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Enantioselective three-component difunctionalization of alkenes with boron reagents represents an attractive strategy for assembling three-dimensional chiral organoboron compounds. However, regio- and enantiocontrol comprise the pivot challenges in these transformations, which predominantly require the use of activated conjugated alkenes. Herein, by utilizing various carbonyl directing groups, including amides, sulfinamides, ketones, and esters, we succeed in realizing a nickel-catalyzed 1,2-borylalkynylation of unactivated alkenes to enable the simultaneous incorporation of a boron entity and an sp-fragment across the double bond. The products contain boryl, alkynyl, and carbonyl functional groups with orthogonal synthetic reactivities, offering three handles for further derivatization to access valuable intermediates. The utility of this ligand-enabled asymmetric protocol has been highlighted through the late-stage decoration of drug-relevant molecules.
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BACKGROUND: The accelerated growth of older individuals worldwide has increased the number of patients presenting with fragility hip fractures. Having a hip fracture can cause excess mortality, and patients with hip fracture have a higher risk of death than those without hip fracture. Most studies have treated hip fracture as a single, homogeneous condition, but hip fracture includes two major anatomic types: intertrochanteric fracture and femoral neck fracture. Few studies have specifically evaluated 1-year mortality risk in older individuals with femoral intertrochanteric fracture. The aim of this study was to evaluate 1-year mortality and factors associated with mortality in older individuals with femoral intertrochanteric fracture. METHODS: A retrospective review was conducted of 563 patients ≥ 65 years old who underwent surgery for femoral intertrochanteric fractures at our institution between January 2010 and August 2018. Patient demographics, comorbidities, and treatment were collected by retrospective chart review. Age, sex, Body Mass Index (BMI), American Society of Anesthesiologists (ASA) classification, Charlson comorbidity index (CCI), Arbeitsgemeinschaft Für Osteosynthesefragen (AO) fracture classification, haemoglobin value at admission, time to surgery, operation time, and intraoperative blood loss were risk factors to be tested. Multivariable logistic regression was used to evaluate associations between variables and death. RESULTS: Among the 563 patients, 49 died within 1 year after surgery, and the 1-year mortality rate was 8.7%. Multivariate analysis identified age > 80 years (OR = 4.038, P = 0.011), haemoglobin < 100 g/l (OR = 2.732, P = 0.002), ASA score ≥ 3 (OR = 2.551, P = 0.005), CCI ≥ 3 (OR = 18.412, P = 0.018) and time to surgery > 14 d (OR = 3.907, P = 0.030) as independent risk factors for 1-year mortality. Comorbidities such as myocardial infarction and chronic pulmonary disease were associated with 1-year mortality after adjusting for age > 80 years and time to surgery > 14 days. CONCLUSIONS: Patients over 80 years old with haemoglobin < 100 g/l, ASA score ≥ 3, CCI ≥ 3, and multiple comorbidities, especially myocardial infarction and chronic pulmonary disease before surgery, are at a higher risk of 1-year mortality. Doctors should pay more attention to these vulnerable patients, and a surgical delay greater than 14 days should be avoided.
