RESUMEN
The existence of multiple serotypes renders vaccine development challenging for most viruses in the Enterovirus genus. An alternative and potentially more viable strategy for control of these viruses is to develop broad-spectrum antivirals by targeting highly conserved proteins that are indispensable for the virus life cycle, such as the 3C protease. Previously, two single-chain antibody fragments, YDF and GGVV, were reported to effectively inhibit human rhinovirus 14 proliferation. Here, we found that both single-chain antibody fragments target sites on the 3C protease that are distinct from its known drug site (peptidase active site) and possess different mechanisms of inhibition. YDF does not block the active site but instead noncompetitively inhibits 3C peptidase activity through an allosteric effect that is rarely seen for antibody protease inhibitors. Meanwhile, GGVV antagonizes the less-explored regulatory function of 3C in genome replication. The interaction between 3C and the viral genome 5' noncoding region has been reported to be important for enterovirus genome replication. Here, the interface between human rhinovirus 14 3C and its 5' noncoding region was probed by hydrogen-deuterium exchange coupled mass spectrometry and found to partially overlap with the interface between GGVV and 3C. Consistently, prebinding of GGVV completely abolishes interaction between human rhinovirus 14 3C and its 5' noncoding region. The epitopes of YDF and GGVV, therefore, represent two additional sites of therapeutic vulnerability in rhinovirus. Importantly, the GGVV epitope appears to be conserved across many enteroviruses, suggesting that it is a promising target for pan-enterovirus inhibitor screening and design.
Asunto(s)
Antivirales/farmacología , Cisteína Endopeptidasas/química , Enterovirus/efectos de los fármacos , Anticuerpos de Cadena Única/farmacología , Proteínas Virales/antagonistas & inhibidores , Proteínas Virales/química , Proteasas Virales 3C , Regiones no Traducidas 5' , Regulación Alostérica , Sitio Alostérico , Secuencia de Aminoácidos , Antivirales/química , Antivirales/metabolismo , Cisteína Endopeptidasas/metabolismo , Enterovirus/enzimología , Epítopos , Genoma Viral , ARN Viral/metabolismo , Anticuerpos de Cadena Única/química , Anticuerpos de Cadena Única/metabolismo , Proteínas Virales/metabolismoRESUMEN
Oligomer metasurfaces have attracted a lot of attention in recent years because of their ability to drive strong resonance effects. In this work, by perturbing the symmetry of the structure, we find that there are a large number of resonance modes in the oligomer metasurfaces associated with the optical bound states in the continuum (BICs) near the communication wavelength. When the positions of two nanodisks of the hexamer oligomers are moved along the x- or y-directions at the same time, the mirror symmetry is broken, and an electric quadrupole BIC and three magnetic dipole BICs are excited. The results of near-field distribution of three-dimensional nanodisks and far-field scattering of multiple dipoles in each quasi-BIC reveal that the four BICs present different optical characteristics. It is noted that the method of symmetry breaking by moving the position of nanodisks can accurately control the asymmetric parameter of symmetry-protected BICs, which provides a route for the realization of ultrahigh quality (Q)-factor oligomer metasurfaces in experiment.
RESUMEN
OBJECTIVE: To assess the survival and the predictors of mortality in patients with severe cervical spinal cord injuries (CSCI). DESIGN: Retrospective study. PARTICIPANTS: From January 1, 2010, to May 31, 2018, patients who suffered from severe CSCIs in Western China were enrolled in this study (N=222). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Survival rates and mortality risk factors. Measures were calculated by the product-limit method (Kaplan-Meier) and the Cox model. RESULTS: The overall 1-year, 3-year, 5-year, and 8-year postoperative mortalities were 24.4%, 30.6%, 33.3%, 36.2%, and 39.0%, respectively. Most deaths occurred within 36 months after the injury. According to the Cox proportional hazards model, the significant predictors of survival were as follows: (1) age; (2) neurologic level; (3) treatment options (surgical or conservative); (4) ventilator support (P<.05). The 8-year mortality for older patients (>50y) was 50.2%, which was significantly higher than that for younger patients (32.4%, <50y). The risk of death was 2.053 times higher in higher levels of injury (C1-C4) than in lower levels of injury (C5-C8) (P<.05). Compared with conservative treatment, patients who received surgical treatment (either anterior or posterior decompression) had a lower risk of death (P<.05). No significant difference was detected in the risk of death between early surgery (<3d) and mid-term surgery (3-7d) (P>.05). However, patients who received late-term surgery (>7d) had a higher mortality risk (P<.05). The overall 8-year mortality risk of patients who needed ventilator support was much higher than those who did not need ventilator support (P<.05). CONCLUSIONS: Age, neurologic level, ventilator dependence, treatment options, and timing to surgery were main risk factors for mortality in patients with severe CSCIs. Better understanding of the predictors for survival could possibly contribute to the improvement of survival rates.
