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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 Histocompatibilidad Clase II , Linfocitos T , Animales , Humanos , Ratones , Dimerización , Fibrinógeno/metabolismo , Ligandos , MutaciónRESUMEN
Doping anions into LiFePO4 can improve the electrochemical performance of lithium-ion batteries. In this study, structures, electronic properties and Li-ion migration of anion (F- , Cl- , and S2- ) doping into LiFePO4 were systematically investigated by means of density functional theory calculations. Anion substitution for oxygen atoms leads to an expansion of the LiFePO4 lattice, significantly facilitating Li-ion diffusion. For Cl- and F- anion doped into LiFePO4 , the energy barrier of Li-ion migration gets lowered to 0.209 eV and 0.283â eV from 0.572â eV. The introduction of anions narrows the forbidden band of LiFePO4 , enhancing its electronic conductivity. This work pays a way towards the rational design of high-performance lithium-ion batteries.
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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.
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Artroplastia de Reemplazo de Cadera , Displasia del Desarrollo de la Cadera , Prótesis de Cadera , Procedimientos Quirúrgicos Robotizados , Humanos , Artroplastia de Reemplazo de Cadera/efectos adversos , Artroplastia de Reemplazo de Cadera/métodos , Articulación de la Cadera/cirugía , Prótesis de Cadera/efectos adversos , Procedimientos Quirúrgicos Robotizados/efectos adversos , Estudios de Cohortes , Estudios Retrospectivos , Displasia del Desarrollo de la Cadera/cirugía , Reproducibilidad de los Resultados , Acetábulo/cirugía , Resultado del TratamientoRESUMEN
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 Reemplazo de Cadera , Osteotomía , Huesos Pélvicos , Humanos , Osteotomía/métodos , Osteotomía/efectos adversos , Femenino , Masculino , Estudios de Casos y Controles , Artroplastia de Reemplazo de Cadera/métodos , Artroplastia de Reemplazo de Cadera/efectos adversos , Adulto , Huesos Pélvicos/cirugía , Huesos Pélvicos/diagnóstico por imagen , Rango del Movimiento Articular , Articulación de la Cadera/cirugía , Articulación de la Cadera/fisiopatología , Articulación de la Cadera/diagnóstico por imagen , Adulto Joven , Luxación de la Cadera/cirugía , Luxación de la Cadera/etiología , Adolescente , Resultado del Tratamiento , Luxación Congénita de la Cadera/cirugíaRESUMEN
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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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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BACKGROUND: Total hip arthroplasty (THA) for fibrous-fused hips is technically demanding. This study aimed to evaluate the precision and accuracy, as well as the rate of conversion of robotic-assisted THA in such difficult patients. METHODS: We retrospectively analyzed 67 patients (84 hips) who underwent THA with fibrous-fused hips between August 2018 and June 2021 at our institution. Demographics, acetabular cup positioning, leg-length discrepancies, and postoperative Harris hip scores were recorded for all patients. Thirty-six patients (44 hips) who underwent robotic-assisted THA and 31 patients (40 hips) who underwent manual THA were enrolled in this study. RESULTS: The robot accurately executed the preoperative plan, and there were no statistically significant differences between the preoperative planned anteversion, inclination, and postoperative measurements. In the robotic group, the percentage of acetabular cups in the safe zone was significantly higher than in the manual group (87.2 versus 55%, respectively, P = .042). The rate of conversion to manual THA for various reasons in the robotic-assisted THA group was 11.4% (5/44). Compared with manual THA, the mean increase in operative time for conversion from robotic-assisted to manual THA was 24 min (P < .001). CONCLUSION: In patients who have fibrous-fused hips, preoperative planning can be accurately executed by robotic-assisted technology. Compared with manual THA, robotic-assisted THA had a remarkable advantage in improving the frequency of achieving cup positioning within the target zone. Overall, robotic-assisted technology was helpful in such difficult cases, and the approximately 11.4% of cases converted to manual THA are reminders that surgeons should be thoroughly prepared preoperatively.
