradually with the relaxation of the restrictions. Similar changes occurred in the number of acute complicated appendicitis visits. In addition, after the lifting of restrictions and the COVID-19 outbreak, the proportion of acute complicated appendicitis in the exposed group increased significantly (P < 0.001) and an increase in the number of complicated appendicitis visits was observed (P < 0.001) compared with the control group. In addition, the age distribution of acute appendicitis during this period showed an ageing trend (P = 0.001). Conclusion: COVID-19 infections may be more likely to progress to complicated appendicitis after an episode of appendicitis, even if they have been cured for the same period of time. In addition, the proportion of elderly patients with appendicitis increased after the COVID-19 epidemic.
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Bacteria dysbiosis and its accompanying inflammation or compromised mucosal integrity is associated with an increased risk of HIV-1 transmission. However, HIV-1 may also bind bacteria or bacterial products to impact infectivity and transmissibility. This study evaluated HIV-1 interactions with bacteria through glycan-binding lectins. The Streptococcal Siglec-like lectin SLBR-N, a part of the fimbriae shrouding the bacteria surface that recognizes α2,3 sialyated O-linked glycans, was noted for its ability to enhance HIV-1 infectivity in the context of cell-free infection and cell-to-cell transfer. Enhancing effects were recapitulated with O-glycan-binding plant lectins, signifying the importance of O-glycans. N-glycan-binding bacterial lectins FimH and Msl had no effect. SLBR-N was demonstrated to capture and transfer infectious HIV-1 virions, bind to O-glycans on HIV-1 Env, and increase HIV-1 resistance to neutralizing antibodies targeting different regions of Env. This study highlights the potential contribution of O-glycan-binding lectins from commensal bacteria at the mucosa in promoting HIV-1 infection.
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The advancement of metal-air batteries is critically contingent on the progression of efficient catalysts for the oxygen reduction reaction (ORR). The potential applications of a series of FeN4-doped carbon nanotubes (Fe-N4CNTs) of varying diameters as ORR catalysts were examined using density functional theory. We explored the stability and electronic properties of Fe-N4CNTs by analyzing the energy and examining the density of states. A marked dependence of the catalytic performance on the nanotube diameter was observed: as the transition from (5, 5) to (10, 10) Fe-N4CNTs occurred, the catalytic activity on the outer surface of the carbon tubes enhanced progressively, with the overpotential reducing from 0.94 to 0.86 V. Conversely, the catalytic activity on the inner surface of the carbon tubes decreased progressively with the overpotential also increasing from 0.62 to 1.04 V. In addition, we found that curvature significantly affected the electronic structure and charge transfer at the FeN4 site, regulating the adsorption and desorption of reactants, intermediates, and products during electrocatalysis and thus influencing the catalytic activity of the Fe-N4CNTs. This investigation offers valuable guidance for the design of Fe-based single-atom catalysts and the practical application of Fe-N-C materials.
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Gel polymer electrolytes (GPEs) hold great promise for the practical application of lithium metal batteries. However, conventional GPEs hardly resists lithium dendrites growth and maintains long-term cycling stability of the battery due to its poor mechanical performance. Inspired by the slide-ring structure of polyrotaxanes (PRs), herein we developed a dynamic slide-crosslinked gel polymer electrolyte (SCGPE) with extraordinary stretchability of 970.93% and mechanical strength of 1.15 MPa, which is helpful to buffer the volume change of electrodes and maintain mechanical integrity of the battery structure during cycling. Notably, the PRs structures can provide fast ion transport channels to obtain high ionic conductivity of 1.73×10-3 S cm-1 at 30°C. Additionally, the strong polar groups in SCGPE restrict the free movement of anions to achieve high lithium-ion transference number of 0.71, which is favorable to enhance Li+ transport dynamics and induce uniform Li+ deposition. Benefiting from these features, the constructed Li|SCGPE-3|LFP cells exhibit ultra-long and stable cycle life over 1000 cycles and high-capacity retention (89.6% after 1000 cycles). Even at a high rate of 16C, the cells deliver a high capacity of 79.2 mAh g-1. The slide-crosslinking strategy in this work provides a new perspective on the design of advanced GPEs for LMBs.