Asunto(s)
Vértebras Cervicales/lesiones , Traumatismos de la Médula Espinal/mortalidad , Adolescente , Adulto , Factores de Edad , Anciano , Vértebras Cervicales/cirugía , China/epidemiología , Tratamiento Conservador , Femenino , Humanos , Puntaje de Gravedad del Traumatismo , Masculino , Persona de Mediana Edad , Procedimientos Neuroquirúrgicos , Modelos de Riesgos Proporcionales , Respiración Artificial , Estudios Retrospectivos , Factores de Riesgo , Traumatismos de la Médula Espinal/terapia , Tasa de Supervivencia , Tiempo de Tratamiento , Adulto JovenRESUMEN
BACKGROUND: The aim of this study is to determine, via retrospective study, the effects of vascular morphology and related factors on the success of selective arterial catheterization of the left vertebral artery when approached via right-sided radial artery cerebral angiography. METHODS: Patients who had undergone diagnostic cerebral angiography were enrolled, and their medical history, catheter type, and vessel morphology were analyzed. RESULTS: A total of 205 patients were enrolled in this study from February 2014 to December 2015. After exclusion according to defined criteria, 161 patients were incorporated into the final analysis. Selective catheterization of the bilateral subclavian artery and the bilateral common carotid artery were conducted successfully in all patients, and the success rate of selective catheterization of the left vertebral artery was 82.0%. The success rate of the left vertebral artery catheterization was positively correlated with the angle between the left vertebral artery and the left subclavicular artery (P < 0.001), with 90° serving as a demarcation point, and this was higher in patients without innominate artery distortion (90.2-75.0%), although this finding was not statistically significant. However, the morphology of the aortic artery did not affect the success rate of selective catheterization of the left vertebral artery (P = 0.189), and there was no significant difference (P = 0.231) in the success rate of selective catheterization if the left vertebral artery was predominant (91.0%, 81/89) or balanced (84.7%, 61/72). A total of 0.9% (2/161) of the patients experienced surgery-related complications. Both these patients exhibited bleeding at the puncture point when they were deflated 2 hr after the operation. They were pressurized and depressurization was again conducted for an appropriate period of time. CONCLUSIONS: The angle between the left vertebral artery and the left subclavicular artery is the primary vessel-associated morphological factor affecting the success rate of selective catheterization of the left vertebral artery in the right-sided radial artery cerebral angiography, while innominate artery distortion also had some more limited impact on this success rate.