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Fracturas de Cadera , Centros de Atención Terciaria , Humanos , Masculino , Femenino , Anciano , Estudios Retrospectivos , Fracturas de Cadera/mortalidad , Fracturas de Cadera/cirugía , China/epidemiología , Anciano de 80 o más Años , Factores de Riesgo , Centros de Atención Terciaria/tendencias , Medición de Riesgo/métodosRESUMEN
BACKGROUND: The next-generation sequencing (NGS) has developed rapidly in the past decade and is becoming a promising diagnostic tool for periprosthetic infection (PJI). However, its diagnostic value for PJI is still uncertain. The purpose of this systematic review and meta-analysis was to evaluate the diagnostic value of NGS compared to culture. METHODS: In this systematic review and meta-analysis, electronic databases including PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science and clinicaltrials.gov were searched for studies from inception to 12 November 2023. Diagnostic parameters, such as sensitivity, specificity, diagnostic odds ratio and area under the summary receiver-operating characteristic (SROC) curve (AUC), were calculated for the included studies. A systematic review and meta-analysis was performed. RESULTS: A total of 22 studies with 2461 patients were included in our study. The pooled sensitivity, specificity and diagnostic odds ratio of NGS were 87% (95% confidence interval [CI]: 83-90), 94% (95% CI: 91-96) and 111 (95% CI: 70-177), respectively. On the other hand, the pooled sensitivity, specificity and diagnostic odds ratio of culture were 63% (95% CI: 58-67), 98% (95% CI: 96-99) and 93 (95% CI: 40-212), respectively. The SROC curve for NGS and culture showed that the AUCs are 0.96 (95% CI: 0.94-0.98) and 0.82 (95% CI: 0.79-0.86), respectively. CONCLUSION: This systematic review and meta-analysis found NGS had higher sensitivity and diagnostic accuracy but slightly lower specificity than culture. Based on the pooled results, we suggested NGS may have the potential to be a new tool for the diagnosis of PJI. LEVEL OF EVIDENCE: Level IV.
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BACKGROUND: Extended reality (XR), including virtual reality, augmented reality, and mixed reality, has been increasingly used in postoperative rehabilitation of total knee arthroplasty (TKA). The purpose of this systematic review and meta-analysis was to evaluate the effectiveness of XR-based rehabilitation in TKA compared to conventional rehabilitation. METHODS: In this study, we searched PubMed (MEDLINE), Embase (OVID), Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, and clinicaltrials.gov from inception to February 15, 2023 for eligible studies. A total of 14 randomized controlled trials with 989 patients were included in our study. The primary outcomes were pain and function. The secondary outcomes were anxiety and quality of life. A systematic review and meta-analysis was performed. RESULTS: The pooled data indicated XR-based rehabilitation significantly improved the visual analog scale (standardized mean difference [SMD] = -0.31, 95% Confidence Interval [CI] [-0.47 to -0.15], P = .0001), the Western Ontario and McMaster Universities Osteoarthritis Index (SMD = -0.46, 95% CI [-0.86 to -0.06], P = .02), range of motion (SMD = 0.40, 95% CI [0.09 to 0.72], P = .01), and anxiety scores (mean difference = -3.95, 95% CI [-7.76 to -0.13], P = .04) than conventional rehabilitation, but Timed Up and Go test and quality of life were similar in the 2 groups. CONCLUSION: This systematic review and meta-analysis found XR-based rehabilitation improved pain, function, and anxiety, but not quality of life in TKA compared to conventional rehabilitation within 1 month postoperatively. Based on the pooled results, we suggested that XR-based rehabilitation may have benefit in patients' postoperative rehabilitation in TKA.
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Artroplastia de Reemplazo de Rodilla , Realidad Aumentada , Humanos , Artroplastia de Reemplazo de Rodilla/rehabilitación , Calidad de Vida , Equilibrio Postural , Estudios de Tiempo y Movimiento , Dolor Postoperatorio , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
PURPOSE: Patients with total knee arthroplasty (TKA) often suffer from severe postoperative pain, which seriously hinders postoperative rehabilitation. Extended reality (XR), including virtual reality, augmented reality, and mixed reality, has been increasingly used to relieve pain after TKA. The purpose of this study was to evaluate the effectiveness of XR on relieving pain after TKA. METHODS: The electronic databases including PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), and clinicaltrials.gov were searched for studies from inception to July 20, 2023. The outcomes were pain score, anxiety score, and physiological parameters related to pain. Meta-analysis was performed using the Review Manager 5.4 software. RESULTS: Overall, 11 randomized control trials (RCTs) with 887 patients were included. The pooled results showed XR had lower pain scores (SMD = - 0.31, 95% CI [- 0.46 to - 0.16], P < 0.0001) and anxiety scores (MD = - 3.95, 95% CI [- 7.76 to - 0.13], P = 0.04) than conventional methods. The subgroup analysis revealed XR had lower pain scores within 2 weeks postoperatively (SMD = - 0.49, 95% CI [- 0.76 to - 0.22], P = 0.0004) and XR had lower pain scores when applying XR combined with conventional methods (SMD = - 0.43, 95% CI [- 0.65 to - 0.20], P = 0.0002). CONCLUSION: This systematic review and meta-analysis found applying XR could significantly reduce postoperative pain and anxiety after TKA. When XR was combined with conventional methods, postoperative pain can be effectively relieved, especially within 2 weeks after the operation. XR is an effective non-pharmacological analgesia scheme.