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Artroplastia de Reemplazo de Cadera , Prótesis de Cadera , Procedimientos Quirúrgicos Robotizados , Robótica , Humanos , Estudios Retrospectivos , Acetábulo/cirugíaRESUMEN
All-solid-state lithium metal batteries (LMBs) are considered as the promising higher-energy and improved-safety energy-storage systems. Nevertheless, the electrolyte-electrodes interfacial issues due to the limited solid physical contact lead to discontinuous interfacial charge transport and large interfacial resistance, thereby suffering from unsatisfactory electrochemical performance. Herein, we construct an integrated cathode/polymer electrolyte for all-solid-state LMBs under the action of polymer chains exchange and recombination originating from multiple dynamic bonds in our well-designed dynamic supramolecular ionic conductive elastomers (DSICE) molecular structure. The DSICE acts as polymer electrolytes with excellent electrochemical performance and mechanical properties, achieving the ultrathin pure polymer electrolyte thickness (12â µm). Notably, the DSICE also functions as lithium iron phosphate (LiFePO4 , LFP) cathode binders with enhanced adhesive capability. Such well-constructed Li|DSICE|LFP-DSICE cells generate delicate electrolyte-electrodes interfacial contact at the molecular level, providing continuous Li+ transport pathways and promoting uniform Li+ deposition, further delivering superior long-term charge/discharge stability (>600â cycles, Coulombic efficiency, >99.8 %) and high capacity retention (80 % after 400â cycles). More practically, the Li|DSICE|LFP-DSICE pouch cells show stable electrochemical performance, excellent flexibility and safety under abusive tests.
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HIV-1 envelope (Env) is a trimer of gp120-gp41 heterodimers, synthesized from a precursor gp160 that contains an ER-targeting signal peptide (SP) at its amino-terminus. Each trimer is swathed by ~90 N-linked glycans, comprising complex-type and oligomannose-type glycans, which play an important role in determining virus sensitivity to neutralizing antibodies. We previously examined the effects of single point SP mutations on Env properties and functions. Here, we aimed to understand the impact of the SP diversity on glycosylation of virus-derived Env and virus neutralization by swapping SPs. Analyses of site-specific glycans revealed that SP swapping altered Env glycan content and occupancy on multiple N-linked glycosites, including conserved N156 and N160 glycans in the V1V2 region at the Env trimer apex and N88 at the trimer base. Virus neutralization was also affected, especially by antibodies against V1V2, V3, and gp41. Likewise, SP swaps affected the recognition of soluble and cell-associated Env by antibodies targeting distinct V1V2 configurations, V3 crown, and gp41 epitopes. These data highlight the contribution of SP sequence diversity in shaping the Env glycan content and its impact on the configuration and accessibility of V1V2 and other Env epitopes.
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Epítopos/inmunología , VIH-1/inmunología , Señales de Clasificación de Proteína/fisiología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/metabolismo , Anticuerpos Neutralizantes/inmunología , Glicosilación , Anticuerpos Anti-VIH/inmunología , HumanosRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic since December 2019, and with it, a push for innovations in rapid testing and neutralizing antibody treatments in an effort to solve the spread and fatality of the disease. One such solution to both of these prevailing issues is targeting the interaction of SARS-CoV-2 spike receptor binding domain (RBD) with the human angiotensin-converting enzyme 2 (ACE2) receptor protein. Structural studies have shown that the N-terminal alpha-helix comprised of the first 23 residues of ACE2 plays an important role in this interaction. Where it is typical to design a binding domain to fit a target, we have engineered a protein that relies on multivalency rather than the sensitivity of a monomeric ligand to provide avidity to its target by fusing the N-terminal helix of ACE2 to the coiled-coil domain of the cartilage oligomeric matrix protein. The resulting ACE-MAP is able to bind to the SARS-CoV-2 RBD with improved binding affinity, is expressible in E. coli, and is thermally stable and relatively small (62 kDa). These properties suggest ACE-MAP and the MAP scaffold to be a promising route towards developing future diagnostics and therapeutics to SARS-CoV-2.
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AIMS: Total hip arthroplasty (THA) in patients with hip-dislocation dysplasia remains challenging. This study aims to evaluate whether these patients may benefit from robotic-assisted techniques. METHODS: We reviewed 135 THAs (108 conventional THAs and 27 robotic-assisted THAs) for Crowe type III or IV from January 2017 to August 2019 in our institution. Robotic-assisted THAs were matched with conventional THAs at a 1:1 ratio (27 hips each group) using propensity score matching. The accuracy of cup positioning and clinical outcomes were compared between groups. RESULTS: The inclination of the cup for conventional THAs and robotic THAs was 42.1 ± 5.7 and 41.3 ± 4.6 (p = 0.574), respectively. The anteversion of the cup for conventional THAs was significantly greater than that of robotic THAs (29.5 ± 8.1 and 18.0 ± 4.6; p < 0.001), respectively. The ratio of the acetabular cup in the Lewinnek safe zone was 37% (10/27) in conventional THAs and 96.3% (26/27) in robotic THAs (p < 0.001). Robotic THAs did not achieve better leg length discrepancy than that of conventional THAs (- 0.4 ± 10.9 mm vs. 0.4 ± 8.8 mm, p = 0.774). There was no difference in Harris Hip Score and WOMAC Osteoarthritis index between groups at the 2-year follow-up. No dislocation occurred in all cases at the final follow-up. CONCLUSION: Robotic-assisted THA for patients with high dislocation improves the accuracy of the implantation of the acetabular component with respect to safe zone.