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PURPOSE: Robot-assisted total hip arthroplasty (RA-THA) helps with precise orientation of the prosthesis, but some RA-THA procedures are aborted intraoperatively and are converted to manual total hip arthroplasty (THA). This study aimed to analyse why RA-THA is sometimes aborted intraoperatively and to make recommendations accordingly. METHODS: A total of 429 consecutive Mako THA cases in our prospective database from August 2018 to June 2021 were included in our study. All robotic procedures aborted intraoperatively for any reason were recorded. The patients' demographics, diagnoses, and surgeons' information were included in the statistical analysis to pinpoint the risk factors for intraoperative robot to manual conversion. RESULTS: Intraoperative RA-THA abortions occurred in 17 cases (3.96%) and the patients had to be converted to manual THA. The adverse events leading to intraoperative abortions included pelvic array loosening or malposition (5, 1.17%), inaccurate bone mapping or construction (6, 1.40%), inaccurate initial registration (4, 0.93%), and other reasons (2, 0.47%). CONCLUSION: Robot-related adverse events could be found in all perioperative steps of RA-THA, and some of these events might result in intraoperative abortion. Complex hip disease was a statistically significant factor for an increased risk of intraoperative abortion of RA-THA. Standardized surgical procedures and preoperative assessments can be helpful in reducing the rate of RA-THA abortions.
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Tauopathies are a group of neurodegenerative diseases characterized by the presence of tau inclusions. We have developed over fifty anti-tau single-domain antibodies (sdAbs) derived from phage display libraries of a llama immunized with recombinant and pathological tau immunogens. We examined the therapeutic potential of four of these sdAbs in a Drosophila tauopathy model following their transgenic expression either in all neurons or neuronal subtypes. Three of these sdAbs showed therapeutic potential in various assays, effectively clearing pathological tau and attenuating or preventing tau-induced phenotypes that typically manifest as defects in neuronal axonal transport, neurodegeneration, functional impairments, and shortened lifespan. Of these three, one sdAb was superior in every assay, which may at least in part be attributed to its tau-binding epitope. These findings support its development as a gene therapy for tauopathies.
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Anticorpos de Domínio Único , Tauopatias , Proteínas tau , Proteínas tau/metabolismo , Proteínas tau/imunologia , Animais , Tauopatias/imunologia , Tauopatias/patologia , Anticorpos de Domínio Único/imunologia , Anticorpos de Domínio Único/farmacologia , Humanos , Modelos Animais de Doenças , Drosophila , Animais Geneticamente Modificados , Neurônios/metabolismo , Neurônios/patologia , Camelídeos Americanos/imunologia , Drosophila melanogaster/imunologiaRESUMO
The single-walled carbon nanotube (SWCNT) commonly serves as a conductive additive for SiO-based anode materials due to the excellent conductivity and mechanical properties. However, the potential action mechanisms for the SWCNT beyond conductivity and mechanical features have rarely been studied. Herein, an interfacial electron-shielding effect and preferential adsorption to the electrolyte components for the SWCNT are revealed through a series of advanced characterizations and density functional theory (DFT) simulations. It can be determined that SWCNT networks could restrict the transmission of the electron from SiO interface to electrolyte with the reduced decomposition, because of the typical axial conductivity of the SWCNT. Moreover, the SWCNT shows stronger adsorption energy for LiPF6 and ethylene carbonate (EC) molecules, rather than nonselectivity of traditional carbon additives, facilitating the generation of inorganic-rich and denser solid electrolyte interface (SEI) film. As a result, benefiting from the electron-shielding effect, preferential adsorption, and mechanical protection, the SWCNT endows the SiO@C anode with a higher average Coulombic efficiency (CE) value of 99.4% over 100 cycles and a long cycling stability.