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Artroplastia de Reemplazo de Rodilla , Dolor Postoperatorio , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Artroplastia de Reemplazo de Rodilla/efectos adversos , Dolor Postoperatorio/etiología , Dolor Postoperatorio/prevención & control , Dimensión del Dolor , Manejo del Dolor/métodos , Realidad Aumentada , Resultado del Tratamiento , Ansiedad/etiología , Ansiedad/prevención & controlRESUMEN
BACKGROUND: Blood-spinal cord barrier (BSCB) disruption is a key event after spinal cord injury (SCI), which permits unfavorable blood-derived substances to enter the neural tissue and exacerbates secondary injury. However, limited mechanical impact is usually followed by a large-scale BSCB disruption in SCI. How the BSCB disruption is propagated along the spinal cord in the acute period of SCI remains unclear. Thus, strategies for appropriate clinical treatment are lacking. METHODS: A SCI contusion mouse model was established in wild-type and LysM-YFP transgenic mice. In vivo two-photon imaging and complementary studies, including immunostaining, capillary western blotting, and whole-tissue clearing, were performed to monitor BSCB disruption and verify relevant injury mechanisms. Clinically applied target temperature management (TTM) to reduce the core body temperature was tested for the efficacy of attenuating BSCB disruption. RESULTS: Barrier leakage was detected in the contusion epicenter within several minutes and then gradually spread to more distant regions. Membrane expression of the main tight junction proteins remained unaltered at four hours post-injury. Many junctional gaps emerged in paracellular tight junctions at the small vessels from multiple spinal cord segments at 15 min post-injury. A previously unnoticed pathological hemodynamic change was observed in the venous system, which likely facilitated gap formation and barrier leakage by exerting abnormal physical force on the BSCB. Leukocytes were quickly initiated to transverse through the BSCB within 30 min post-SCI, actively facilitating gap formation and barrier leakage. Inducing leukocyte transmigration generated gap formation and barrier leakage. Furthermore, pharmacological alleviation of pathological hemodynamic changes or leukocyte transmigration reduced gap formation and barrier leakage. TTM had very little protective effects on the BSCB in the early period of SCI other than partially alleviating leukocyte infiltration. CONCLUSIONS: Our data show that BSCB disruption in the early period of SCI is a secondary change, which is indicated by widespread gap formation in tight junctions. Pathological hemodynamic changes and leukocyte transmigration contribute to gap formation, which could advance our understanding of BSCB disruption and provide new clues for potential treatment strategies. Ultimately, TTM is inadequate to protect the BSCB in early SCI.
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Contusiones , Traumatismos de la Médula Espinal , Ratas , Ratones , Animales , Ratas Sprague-Dawley , Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/metabolismo , Barrera Hematoencefálica/metabolismo , Leucocitos/patología , Contusiones/metabolismoRESUMEN
The organic pollutants in industrial wastewater continuously endanger human health. Therefore, effective treatment of organic pollutants is very urgent. Photocatalytic degradation technology is an excellent solution to remove it. TiO2 photocatalysts are easy to prepare and have high catalytic activity, unfortunately, TiO2 only absorbs ultraviolet light limiting its utilization of visible light. In this study, a facile environmentally friendly synthesis of Ag-coated on micro-wrinkled TiO2-based catalysts in order to extend the absorption of Visible light. Firstly, a fluorinated titanium dioxide precursor was prepared by a one-step solvothermal method, and the precursor was calcined at high temperature in a nitrogen atmosphere to form a carbon dopant, and then a surface silver-deposited carbon/fluorine co-doped TiO2 photocatalyst C/F-Ag-TiO2 was prepared by a hydrothermal method The results showed that the Ag was coated on the wrinkled TiO2 layer and C/F-Ag-TiO2 photocatalyst was synthetized successfully. Benefit from the synergistic effect of doped carbon and fluorine atoms in combination with the quantum size effect of the surface silver nanoparticles, the band gap energy of C/F-Ag-TiO2 (2.56 eV) is obviously lower than anatase (3.2eV). The photocatalyst achieved an impressive degradation rate of 84.2% for Rhodamine B in 4 h, with a degradation rate constant of 0.367 h-1, which was 17 times higher than that of P25 under visible light. Therefore, the C/F-Ag-TiO2 composite is a promising candidate as a highly efficient photocatalyst for environmental remediation.