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Artroplastia de Reemplazo de Cadera , Luxación Congénita de la Cadera , Luxación de la Cadera , Prótesis de Cadera , Luxaciones Articulares , Procedimientos Quirúrgicos Robotizados , Acetábulo/cirugía , Artroplastia de Reemplazo de Cadera/efectos adversos , Artroplastia de Reemplazo de Cadera/métodos , Computadores , Luxación de la Cadera/cirugía , Luxación Congénita de la Cadera/cirugía , Humanos , Luxaciones Articulares/cirugía , Puntaje de Propensión , Estudios Retrospectivos , Procedimientos Quirúrgicos Robotizados/efectos adversosRESUMEN
Acetylcholinesterase inhibitors (AChEIs), the most developed treatment strategies for Alzheimer's disease (AD), will be used in clinic for, at least, the next decades. Their side effects are in highly variable from drug to drug with mechanisms remaining to be fully established. The withdrawal of tacrine (Cognex) in the market makes it as an interesting case study. Here, we found tacrine could disrupt the proper trafficking of proline-rich membrane anchor-linked tetrameric acetylcholinesterase (AChE) in the endoplasmic reticulum (ER). The exposure of tacrine in cells expressing AChE, e.g., neurons, caused an accumulation of the misfolded AChE in the ER. This misfolded enzyme was not able to transport to the Golgi/plasma membrane, which subsequently induced ER stress and its downstream signaling cascade of unfolded protein response. Once the stress was overwhelming, the cooperation of ER with mitochondria increased the loss of mitochondrial membrane potential. Eventually, the tacrine-exposed cells lost homeostasis and underwent apoptosis. The ER stress and apoptosis, induced by tacrine, were proportional to the amount of AChE. Other AChEIs (rivastigmine, bis(3)-cognitin, daurisoline, and dauricine) could cause the same problem as tacrine by inducing ER stress in neuronal cells. The results provide guidance for the drug design and discovery of AChEIs for AD treatment. SIGNIFICANCE STATEMENT: Acetylcholinesterase inhibitors (AChEIs) are the most developed treatment strategies for Alzheimer's disease (AD) and will be used in clinic for at least the next decades. This study reports that tacrine and other AChEIs disrupt the proper trafficking of acetylcholinesterase in the endoplasmic reticulum. Eventually, the apoptosis of neurons and other cells are induced. The results provide guidance for drug design and discovery of AChEIs for AD treatment.
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Acetilcolinesterasa/metabolismo , Apoptosis/efectos de los fármacos , Inhibidores de la Colinesterasa/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Neuronas/efectos de los fármacos , Tacrina/farmacología , Animales , Apoptosis/fisiología , Línea Celular Tumoral , Células Cultivadas , Inhibidores de la Colinesterasa/química , Relación Dosis-Respuesta a Droga , Estrés del Retículo Endoplásmico/fisiología , Células HEK293 , Humanos , Ratones , Simulación del Acoplamiento Molecular/métodos , Neuronas/enzimología , Células RAW 264.7 , Ratas , Ratas Sprague-Dawley , Tacrina/químicaRESUMEN
Programmed cell death protein 1 (PD-1) is an inhibitory receptor on T lymphocytes that is critical for modulating adaptive immunity. As such, it has been successfully exploited for cancer immunotherapy. Programmed death ligand 1 (PD-L1) and PD-L2 are ligands for PD-1; the former is ubiquitously expressed in inflamed tissues, whereas the latter is restricted to antigen-presenting cells. PD-L2 binds to PD-1 with 3-fold stronger affinity compared with PD-L1. To date, this affinity discrepancy has been attributed to a tryptophan (W110PD-L2) that is unique to PD-L2 and has been assumed to fit snuggly into a pocket on the PD-1 surface. Contrary to this model, using surface plasmon resonance to monitor real-time binding of recombinantly-expressed and -purified proteins, we found that W110PD-L2 acts as an "elbow" that helps shorten PD-L2 engagement with PD-1 and therefore lower affinity. Furthermore, we identified a "latch" between the C and D ß-strands of the binding face as the source of the PD-L2 affinity advantage. We show that the 3-fold affinity advantage of PD-L2 is the consequence of these two opposing features, the W110PD-L2 "elbow" and a C-D region "latch." Interestingly, using phylogenetic analysis, we found that these features evolved simultaneously upon the emergence of placental mammals, suggesting that PD-L2-affinity tuning was part of the alterations to the adaptive immune system required for placental gestation.