Asunto(s)
Cateterismo Periférico/métodos , Angiografía Cerebral/métodos , Trastornos Cerebrovasculares/diagnóstico por imagen , Arteria Radial/diagnóstico por imagen , Arteria Vertebral , Anciano , Puntos Anatómicos de Referencia , Arteria Carótida Común/diagnóstico por imagen , Cateterismo Periférico/efectos adversos , Cateterismo Periférico/instrumentación , Angiografía Cerebral/efectos adversos , Angiografía Cerebral/instrumentación , Trastornos Cerebrovasculares/cirugía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Punciones , Estudios Retrospectivos , Arteria Subclavia/diagnóstico por imagen , Resultado del Tratamiento , Dispositivos de Acceso Vascular , Arteria Vertebral/diagnóstico por imagenRESUMEN
BACKGROUND: The goal of this study is to evaluate the safety and efficacy of a novel catheter for right radial artery approach cerebral angiography. METHODS: Patients from the Neurology Department of The Second Affiliated Hospital of Guangxi Traditional Chinese Medical University who underwent diagnostic cerebral angiography of either the left vertebral artery dominant type or balanced type were enrolled in this study. RESULTS: A total of 167 patients were treated between February 2016 and December 2017, of whom 44 were excluded based on study exclusion criteria and 123 were enrolled in the present analysis. Bilateral subclavian artery catheterization and bilateral common carotid artery catheterization were conducted successfully in all 123 patients. The success rate of selective catheterization of the left vertebral artery was 87.8% (108/123). The success rate of selective catheterization of the right vertebral artery using the novel catheter was 89.0% (73/82). The average fluoroscopy time was 6.5 ± 3.4 min, the average operation duration was 47 ± 3.7 (range 50-90) min, and the average dosage of contrast agent was 112.3 ± 8.1 mL. One patient exhibited an absence of pulse in the punctual radial artery after the removal of the arterial compression band, but there was no evidence of ischemia of the distal hand. One patient who was undergoing dual anti-platelet drug treatment suffered from bleeding at the puncture point when deflated for 2 hr after operation; this patient was re-pressurized and re-timed. CONCLUSIONS: This novel catheter improved the success rate of selective left vertebral artery catheterization, and allowed for simplification of the relevant surgical steps. The controllability of this novel catheter was satisfactory, and its associated surgical risk was found to be low.
Asunto(s)
Arteria Carótida Común , Cateterismo Periférico/instrumentación , Angiografía Cerebral/instrumentación , Trastornos Cerebrovasculares/diagnóstico por imagen , Arteria Radial , Arteria Subclavia , Dispositivos de Acceso Vascular , Arteria Vertebral , Anciano , Anciano de 80 o más Años , Arteria Carótida Común/diagnóstico por imagen , Cateterismo Periférico/efectos adversos , Angiografía Cerebral/efectos adversos , Diseño de Equipo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Arteria Radial/diagnóstico por imagen , Factores de Riesgo , Arteria Subclavia/diagnóstico por imagen , Arteria Vertebral/diagnóstico por imagenRESUMEN
PURPOSE: To build a mathematical model which could calculate the desired laminoplasty opening size (LOS) based on the target sagittal canal diameter (SCD) before single-door cervical laminoplasty (SDCL) when taking the effects of surgery drill into consideration. METHODS: The model was based on geometric analysis on deformation of spinal canal; the formula was derived and characterized as: y (mm) = 2 [Formula: see text] × sin(ß/2) = c - d (y is the size of LOS, [Formula: see text] the size of transverse canal diameter, ß the size of laminoplasty opening size, c the size of mini-plate and d the diameter of the drill bit used during the surgery operation). The parameters of pre- and postoperative computed tomography scans of 20 patients who had undergone SDCL were measured by the picture archiving and communication system (PACS) software and a new instrument named as Lei's ruler, respectively. RESULTS: The effects of surgery SDCL were very significant; for each patient, the SCD was enlarged dramatically after the surgery (P < 0.01). The differences between the data obtained by PACS and Lei's ruler were no statistically significant (P > 0.05). According to the derived formula, the 95% confidence intervals of SCD after the surgery were within the range of 14 mm and 14.5 mm. CONCLUSION: Applying the mathematical model and derived formula, the desired LOS could be calculated according to the target SCD which could help the surgeon select an optimum mini-plate before SDCL. At the same time, a new measuring device named Lei's ruler is designed for the convenience of the derived formula. These slides can be retrieved under Electronic Supplementary Material.
Asunto(s)
Vértebras Cervicales/cirugía , Laminoplastia/métodos , Modelos Teóricos , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The guanine nucleotide exchange factor GEF-H1 (also known as ARHGEF2) is identified as a member of the Dbl family of GEFs. It regulates RhoA-dependent cell signaling pathways and plays important roles in biological processes. GEF-H1 contains an N-terminal zinc finger domain, a Dbl-homologous (DH) domain followed by a Pleckstrin homology (PH) domain, and a C-terminal domain. The specific roles of its PH domain are poorly understood. Here we report the crystal structure of human GEF-H1 PH domain to 2.45 Å resolution. A conserved surface is formed by ß8, ß9, ß10, and it may mediate protein-protein interactions. Although the folding resembles other PH domains that have defined structures, superposition of different PH domains clearly shows that the loop between ß6/ß7 and the loop between ß3/ß4 are so close that they will prevent its binding with phosphoinositide due to steric hindrance, and this has been proved by isothermal titration calorimetry (ITC) and thermal shift assay (TSA). Our studies provide a structural framework for further work on the function of GEF-H1.