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Contaminantes Ambientales , Nanopartículas del Metal , Humanos , Plata , Flúor , Luz , Titanio , Carbono , CatálisisRESUMEN
A NiH-catalyzed migratory hydroalkylation of alkenyl amines with predictable and switchable regioselectivity is reported. By utilizing a ligand-controlled, directing group-assisted strategy, various alkyl units are site-selectively installed at inert sp3 C-H sites far away from the original C=C bonds. A range of structurally diverse α- and ß-branched protected amines are conveniently synthesized via stabilization of 5- and 6-membered nickelacycles respectively. This method exhibits broad scope and high functional group tolerance, and can be applied to late-stage modification of medicinally relevant molecules.
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Alquenos , Aminas , Catálisis , Ligandos , Estructura Molecular , EstereoisomerismoRESUMEN
BACKGROUND: Previous observational studies have reported sarcopenia can affect the structure and function of brain cortical structure. However, the causality inferred from those studies was subjected to residual confounding and reverse causation. Herein, we use a two-sample Mendelian randomization (MR) analysis to illustrate the causal effect of sarcopenia-associated traits on brain cortical structure. METHODS: We selected appendicular lean mass (ALM), hand grip strength (left and right) (HGSL and HGSR), and usual walking pace (UWP) to symbolize sarcopenia. The definition of brain cortical structure is human brain cortical surface area (SA) and cortical thickness (TH) globally and in 34 functional regions measured by magnetic resonance imaging. Instrumental variables at the genome-wide significance level were obtained from publicly available datasets, and inverse variance weighted as the primary method was used for MR analysis. RESULT: At the global level, we found ALM (ß=2604.68, 95 % confidence interval (CI): 1886.17 to 3323.19, P = 1.20 × 10-12) and HGSR (ß=4733.05, 95 % CI: 2245.08 to 7221.01, P = 1.93 × 10-4) were associated with increased SA. At the region level, the SA of 25 functional gyrus without global weighted was influenced by ALM. The HGSR significantly increased SA of medial orbitofrontal and precentral gyrus without global weighted and ALM was associated with decrease of TH of lateral occipital gyrus with global weighted. No pleiotropy was detected. CONCLUSION: This was the first MR study investigated the causal effect of sarcopenia-associated traits on brain cortical structure. In our study, we revealed genetically predicted sarcopenia-associated traits including ALM and HGSR could affect brain cortical structure.
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Fuerza de la Mano , Sarcopenia , Humanos , Análisis de la Aleatorización Mendeliana , Sarcopenia/complicaciones , Sarcopenia/diagnóstico por imagen , Sarcopenia/genética , Encéfalo/diagnóstico por imagen , FenotipoRESUMEN
Natural polymer-based hydrogels have been widely applied in bone tissue engineering due to their excellent biocompatibility and outstanding ability of drug encapsulation. However, they have relatively weak mechanical properties and lack bioactivity. Hence, we developed a bioactive nanoparticle composite hydrogel by incorporating LAPONITE®, which is an osteo-inductive inorganic nanoparticle. The incorporation of the nanoparticle significantly enhanced its mechanical properties. In vitro evaluation indicated that the nanocomposite hydrogel could exhibit good biocompatibility. Besides, the nanocomposite hydrogel was proved to have excellent osteogenic ability with up-regulated expression of osteogenic markers such as type I collagen (COL-I), runt-related transcription factor-2 (Runx-2) and osteocalcin (OCN). Furthermore, the in vivo study confirmed that the composite nanocomposite hydrogel could significantly promote new bone formation, providing a prospective strategy for bone tissue regeneration.