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Antígeno B7-H1/química , Placenta/metabolismo , Proteína 2 Ligando de Muerte Celular Programada 1/química , Secuencia de Aminoácidos , Animales , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/metabolismo , Proliferación Celular , Femenino , Humanos , Ligandos , Activación de Linfocitos , Ratones , Mutagénesis Sitio-Dirigida , Filogenia , Embarazo , Proteína 2 Ligando de Muerte Celular Programada 1/clasificación , Proteína 2 Ligando de Muerte Celular Programada 1/genética , Proteína 2 Ligando de Muerte Celular Programada 1/metabolismo , Unión Proteica , Dominios Proteicos , Estructura Terciaria de Proteína , Alineación de Secuencia , Electricidad EstáticaRESUMEN
Rationally tailoring the coordination environments of metal single atoms (SAs) is an effective approach to promote their catalytic performances, which, however, remains as a challenge to date. Here, we report a novel misplaced deposition strategy for the fabrication of differently coordinated dual-metal hetero-SAs. Systematic characterization results imply that the as-synthesized dual-metal hetero-SAs (exemplified by Cu and Co) are affixed to a hierarchical carbon support via Cu-C4 and Co-N4 coordination bonds. Density functional theory studies reveal that the strong synergistic interactions between the asymmetrically deployed CuC4 and CoN4 sites lead to remarkably polarized charge distributions, i.e., electron accumulation and deficiency around CuC4 and CoN4 sites, respectively. The obtained CuC4/CoN4@HC catalyst exhibits significantly enhanced capability in substrate adsorption and O2 activation, achieving superior catalytic performances in the oxidative esterification of aromatic aldehydes in comparison with the Cu- and Co-based SA counterparts.
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The RV144 vaccine trial revealed a correlation between reduced risk of HIV infection and the level of nonneutralizing-antibody (Ab) responses targeting specific epitopes in the second variable domain (V2) of the HIV gp120 envelope (Env) protein, suggesting this region as a target for vaccine development. To favor induction of V2-specific Abs, we developed a vaccine regimen that included priming with DNA expressing an HIV V1V2 trimeric scaffold immunogen followed by booster immunizations with a combination of DNA and protein in rhesus macaques. Priming vaccination with DNA expressing the HIV recombinant subtype CRF01_AE V1V2 scaffold induced higher and broader V2-specific Ab responses than vaccination with DNA expressing CRF01_AE gp145 Env. Abs recognizing the V2 peptide that was reported as a critical target in RV144 developed only after the priming immunization with V1V2 DNA. The V2-specific Abs showed several nonneutralizing Fc-mediated functions, including ADCP and C1q binding. Importantly, robust V2-specific Abs were maintained upon boosting with gp145 DNA and gp120 protein coimmunization. In conclusion, priming with DNA expressing the trimeric V1V2 scaffold alters the hierarchy of humoral immune responses to V2 region epitopes, providing a method for more efficient induction and maintenance of V2-specific Env Abs associated with reduced risk of HIV infection.IMPORTANCE The aim of this work was to design and test a vaccine regimen focusing the immune response on targets associated with infection prevention. We demonstrated that priming with a DNA vaccine expressing only the HIV Env V1V2 region induces Ab responses targeting the critical region in V2 associated with protection. This work shows that V1V2 scaffold DNA priming immunization provides a method to focus immune responses to the desired target region, in the absence of immune interference by other epitopes. This induced immune responses with improved recognition of epitopes important for protective immunity, namely, V2-specific humoral immune responses inversely correlating with HIV risk of infection in the RV144 trial.