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BACKGROUND: Joint hypermobility may be associated with developmental dysplasia of the hip (DDH), but no definite conclusion has been reached. On the basis of long-term clinical observations, we hypothesized that joint hypermobility was associated with the occurrence, imaging findings, and clinical symptoms of DDH. METHODS: We conducted a case-control study that included 175 Chinese Han patients between 13 and 45 years of age with Hartofilakidis type-A hip dysplasia. All of these patients underwent periacetabular osteotomy (PAO) between November 2021 and February 2023. An additional 76 individuals of comparable age and sex but without hip dysplasia were selected from the general population to serve as healthy controls. The Beighton 9-point scoring system was used to evaluate joint hypermobility, and a score of ≥4 was defined as generalized joint hypermobility. Standing anteroposterior pelvic radiographs were reviewed. For patients with DDH, the lateral center-edge angle, Tönnis angle, Sharp angle, lateralization of the femoral head, and patient-reported outcomes (iHOT-12, HHS, and WOMAC) were also collected to determine the radiographic severity or clinical symptoms of DDH. RESULTS: Patients with DDH had an elevated prevalence of generalized joint hypermobility compared with that in the healthy population (27% versus 12%; p = 0.009). Among patients with DDH, those with concomitant generalized joint hypermobility had lower lateral center-edge angles (3.55° versus 9.36°; p = 0.012), greater lateralization of the femoral head (13.78 versus 12.17 mm; p = 0.020), greater standardized lateralization of the femoral head (0.64 versus 0.54; p = 0.009), and lower iHOT-12 scores (35.22 versus 40.96; p = 0.009) than did those without concomitant generalized joint hypermobility. Further multivariable linear regression analysis revealed that higher Beighton scores and younger age were predictive of more severe hip dysplasia. However, the Beighton score was not found to be independently associated with patient-reported outcomes according to multivariable linear regression analysis. CONCLUSIONS: The prevalence of generalized joint hypermobility was greater in patients with DDH than in healthy controls. A higher degree of joint hypermobility was also correlated with more severe hip dysplasia. These results suggest that joint laxity, in addition to bone or cartilage factors, is an important factor related to DDH. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.
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The vaccine elicitation of HIV tier-2-neutralization antibodies has been a challenge. Here, we report the isolation and characterization of a CD4-binding site (CD4bs) specific monoclonal antibody, HmAb64, from a human volunteer immunized with a polyvalent DNA prime-protein boost HIV vaccine. HmAb64 is derived from heavy chain variable germline gene IGHV1-18 and light chain germline gene IGKV1-39. It has a third heavy chain complementarity-determining region (CDR H3) of 15 amino acids. On a cross-clade panel of 208 HIV-1 pseudo-virus strains, HmAb64 neutralized 20 (10%), including tier-2 strains from clades B, BC, C, and G. The cryo-EM structure of the antigen-binding fragment of HmAb64 in complex with a CNE40 SOSIP trimer revealed details of its recognition; HmAb64 uses both heavy and light CDR3s to recognize the CD4-binding loop, a critical component of the CD4bs. This study demonstrates that a gp120-based vaccine can elicit antibodies capable of tier 2-HIV neutralization.