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Fibroínas , Nanopartículas , Hidrogeles , Nanogeles , Regeneración Ósea , Ingeniería de Tejidos , SedaRESUMEN
Speckle-type POZ protein (SPOP) acts as a cullin3-RING ubiquitin ligase adaptor, which facilitates the recognition and ubiquitination of substrate proteins. Previous research suggests that targeting SPOP holds promise in the treatment of clear cell renal cell carcinoma (ccRCC). On the basis of the reported SPOP inhibitor 230D7, a series of ß-lactam derivatives were synthesized in this study. The biological activity assessment of these compounds revealed E1 as the most potent inhibitor, which can disrupt the SPOP-substrate interactions in vitro and suppress the colony formation of ccRCC cells. Taken together, this study provided compound E1 as a potent inhibitor against ccRCC and offered insight into the development of the ß-lactam SPOP inhibitor.
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BACKGROUND: Extended reality (XR), including virtual reality (VR), augmented reality (AR), and mixed reality (MR), has been used in the training of total hip arthroplasty (THA). This study aims to examine the effectiveness of XR training in THA. METHODS: In this systematic review and meta-analysis, we searched PubMed (MEDLINE), EMBASE (OVID), Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, and clinicaltrials.gov from inception to September 2022 for eligible studies. The Review Manager 5.4 software was applied to compare accuracy of inclination and anteversion, and surgical duration between XR training and conventional methods. RESULTS: We identified 213 articles, of which 4 randomized clinical trials and 1 prospective controlled study including 106 participants met inclusion criteria. The pooled data indicated the XR training had better accuracy of inclination and shorter surgical duration than conventional methods (MD = -2.07, 95% CI [- 4.02 to -0.11], P = 0.04; SMD = -1.30, 95% CI [- 2.01 to -0.60], P = 0.0003), but the accuracy of anteversion was similar in the two groups. CONCLUSIONS: This systematic review and meta-analysis found XR training had better accuracy of inclination and shorter surgical duration than conventional methods in THA, but the accuracy of anteversion was similar. Based on the pooled results, we suggested that XR training can better improve trainees' surgical skills than conventional methods in THA.
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Artroplastia de Reemplazo de Cadera , Realidad Aumentada , Realidad Virtual , Humanos , Estudios ProspectivosRESUMEN
BACKGROUND: Extended reality (XR), including virtual reality, augmented reality (AR), and mixed reality, has been used to help achieve accurate acetabular cup placement in total hip arthroplasty (THA). This study aimed to compare the differences between XR-assisted and conventional THA. METHODS: In this systematic review and meta-analysis, electronic databases including PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), and clinicaltrials.gov were searched for studies from inception to September 10, 2023. The outcomes were accuracy of inclination and anteversion, duration of surgery, and intraoperative blood loss. Meta-analysis was performed using Review Manager 5.4 software. RESULTS: A total of five studies with 396 patients were included in our study. The pooled results indicated AR-assisted THA had better accuracy of inclination and anteversion than conventional THA (SMD = - 0.51, 95% CI [- 0.96 to - 0.07], P = 0.02; SMD = - 0.96, 95% CI [- 1.19 to - 0.72], P < 0.00001), but duration of surgery and intraoperative blood loss were similar in the two groups. CONCLUSION: This systematic review and meta-analysis found that AR-assisted THA had better accuracy of inclination and anteversion than conventional THA, but the duration of surgery and intraoperative blood loss were similar in the two groups. Based on the pooled results, we suggested that AR can provide more precise acetabular cup placement than conventional methods in THA.