Asunto(s)
Fosfatidilinositoles/química , Factores de Intercambio de Guanina Nucleótido Rho/química , Secuencia de Aminoácidos , Proteínas Sanguíneas/química , Cristalografía por Rayos X , Humanos , Datos de Secuencia Molecular , Fosfoproteínas/química , Unión Proteica , Estructura Terciaria de Proteína , Factores de Intercambio de Guanina Nucleótido Rho/ultraestructuraRESUMEN
Methionine sulfoxide reductase A (MsrA), a specific enzyme that converts methionine-S-sulfoxide to methionine, plays an important role in the regulation of protein function and the maintenance of redox homeostasis. In this study, we examined the impact of hepatic MsrA overexpression on lipid metabolism and atherosclerosis in apoE-deficient (apoE(-/-)) mice. In vitro study showed that in HepG2 cells, lentivirus-mediated human MsrA (hMsrA) overexpression upregulated the expression levels of several key lipoprotein-metabolism-related genes such as liver X receptor α, scavenger receptor class B type I, and ABCA1. ApoE(-/-) mice were intravenously injected with lentivirus to achieve high-level hMsrA expression predominantly in the liver. We found that hepatic hMsrA expression significantly reduced plasma VLDL/LDL levels, improved plasma superoxide dismutase, and paraoxonase-1 activities, and decreased plasma serum amyloid A level in apoE(-/-) mice fed a Western diet, by significantly altering the expression of several genes in the liver involving cholesterol selective uptake, conversion and excretion into bile, TG biosynthesis, and inflammation. Moreover, overexpression of hMsrA resulted in reduced hepatic steatosis and aortic atherosclerosis. These results suggest that hepatic MsrA may be an effective therapeutic target for ameliorating dyslipidemia and reducing atherosclerosis-related cardiovascular diseases.
Asunto(s)
Apolipoproteínas E/deficiencia , Aterosclerosis/metabolismo , Metionina Sulfóxido Reductasas/biosíntesis , Animales , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Aterosclerosis/enzimología , Células Cultivadas , Colesterol/metabolismo , Células Hep G2 , Humanos , Metabolismo de los Lípidos , Hígado/metabolismo , Masculino , Metionina Sulfóxido Reductasas/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de LDL/metabolismoRESUMEN
Tryptophan 2,3-dioxygenase (TDO), one of the two key enzymes in the kynurenine pathway, catalyzes the indole ring cleavage at the C2-C3 bond of L-tryptophan. This is a rate-limiting step in the regulation of tryptophan concentration in vivo, and is thus important in drug discovery for cancer and immune diseases. Here, we report the crystal structure of human TDO (hTDO) without the heme cofactor to 2.90 Å resolution. The overall fold and the tertiary assembly of hTDO into a tetramer, as well as the active site architecture, are well conserved and similar to the structures of known orthologues. Kinetic and mutational studies confirmed that eight residues play critical roles in L-tryptophan oxidation.
Asunto(s)
Triptófano Oxigenasa/química , Triptófano Oxigenasa/metabolismo , Secuencia de Aminoácidos , Dominio Catalítico , Cristalografía por Rayos X , Hemo/metabolismo , Humanos , Cinética , Modelos Moleculares , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Oxidación-Reducción , Conformación Proteica , Homología de Secuencia de Aminoácido , Triptófano/metabolismo , Triptófano Oxigenasa/genéticaRESUMEN
BACKGROUND: Nonfusion technologies, such as motion-preservation devices, have begun a new era of treatment options in spine surgery. Motion-preservation approaches mainly include total disc replacement for anterior cervical discectomy and fusion. However, for multisegment fusion, such as anterior cervical corpectomy and fusion, the options are more limited. Therefore, we designed a novel 3D-printed motion-preservation artificial cervical corpectomy construct (ACCC) for multisegment fusion. The aim of this study was to explore the feasibility of ACCC in a goat model. METHODS: Goats were treated with anterior C3 corpectomy and ACCC implantation and randomly divided into two groups evaluated at 3 or 6 months. Radiography, 3D CT reconstruction and MRI evaluations were performed. Biocompatibility was evaluated using micro-CT and histology. RESULTS: Postoperatively, all goats were in good condition, with free neck movement. Implant positioning was optimal. The relationship between facet joints was stable. The range of motion of the C2-C4 segments during flexion-extension at 3 and 6 months postoperatively was 7.8° and 7.3°, respectively. The implants were wrapped by new bone tissue, which had grown into the porous structure. Cartilage tissue, ossification centres, new blood vessels, and bone mineralization were observed at the porous metal vertebrae-bone interface and in the metal pores. CONCLUSIONS: The ACCC provided stabilization while preserving the motion of the functional spinal unit and promoting bone regeneration and vascularization. In this study, the ACCC was used for anterior cervical corpectomy and fusion (ACCF) in a goat model. We hope that this study will propel further research of motion-preservation devices.