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Vacinas contra a AIDS , Anticorpos Neutralizantes , Antígenos CD4 , Anticorpos Anti-HIV , HIV-1 , Humanos , Vacinas contra a AIDS/imunologia , HIV-1/imunologia , Anticorpos Anti-HIV/imunologia , Anticorpos Neutralizantes/imunologia , Antígenos CD4/imunologia , Antígenos CD4/metabolismo , Vacinas de DNA/imunologia , Anticorpos Monoclonais/imunologia , Infecções por HIV/prevenção & controle , Infecções por HIV/imunologia , Infecções por HIV/virologia , Microscopia Crioeletrônica , Proteína gp120 do Envelope de HIV/imunologia , Proteína gp120 do Envelope de HIV/química , Sítios de Ligação , Regiões Determinantes de Complementaridade/imunologia , Regiões Determinantes de Complementaridade/químicaRESUMO
Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of α-synuclein (α-syn) in the brain, leading to motor and neuropsychiatric symptoms. Currently, there are no known cures for synucleinopathies, and treatments mainly focus on symptom management. In this study, we developed a single-domain antibody (sdAb)-based protein degrader with features designed to enhance proteasomal degradation of α-syn. This sdAb derivative targets both α-syn and Cereblon (CRBN), a substrate-receptor for the E3-ubiquitin ligase CRL4CRBN, and thereby induces α-syn ubiquitination and proteasomal degradation. Our results indicate that this therapeutic candidate enhances proteasomal degradation of α-syn, in addition to the endogenous lysosomal degradation machinery. By promoting proteasomal degradation of α-syn, we improved clearance of α-syn in primary culture and mouse models of synucleinopathy. These findings indicate that our sdAb-based protein degrader is a promising therapeutic candidate for synucleinopathies. Considering that only a small percentage of antibodies enter the brain, more potent sdAbs with greater brain entry than whole antibodies could enhance clinical benefits of antibody-based therapies.
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Sinucleinopatias , alfa-Sinucleína , Animais , Sinucleinopatias/metabolismo , alfa-Sinucleína/metabolismo , alfa-Sinucleína/imunologia , Camundongos , Humanos , Anticorpos de Domínio Único , Modelos Animais de Doenças , Encéfalo/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismoRESUMO
A new glycoside (1) along with six known analogues (1-7) were isolated from Codonopsis pilosula collected at Shanxi in China. The structure of 1 was established based on comprehensive spectroscopic data and literature comparison. The anti-inflammatory effects of isolated compounds were further investigated in LPS-induced RAW264.7 macrophage.
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PURPOSE: Pelvic support osteotomy (PSO) is regarded to provide pelvic stability and improve abductor function to delay or even avoid total hip arthroplasty (THA) in young patients with high-riding hip dysplasia. However, some of these patients eventually have to undergo THA. Because of the double-angulation deformity of the femur after PSO, subsequent THA is challenging. This study aimed to analyze whether PSO surgery is suitable for high-riding hip dysplasia and summarize orthopaedic strategy during THA for patients with previous PSO. METHODS: This case-control study included eight cases of THA for high-riding hip dysplasia patients with previous PSO (study group) and 24 cases of high-riding hip dysplasia patients without any hip surgical therapy (control group) by a 1:3 match (from May 2018 to January 2022). We compared demographics and joint function before and after THA between two groups and recorded all patients' preoperative imaging data, surgical procedures, postoperative imaging data, and complications. The surgical techniques for patients with previous PSO were highlighted. RESULTS: There was no statistical difference between the two groups in demographic (p > 0.05). The study group had worse hip Harris score (HHS), range of motion (ROM), visual analogue scale (VAS), and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) (p < 0.05) compared with the control group before THA. All patients had concurrent THA and osteotomy at the proximal femur, but the study group experienced longer operation time (p = 0.047) with more blood loss (p = 0.027) and higher complication rate compared with the control group (p = 0.009). At the last follow-up, the study group's HHS, ROM, VAS, and WOMAC were still worse than those in the control group. CONCLUSIONS: PSO did not improve the joint function of high-riding hip dysplasia patients but brought challenges to subsequent THA and affected the surgical outcomes. In short, we suggested that PSO is unsuitable for routine high-riding hip dysplasia patients.