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Artroplastia de Reemplazo de Cadera , Realidad Aumentada , Prótesis de Cadera , Cirugía Asistida por Computador , Humanos , Artroplastia de Reemplazo de Cadera/métodos , Pérdida de Sangre Quirúrgica , Acetábulo/cirugía , Cirugía Asistida por Computador/métodosRESUMEN
PURPOSE: The aim of this study was to analyze the relationship between the timing of surgery and perioperative blood loss, red blood cell (RBC) transfusion rate, and RBC transfusion volume in older patients with hip fracture. METHODS: From January 2020 to August 2022, this retrospective study enrolled older patients with hip fracture who underwent surgery in our hospital. The demographics, fracture type, type of surgery, time from injury to hospital, timing of surgery, medical history (hypertension, diabetes), duration of surgery, intraoperative blood loss, laboratory tests, and preoperative, postoperative and perioperative RBC transfusion requirements were recorded and analyzed. According to the surgical treatment within 48 h or after 48 h after admission, the patients were divided into early surgery group (ES) and delayed surgery group (DS). RESULTS: A total of 243 older patients with hip fracture were finally included in the study. Among these, 96 patients (39.51%) underwent surgery within 48 h of admission and 147 (60.49%) underwent surgery after this time. Total blood loss (TBL) in the ES group was lower than that in the DS group (576.03 ± 265.57 ml vs 699.26 ± 380.58 ml, P = 0.003). Preoperative RBC transfusion rate, and preoperative and perioperative RBC transfusion volume in the ES group were significantly lower than those in the DS group (15.63% vs 26.53%, P = 0.046; 50.00 ± 128.15 ml vs 117.01 ± 225.85 ml, P = 0.004; 80.21 ± 196.63 ml vs 144.90 ± 253.52 ml, P = 0.027). CONCLUSION: Timing of surgery within 48 h of admission for older patients with hip fracture was associated with reduced the total blood loss and RBC transfusion requirements during the perioperative period.
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Transfusión de Eritrocitos , Fracturas de Cadera , Humanos , Anciano , Estudios Retrospectivos , Pérdida de Sangre Quirúrgica/prevención & control , Fracturas de Cadera/cirugía , Transfusión SanguíneaRESUMEN
The neurovascular unit (NVU) reflects the close temporal and spatial link between neurons and blood vessels. However, the understanding of the NVU in the spinal cord is far from clear and largely based on generalized knowledge obtained from the brain. Herein, we review the present knowledge of the NVU and highlight candidate approaches to investigate the NVU, particularly focusing on the spinal cord. Several unique features maintain the highly regulated microenvironment in the NVU. Autoregulation and neurovascular coupling ensure regional blood flow meets the metabolic demand according to the blood supply or local neural activation. The blood-central nervous system barrier partitions the circulating blood from neural parenchyma and facilitates the selective exchange of substances. Furthermore, we discuss spinal cord injury (SCI) as a common injury from the perspective of NVU dysfunction. Hopefully, this review will help expand the understanding of the NVU in the spinal cord and inspire new insights into SCI.
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Encéfalo , Traumatismos de la Médula Espinal , Humanos , Encéfalo/irrigación sanguínea , Neuronas/fisiología , Cabeza , Barrera HematoencefálicaRESUMEN
In our previous study, we successfully designed a dual-crosslinked network hydrogel by introducing the monomers acrylamide (AM), carboxymethylcellulose (CMC), zeolitic imidazolate framework-8 (ZIF-8), and alendronate (Aln). With the simultaneous presentation of physical and chemical crosslinks, the fabricated hydrogel with 10 % concentration of Aln@ZIF-8 (PAM-CMC-10%Aln@ZIF-8) exhibited excellent mechanical characteristics, high Aln loading efficiency (63.83 %), and a slow release period (6 d). These results demonstrate that PAM-CMC-10%Aln@ZIF-8 is a potential carrier for delaying Aln. In this study, we mainly focused on the biocompatibility and osteogenic ability of PAM-CMC-10%Aln@ZIF-8 in vitro, which is a continuation of our previous work. First, this study investigated the biocompatibility of dual-crosslinked hydrogels using calcein-AM/Propidium Iodide and cell counting kit-8. The morphology of rat bone mesenchymal stem cells was assessed using FITC-phalloidin/DAPI and vinculin immunostaining. Finally, osteogenic induction ability in vitro was assessed via alkaline phosphatase expression and alizarin red S staining, which was also confirmed using real-time PCR at the gene level and immunofluorescence at the protein level. The results indicated that the introduction of Aln enabled a dual-crosslinked hydrogel with superior biocompatibility and outstanding osteogenic differentiation ability in vitro, providing a solid foundation for subsequent animal experiments in vivo.