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Vacunas contra el SIDA/inmunología , Anticuerpos Anti-VIH/inmunología , Proteína gp120 de Envoltorio del VIH/química , Proteína gp120 de Envoltorio del VIH/inmunología , VIH/inmunología , Inmunización/métodos , Vacunas contra el SIDA/administración & dosificación , Vacunas contra el SIDA/genética , Animales , Anticuerpos Neutralizantes/inmunología , Epítopos/química , Epítopos/genética , Epítopos/inmunología , Células HEK293 , Antígenos VIH/química , Antígenos VIH/genética , Antígenos VIH/inmunología , Proteína gp120 de Envoltorio del VIH/genética , Humanos , Inmunización Secundaria , Inmunogenicidad Vacunal , Macaca mulatta , Conformación Proteica , Vacunas de ADN/administración & dosificación , Vacunas de ADN/genética , Vacunas de ADN/inmunologíaRESUMEN
The HIV vaccine field now recognizes the potential importance of generating polyfunctional antibodies (Abs). The only clinical HIV vaccine trial to date to show significant efficacy (RV144) found that reduced infection rates correlated with the level of nonneutralizing Abs specific for the V2 region of the envelope glycoprotein. We have conducted a comprehensive preclinical reverse vaccinology-based vaccine program that has included the design and production and testing of numerous scaffolded V2 region immunogens. The most immunogenic vaccine regimen in nonhuman primates among those studied as part of this program consisted of a cocktail of three immunogens presenting V2 from different viruses and clades in the context of different scaffolds. Presently we demonstrate that the V2-specific Ab response from this regimen was highly durable and functionally diverse for the duration of the study (25 weeks after the final immunization). The total IgG binding response at this late time point exhibited only an â¼5× reduction in potency. Three immunizations appeared essential for the elicitation of a strong Ab-dependent cellular cytotoxicity (ADCC) response for all animals, as opposed to the Ab-dependent cellular phagocytosis (ADCP) and virus capture responses, which were comparably potent after only 2 immunizations. All functionalities measured were highly durable through the study period. Therefore, testing this vaccine candidate for its protective capacity is warranted.IMPORTANCE The only HIV vaccine trial for which protective efficacy was detected correlated this efficacy with V2-specific Abs that were effectively nonneutralizing. This result has fueled a decade of HIV vaccine research focused on designing an HIV vaccine capable of eliciting V2-focused, polyfunctional Abs that effectively bind HIV and trigger various leukocytes to kill the virus and restrict viral spread. From the numerous vaccine candidates designed and tested as part of our V2-focused preclinical vaccine program, we have identified immunogens and a vaccine regimen that induces a highly durable and polyfunctional V2-focused Ab response in rhesus macaques, described herein.
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Vacunas contra el SIDA/inmunología , Anticuerpos Anti-VIH/inmunología , Antígenos VIH/inmunología , VIH-1/inmunología , Fragmentos Fc de Inmunoglobulinas/inmunología , Macaca mulatta/inmunología , Proteínas del Envoltorio Viral/inmunología , Animales , Formación de Anticuerpos , Modelos Animales de Enfermedad , Antígenos VIH/genética , Proteína gp120 de Envoltorio del VIH/genética , Proteína gp120 de Envoltorio del VIH/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/prevención & control , Inmunización , Inmunogenicidad Vacunal/inmunología , Proteínas del Envoltorio Viral/genéticaRESUMEN
Angiogenesis is a complicated pathological process and plays an important role in modulating tumor development. Flavonoids, sharing the basic functional group with estrogen, have been utilized as chemopreventive agents to inhibit endothelial cell angiogenesis and also suppress tumor cell proliferation. Ononin, also referred to as formononetin-7-O-ß-d-glucoside, is one of the bioactive chemicals found within many functional food or plants. The anticancer functions of ononin have been reported both in vitro and in vivo. However, the anti-angiogenetic properties of ononin have not been reported. The possible efficacies of ononin against angiogenesis was verified in cultured endothelial cells. Ononin suppressed vascular endothelial growth factor (VEGF)-induced HUVEC migration, invasion. and tube formation activity after 48 h. The apoptosis rate and specific markers, i.e., Bax/Bc-2 ratio, cleaved caspase 3/9 (Cl-caspase 3/9), and cytochrome c (Cyto c), were enhanced in the ononin-treated group. On the other hand, the protein expressions levels of hypoxia-inducible factor 1α (HIF-1α), mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK), and vascular endothelial growth factor receptor 2 (VEGFR2) were restricted after ononin treatment for 2 days in VEGF-pretreated endothelial cells. In summary, ononin acts as a candidate for angiogenetic-related disease prevention and treatment.