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Artroplastia de Quadril , Osteotomia , Ossos Pélvicos , Humanos , Osteotomia/métodos , Osteotomia/efeitos adversos , Feminino , Masculino , Estudos de Casos e Controles , Artroplastia de Quadril/métodos , Artroplastia de Quadril/efeitos adversos , Adulto , Ossos Pélvicos/cirurgia , Ossos Pélvicos/diagnóstico por imagem , Amplitude de Movimento Articular , Articulação do Quadril/cirurgia , Articulação do Quadril/fisiopatologia , Articulação do Quadril/diagnóstico por imagem , Adulto Jovem , Luxação do Quadril/cirurgia , Luxação do Quadril/etiologia , Adolescente , Resultado do Tratamento , Luxação Congênita de Quadril/cirurgiaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Ziziphi Spinosae Semen and Polygalae Radix (ZSS-PR) constitute a traditional Chinese herbal combination with notable applications in clinical and experimental settings due to their evident sedative and calming effects. Aligned with traditional Chinese medicine principles, Ziziphi Spinosae Semen supports cardiovascular health, nourishes the liver, and induces mental tranquillity. Simultaneously, Polygalae Radix elicits calming effects, fosters clear thinking, and reinstates proper coordination between the heart and kidneys. ZSS-PR is commonly employed as a therapeutic intervention for various insomnia types, demonstrating distinct clinical efficacy. Our previous study findings provide evidence that ZSS-PR administration significantly reduces sleep onset latency, increases overall sleep duration, and improves abnormal neurotransmitter levels in a murine insomnia model. AIM OF STUDY: This investigation aimed to scrutinize the intrinsic regulatory mechanism of ZSS-PR in managing insomnia using gut microbiota and serum metabolomics techniques. MATERIALS AND METHODS: Mice were given DL-4-Chlorophenylalanine to induce insomnia and then treated with ZSS-PR. The open-field test assessed the animals' spontaneous activity. Concentrations of neurotransmitters, endocrine hormones, and cytokines in the duodenum were measured using enzyme linked immunosorbent assay, and brain histopathology was evaluated with H&E staining. The impact of ZSS-PR on the metabolic profile was examined by liquid chromatography couped to high resolution mass spectrometry, and 16S rDNA sequencing was used to study the influence of ZSS-PR on the gut microbiota. Additionally, the content of short-chain fatty acids (SCFAs) was analyzed by GC-MS. Finally, correlation analysis investigated relationships between biochemical markers, metabolites, SCFAs, and gut microbiota. RESULTS: ZSS-PR treatment significantly increased movement time and distance in mice with insomnia and improved pathological impairments in the cerebral cortex and hippocampus. It also restored abnormal levels of biochemical markers in the gut of insomnia-afflicted mice, including 5-hydroxytryptamine, dopamine, gastrin, melatonin, tumour necrosis factor-α, and interleukin-1ß. Metabolomics findings showed that ZSS-PR had a significant restorative effect on 15 endogenous metabolites in mice with insomnia. Furthermore, ZSS-PR primarily influenced five metabolic pathways, such as phenylalanine, tyrosine, and tryptophan biosynthesis, glutamine, and glutamate metabolism. Additionally, gut microbiota analysis revealed notable alterations in both diversity and microbial composition after ZSS-PR treatment. These changes were primarily attributed to the relative abundances of microbiota, including Firmicutes, Bacteroidota, Fusobacteriota, Muribaculaceae_unclassified, and Ligilactobacillus. The results of SCFAs analysis demonstrated that ZSS-PR effectively restored abnormal levels of acetic acid, propionic acid, isobutyric acid, butyric acid, isovaleric acid, and valeric acid in insomniac mice. Subsequent correlation analysis revealed that microbiota show obvious correlations with both biochemical markers and metabolites. CONCLUSIONS: The results provide compelling evidence that ZSS-PR effectively mitigates abnormal activity, reduces cerebral pathological changes, and restores abnormal levels of neurotransmitters, endocrine hormones, and cytokines in mice with insomnia. The underlying mechanism is intricately linked to the modulation of gut microbiota and endogenous metabolic pathways.