Asunto(s)
Vértebras Cervicales , Cabras , Impresión Tridimensional , Fusión Vertebral , Animales , Vértebras Cervicales/cirugía , Vértebras Cervicales/diagnóstico por imagen , Fusión Vertebral/métodos , Rango del Movimiento Articular , Modelos Animales , Materiales Biocompatibles , Ensayo de Materiales/métodos , Factores de Tiempo , Discectomía/métodosRESUMEN
Background and objective: Our group has developed a novel artificial cervical joint complex (ACJC) as a motion preservation instrument for cervical corpectomy procedures. Through finite element analysis (FEA), this study aims to assess this prosthesis's mobility and stability in the context of physiological reconstruction of the cervical spine. Materials and methods: A finite element (FE)model of the subaxial cervical spine (C3-C7) was established and validated. ACJC arthroplasty, anterior cervical corpectomy and fusion (ACCF), and two-level cervical disc arthroplasty (CDA) were performed at C4-C6. Range of motion (ROM), intervertebral disc pressure (IDP), facet joint stress (FJS), and maximum von Mises stress on the prosthesis and vertebrae during loading were compared. Results: Compared to the intact model, the ROM in all three surgical groups demonstrated a decline, with the ACCF group exhibiting the most significant mobility loss, and the highest compensatory motion in adjacent segments. ACJC and artificial cervical disc prosthesis (ACDP) well-preserved cervical mobility. In the ACCF model, IDP and FJS in adjacent segments increased notably, whereas the index segments experienced the most significant FJS elevation in the CDA model. The ROM, IDP, and FJS in both index and adjacent segments of the ACJC model were intermediate between the other two. Stress distribution of ACCF instruments and ACJC prosthesis during the loading process was more dispersed, resulting in less impact on the adjacent vertebrae than in the CDA model. Conclusion: The biomechanical properties of the novel ACJC were comparable to the ACCF in constructing postoperative stability and equally preserved physiological mobility of the cervical spine as CDA without much impact on adjacent segments and facet joints. Thus, the novel ACJC effectively balanced postoperative stability with cervical motion preservation.
RESUMEN
Bone defect disease seriously endangers human health and affects beauty and function. In the past five years, the three dimension (3D) printed radially graded triply periodic minimal surface (TPMS) porous scaffold has become a new solution for repairing bone defects. This review discusses 3D printing technologies and applications for TPMS scaffolds. To this end, the microstructural effects of 3D printed TPMS scaffolds on bone regeneration were reviewed and the structural characteristics of TPMS, which can promote bone regeneration, were introduced. Finally, the challenges and prospects of using TPMS scaffolds to treat bone defects were presented. This review is expected to stimulate the interest of bone tissue engineers in radially graded TPMS scaffolds and provide a reliable solution for the clinical treatment of personalised bone defects.
RESUMEN
Structure-guided immunofocusing HIV-1 vaccine design entails a comprehensive understanding of Envs from diverse HIV-1 subtypes, including circulating recombinant forms (CRFs). Here, we present the cryo-EM structures of Envs from two Asia prevalent CRFs (CRF01_AE and CRF07_BC) at 3.0 and 3.5 Å. We compare the structures and glycosylation patterns of Envs from different subtypes and perform cross-clade statistical analyses to reveal the unique features of CRF01_AE V1 region, which are associated with the resistance to certain bNAbs. We also solve a 4.1 Å cryo-EM structure of CRF01_AE Env in complex with F6, the first bNAb from CRF01_AE-infected individuals. F6 recognizes a gp120-gp41 spanning epitope to allosterically destabilize the Env trimer apex and weaken inter-protomer packing, which in turn hinders the receptor binding and induces Env trimer disassembly, demonstrating a dual mechanism of neutralization. These findings broaden our understanding of CRF Envs and shed lights on immunofocusing HIV-1 vaccine design.