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Carboximetilcelulosa de Sodio , Osteogénesis , Ratas , Animales , Diferenciación Celular , Alendronato/farmacología , HidrogelesRESUMEN
Bone defects have attracted increasing attention in clinical settings. To date, there have been no effective methods to repair defective bones. Balsa wood aerogels are considered as an excellent source of chemicals for chemical modification to facilitate the in situ immobilization of zeolitic imidazolate framework-8. Furthermore, dexamethasone has received considerable attention for bone tissue engineering. In this study, for the first time, a simple but effective one-pot method for developing a novel zeolitic imidazolate framework-8 with different concentrations of dexamethasone was developed. These findings illustrate that the novel scaffold has a significant positive impact on osteogenic differentiation in vitro and repairs defects in vivo, suggesting that it can be used in bone tissue engineering.
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Estructuras Metalorgánicas , Osteogénesis , Andamios del Tejido , Estructuras Metalorgánicas/farmacología , Madera , Regeneración Ósea , Cráneo , Dexametasona/farmacologíaRESUMEN
During a molt or eclosion, insects shed their cuticle, an extracellular matrix made by underlying epidermal cells, by cleavage along a defined line. This means that the "cut here line" is pre-formed on the cuticle, and its formation is indispensable for insect life. Here, we show that the proper formation of the operculum ridge (OR), which is the "cut here line" on the puparium (pupal case) of Drosophila melanogaster, involves Notch signaling activation in the epidermal cells just beneath the future OR region (OR-forming cells). The inhibition of Notch signaling causes defects in eclosion due to failure in OR cleavage, the chitin organization and several cuticular proteins localization, glucose dehydrogenase (Gld) activity, and OR-forming cell shape. Our findings provide the first insight into the molecular basis of the structure and formation of the "cut here line" on the cuticle.
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The use of small agonists to target stimulators of interferon genes (STING) has been demonstrated to be a promising strategy for the treatment of various cancers and infectious diseases. Herein, we discovered a series of 1H-pyrrole-3-carbonitrile derivatives as potential STING agonists. On this basis, the structure-activity relationship of this scaffold was studied by introducing various substituents on the aniline ring system. Representative compounds 7F, 7P, and 7R all displayed comparable activities to the reported STING agonist SR-717 in binding various hSTING alleles and induced reporter signal in human THP1 cell lines. Model compound 7F induced phosphorylation of TBK1, IRF3, p65, and STAT3 in a STING-dependent fashion and stimulated the expression of target genes IFNB1, CXCL10, and IL6 in a time-dependent manner in human THP1 cells. Our findings afforded a series of novel STING agonists with promising potential.
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The development of stimulator of interferon genes (STING) agonists has been of potential applications for the treatment of cancer and infectious diseases. Based on the crystal structure of SR-717 bound to hSTING, we designed and synthesized a novel series of bipyridazine derivatives as highly potent STING agonists. Among them, compound 12L led to significant thermal stability shifts of the common alleles of hSTING, as well as that of mSTING. 12L also displayed potent activities in various hSTING alleles and mSTING competition binding assay. Specifically, 12L displayed higher cell-based activities than SR-717 in both human THP1 (EC50 = 0.38 ± 0.03 µM) and mouse RAW 264.7 cells (EC50 = 12.94 ± 1.78 µM), and was validated to activate the downstream signaling pathway of STING via a STING-dependent manner. Furthermore, compound 12L showed favorable pharmacokinetic (PK) properties and antitumor efficacy. These findings suggested that compound 12L has development potential as an antitumor agent.