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Medicamentos de Ervas Chinesas , Microbioma Gastrointestinal , Metabolômica , Polygala , Distúrbios do Início e da Manutenção do Sono , Ziziphus , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Ziziphus/química , Camundongos , Masculino , Medicamentos de Ervas Chinesas/farmacologia , Polygala/química , Modelos Animais de Doenças , Sono/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Animais não EndogâmicosRESUMO
Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of α-synuclein (α-syn) in the brain, leading to motor and neuropsychiatric symptoms. Currently, there are no known cures for synucleinopathies, and treatments mainly focus on symptom management. In this study, we developed a single-domain antibody (sdAb)-based protein degrader with features designed to enhance proteasomal degradation of α-syn. This sdAb derivative targets both α-syn and Cereblon (CRBN), a substrate-receptor for the E3-ubiquitin ligase CRL4CRBN, and thereby induces α-syn ubiquitination and proteasomal degradation. Our results indicate that this therapeutic candidate enhances proteasomal degradation of α-syn, in addition to the endogenous lysosomal degradation machinery. By promoting proteasomal degradation of α-syn, we improved clearance of α-syn in primary culture and mouse models of synucleinopathy. These findings indicate that our sdAb-based protein degrader is a promising therapeutic candidate for synucleinopathies. Considering that only a small percentage of antibodies enter the brain, more potent sdAbs with greater brain entry than whole antibodies could enhance clinical benefits of antibody-based therapies.
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BACKGROUND: Accurate preoperative planning is crucial for successful total hip arthroplasty (THA) for developmental dysplasia of the hip (DDH). The aim of this study was to compare the accuracy of an artificial intelligence-assisted three-dimensional (3D) planning system (AIHIP) with two-dimensional templates in predicting acetabular cup size in THA for DDH. METHOD: This study retrospectively analyzed image data from 103 DDH patients who had THA between May 2019 and August 2023. AIHIP was used for 3D planning, and two-dimensional (2D) templates were used by two experienced surgeons. Accuracy was assessed by comparing predicted and actual cup sizes, and potential factors affecting accuracy were analyzed, including gender, side, BMI, and dysplasia classification. RESULTS: AIHIP had higher accuracy in predicting the acetabular cup size compared to the 2D template. Within ± 0 size, AIHIP's accuracy was 84.1%, while the 2D template's was 64.0% (p < 0.05). Within ± 1 size, AIHIP's accuracy was 95.1%, while the 2D template's was 81.1% (p < 0.05). Accuracy was unaffected by gender, side, or BMI but was by DDH classification. In subgroup analysis, AIHIP's mean absolute error (0.21 ± 0.54) was significantly lower than the 2D template's (0.62 ± 0.95) for Crowe II and Crowe III (p < 0.05). CONCLUSION: AIHIP is superior to 2D templates in predicting the acetabular cup size accurately for THA in DDH patients. AIHIP may be especially beneficial for Crowe II and III DDH patients, as 2D templates may not accurately predict cup size in these cases.
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Artroplastia de Quadril , Displasia do Desenvolvimento do Quadril , Luxação Congênita de Quadril , Prótese de Quadril , Humanos , Inteligência Artificial , Estudos Retrospectivos , Displasia do Desenvolvimento do Quadril/cirurgia , Acetábulo/diagnóstico por imagem , Acetábulo/cirurgia , Artroplastia de Quadril/métodos , Luxação Congênita de Quadril/diagnóstico por imagem , Luxação Congênita de Quadril/cirurgia , SoftwareRESUMO
Programmed cell death-1 (PD-1) is a potent immune checkpoint receptor on T lymphocytes. Upon engagement by its ligands, PD-L1 or PD-L2, PD-1 inhibits T cell activation and can promote immune tolerance. Antagonism of PD-1 signaling has proven effective in cancer immunotherapy, and conversely, agonists of the receptor may have a role in treating autoimmune disease. Some immune receptors function as dimers, but PD-1 has been considered monomeric. Here, we show that PD-1 and its ligands form dimers as a consequence of transmembrane domain interactions and that propensity for dimerization correlates with the ability of PD-1 to inhibit immune responses, antitumor immunity, cytotoxic T cell function, and autoimmune tissue destruction. These observations contribute to our understanding of the PD-1 axis and how it can potentially be manipulated for improved treatment of cancer and autoimmune diseases.