Asunto(s)
Infecciones por VIH , VIH-1 , Vacunas , Humanos , VIH-1/genética , Genes env , Unión Proteica , Glicosilación , Anticuerpos ampliamente neutralizantes , Anticuerpos Anti-VIH , Productos del Gen env del Virus de la Inmunodeficiencia Humana , Anticuerpos NeutralizantesRESUMEN
Neuropathic pain has a complex pathogenesis. Here, we examined the role of caveolin-1 (Cav-1) in the anterior cingulate cortex (ACC) in a chronic constriction injury (CCI) mouse model for the enhancement of presynaptic glutamate release in chronic neuropathic pain. Cav-1 was localized in glutamatergic neurons and showed higher expression in the ACC of CCI versus sham mice. Moreover, the release of glutamate from the ACC of the CCI mice was greater than that of the sham mice. Inhibition of Cav-1 by siRNAs greatly reduced the release of glutamate of ACC, while its overexpression (induced by injecting Lenti-Cav-1) reversed this process. The chemogenetics method was then used to activate or inhibit glutamatergic neurons in the ACC area. After 21 days of injection of AAV-hM3Dq in the sham mice, the release of glutamate was increased, the paw withdrawal latency was shortened, and expression of Cav-1 in the ACC was upregulated after intraperitoneal injection of 2 mg/kg clozapine N-oxide. Injection of AAV-hM4Di in the ACC of CCI mice led to the opposite effects. Furthermore, decreasing Cav-1 in the ACC in sham mice injected with rAAV-hM3DGq did not increase glutamate release. These findings suggest that Cav-1 in the ACC is essential for enhancing glutamate release in neuropathic pain.
Asunto(s)
Ácido Glutámico , Neuralgia , Animales , Ratones , Caveolina 1/genética , Caveolina 1/metabolismo , Ácido Glutámico/metabolismo , Giro del Cíngulo/metabolismo , Neuralgia/metabolismo , Neuralgia/patología , Neuronas/patologíaRESUMEN
NOD-like receptor protein 3 (NLRP3) inflammasomes trigger the inflammatory cascades and participate in various inflammatory diseases, including noise-induced hearing loss (NIHL) caused by oxidative stress. Recently, the anti-inflammatory traditional medicine oridonin (Ori) has been reported to provide hearing protection in mice after noise exposure by blocking the NLRP3-never in mitosis gene A-related kinase 7 (NEK7)-inflammasome complex assembly. Using RNA sequencing analysis, we further elucidated that interleukin 1 receptor type 2 (IL1R2) may be another crucial factor regulated by Ori to protect NIHL. We observed that IL1R2 expression was localized in spiral ganglion neurons, inner and outer hair cells, in Ori-treated mouse cochleae. Additionally, we confirmed that ectopic overexpression of IL1R2 in the inner ears of healthy mice using an adeno-associated virus delivery system significantly reduced noise-induced ribbon synapse lesions and hearing loss by blocking the "cytokine storm" in the inner ear. This study provides a novel theoretical foundation for guiding the clinical treatment of NIHL.