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Inhibidores de la Angiogénesis/farmacología , Glucósidos/farmacología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Isoflavonas/farmacología , Transducción de Señal/efectos de los fármacos , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia , Quinasas de Proteína Quinasa Activadas por Mitógenos , Neovascularización Patológica , Receptor 2 de Factores de Crecimiento Endotelial VascularRESUMEN
A novel coronavirus (SARS-CoV-2) has caused more than 150 million confirmed infections worldwide, while it is not clear whether it affects the coastal waters. This paper proposed a biophysical model based on 16 scenarios with different virus half-life parameters to assess potential viral contamination from 25 municipal sewage outfalls into the Bohai Sea. Viral concentration maps showing spatial and temporal changes are provided based on a biophysical model under multiple scenarios. Results demonstrate that adjacent sea areas can become exposed to SARS-CoV-2 via water-borne transport from outfalls, with a higher risk in winter, because SARS-CoV-2 can be highly stable at low temperature. As coastal waters are the ultimate sink for wastewater and the epidemic will last for long time, this work is of great importance to raise awareness, identify vulnerable areas for marine mammals, and avoid the risk of exposure of tourists at bathing beach.
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COVID-19/transmisión , SARS-CoV-2 , Agua de Mar/virología , Aguas del Alcantarillado/virología , Aguas Residuales/virología , Animales , Humanos , Estaciones del Año , Análisis Espacio-Temporal , TemperaturaRESUMEN
Corylin, a flavonoid isolated from the fruit of Psoralea corylifolia, has an osteogenic effect on osteoblasts in vitro and bone micromass ex vivo. However, the effect and mechanism of corylin in regulating osteoclastogenesis remain unknown. By using murine bone marrow macrophages as the osteoclast precursor, corylin was found to inhibit the receptor activator of nuclear factor (NF) κB ligand (RANKL)-induced osteoclast differentiation via down-regulating osteoclastic marker genes. In parallel, F-actin formation and osteoclast migration were diminished in corylin-treated cultured osteoclasts, and subsequently the expressions of osteoclastic proteins were suppressed: the suppression of protein expression was further illustrated by transcriptomic analysis. Furthermore, corylin inhibited the nuclear translocation of p65, giving rise to a restraint in osteoclastic differentiation through the attenuation of transcription factors nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and nuclear factor of activated T cells c1 (NFATc1). There was no obvious change in apoptosis when the RANKL-induce osteoclasts were cultured in the presence of corylin. The finding supports the potential development of corylin as an osteoclast inhibitor against osteoporosis.
Asunto(s)
Flavonoides/farmacología , Osteoclastos/citología , Osteoclastos/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Femenino , Perfilación de la Expresión Génica , Macrófagos/citología , Macrófagos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Osteoclastos/fisiología , Osteogénesis/fisiología , Fagocitosis/efectos de los fármacos , Ligando RANK/genética , Células RAW 264.7RESUMEN
Wastewater-based epidemiology is a useful approach to estimate population-level exposure to a wide range of substances (e.g., drugs, chemicals, biological agents) by wastewater analysis. An important uncertainty in population normalized loads generated is related to the size and variability of the actual population served by wastewater treatment plants (WWTPs). Here, we built a population model using location-based services (LBS) data to estimate dynamic consumption of illicit drugs. First, the LBS data from Tencent Location Big Data and resident population were used to train a linear population model for estimating population (r2 = 0.92). Then, the spatiotemporal accuracy of the population model was validated. In terms of temporal accuracy, we compared the model-based population with the time-aligned ammonia nitrogen (NH4-N) population within the WWTP of SEG, showing a mean squared error of < 10%. In terms of spatial accuracy, we estimated the model-based population of 42 WWTPs in Dalian and compared it with the NH4-N and design population, indicating good consistency overall (5% less than NH4-N and 4% less than design). Furthermore, methamphetamine consumption and prevalence based on the model were calculated with an average of 111 mg/day/1000 inhabitants and 0.24%, respectively, and dynamically displayed on a visualization system for real-time monitoring. Our study provided a dynamic and accurate population for estimating the population-level use of illicit drugs, much improving the temporal and spatial trend analysis of drug use. Furthermore, accurate information on drug use could be used to assess population health risks in a community.