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Doenças Autoimunes , Neoplasias , Humanos , Receptor de Morte Celular Programada 1 , Tolerância Imunológica , Ativação Linfocitária , Domínios ProteicosRESUMO
Lymphocyte activation gene-3 (LAG-3) is an inhibitory receptor expressed on activated T cells and an emerging immunotherapy target. Domain 1 (D1) of LAG-3, which has been purported to directly interact with major histocompatibility complex class II (MHCII) and fibrinogen-like protein 1 (FGL1), has been the major focus for the development of therapeutic antibodies that inhibit LAG-3 receptor-ligand interactions and restore T cell function. Here, we present a high-resolution structure of glycosylated mouse LAG-3 ectodomain, identifying that cis-homodimerization, mediated through a network of hydrophobic residues within domain 2 (D2), is critically required for LAG-3 function. Additionally, we found a previously unidentified key protein-glycan interaction in the dimer interface that affects the spatial orientation of the neighboring D1 domain. Mutation of LAG-3 D2 residues reduced dimer formation, dramatically abolished LAG-3 binding to both MHCII and FGL1 ligands, and consequentially inhibited the role of LAG-3 in suppressing T cell responses. Intriguingly, we showed that antibodies directed against D1, D2, and D3 domains are all capable of blocking LAG-3 dimer formation and MHCII and FGL-1 ligand binding, suggesting a potential allosteric model of LAG-3 function tightly regulated by dimerization. Furthermore, our work reveals unique epitopes, in addition to D1, that can be targeted for immunotherapy of cancer and other human diseases.
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Antígenos de Histocompatibilidade Classe II , Linfócitos T , Animais , Humanos , Camundongos , Dimerização , Fibrinogênio/metabolismo , Ligantes , MutaçãoRESUMO
PURPOSES: Due to the morphological diversity of deformities, technical difficulties, improperly designed components, and so on, THA remains a challenging task in dysplastic hips, especially in highly dislocated hips. The purpose of this study was to comprehensively evaluate the clinical outcomes of robot-assisted THA in patients with DDH through a large cohort study, including the precision of acetabular cup positioning, indicators of inflammatory response, indicators of muscle damage, and complications. METHODS: We retrospectively analyzed patients with DDH who underwent THA in our prospectively constructed joint registry between August 2018 and August 2022. Finally, 147 manual THAs and 147 robotic-assisted THAs were included in the final analysis. Patient demographics, indicators of inflammation, indicators of muscle damage, operative time, Harris hip scores (HHS), and forgotten joint score (FJS) were recorded for analysis. The precision of the positioning of the acetabular component was assessed with plain radiographs. RESULTS: In the Crowe II/III groups, the reconstructed center of rotation (COR) in the robotic-assisted group was closer to the anatomical COR with less variation than the manual group (absolute horizontal distances of COR 3.5 ± 2.8 vs. 5.4 ± 4.9 mm, p < 0.05; absolute vertical distances of COR 6.4 ± 4.1 vs. 11.7 ± 8.2 mm, p = 0.001). For all Crowe subtypes, the robotic-assisted THA significantly increased the proportion of acetabular cups located in the safety zone within 5° (all p < 0.05). Interleukin-6 and creatine kinase levels were slightly lower and significantly different in the robotic-assisted group at three days postoperatively (all p < 0.05). CONCLUSIONS: Compared to the manual technique, the robot-assisted technique improved the precision and reproducibility of acetabular component positioning, particularly in DDH patients with Crowe types II/III. The robotic-assisted technique did not increase operative time, bleeding, complications, or revision rates, and had a slighter early inflammatory response and muscle damage.