Asunto(s)
Oído Interno , Pérdida Auditiva Provocada por Ruido , Otitis , Ratones , Animales , Pérdida Auditiva Provocada por Ruido/tratamiento farmacológico , Pérdida Auditiva Provocada por Ruido/etiología , Pérdida Auditiva Provocada por Ruido/patología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Oído Interno/metabolismo , Oído Interno/patología , Inflamación/complicaciones , Antiinflamatorios/farmacología , Otitis/complicaciones , Receptores de Interleucina-1RESUMEN
Objective: Prolonged mechanical ventilation in children undergoing cardiac surgery is related to the decrease in cardiac output. The pressure recording analytical method (PRAM) is a minimally invasive system for continuous hemodynamic monitoring. To evaluate the postoperative prognosis, our study explored the predictive value of hemodynamic management for the duration of mechanical ventilation (DMV). Methods: This retrospective study included 60 infants who underwent cardiac surgery. Cardiac index (CI), the maximal slope of systolic upstroke (dp/dtmax), and cardiac cycle efficiency (CCE) derived from PRAM were documented in each patient 0, 4, 8, and 12 h (T0, T1, T2, T3, and T4, respectively) after their admission to the intensive care unit (ICU). A linear mixed model was used to deal with the hemodynamic data. Correlation analysis, receiver operating characteristic (ROC), and a XGBoost machine learning model were used to find the key factors for prediction. Results: Linear mixed model revealed time and group effect in CI and dp/dtmax. Prolonged DMV also have negative correlations with age, weight, CI at and dp/dtmax at T2. dp/dtmax outweighing CI was the strongest predictor (AUC of ROC: 0.978 vs. 0.811, p < 0.01). The machine learning model suggested that dp/dtmax at T2 ≤ 1.049 or < 1.049 in combination with CI at T0 ≤ 2.0 or >2.0 can predict whether prolonged DMV (AUC of ROC = 0.856). Conclusion: Cardiac dysfunction is associated with a prolonged DMV with hemodynamic evidence. CI measured by PRAM immediately after ICU admission and dp/dtmax 8h later are two key factors in predicting prolonged DMV.
RESUMEN
Hepatitis B virus (HBV) infection has been associated with an increased risk for B-cell lymphomas. We previously showed that 20% of diffuse large B-cell lymphoma (DLBCL) patients from China, an endemic area of HBV infection, have chronic HBV infection (surface antigen-positive, HBsAg+) and are characterized by distinct clinical and genetic features. Here, we showed that 24% of follicular lymphoma (FL) Chinese patients are HBsAg+. Compared with the HBsAg- FL patients, HBsAg+ patients are younger, have a higher histological grade at diagnosis, and have a higher incidence of disease progression within 24 months. Moreover, by sequencing the genomes of 109 FL tumors, we observed enhanced mutagenesis and distinct genetic profile in HBsAg+ FLs, with a unique set of preferentially mutated genes (TNFAIP3, FAS, HIST1H1C, KLF2, TP53, PIM1, TMSB4X, DUSP2, TAGAP, LYN, and SETD2) but lack of the hallmark of HBsAg- FLs (ie, IGH/BCL2 translocations and CREBBP mutations). Transcriptomic analyses further showed that HBsAg+ FLs displayed gene-expression signatures resembling the activated B-cell-like subtype of diffuse large B-cell lymphoma, involving IRF4-targeted genes and NF-κB/MYD88 signaling pathways. Finally, we identified an increased infiltration of CD8+ memory T cells, CD4+ Th1 cells, and M1 macrophages and higher T-cell exhaustion gene signature in HBsAg+ FL samples. Taken together, we present new genetic/epigenetic evidence that links chronic HBV infection to B-cell lymphomagenesis, and HBV-associated FL is likely to have a distinct cell-of-origin and represent as a separate subtype of FL. Targetable genetic/epigenetic alterations identified in tumors and their associated tumor microenvironment may provide potential novel therapeutic approaches for this subgroup of patients.
Asunto(s)
Hepatitis B , Linfoma Folicular , Linfoma de Células B Grandes Difuso , China/epidemiología , Hepatitis B/complicaciones , Hepatitis B/diagnóstico , Hepatitis B/genética , Antígenos de Superficie de la Hepatitis B/análisis , Antígenos de Superficie de la Hepatitis B/genética , Antígenos de Superficie de la Hepatitis B/uso terapéutico , Virus de la Hepatitis B/genética , Humanos , Linfoma Folicular/tratamiento farmacológico , Linfoma Folicular/genética , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Microambiente TumoralRESUMEN
In order to enhance the mechanical properties of polyethylene glycol (PEG) polyurethane elastomer, the modified hyperbranched polyester (HBP) was introduced. The chemical structures of HBP/PEG polyurethane films were analyzed by attenuated total reflection-Fourier transfoum infrared spectrum (ATR-FTIR). The results indicate that with the modified hyperbranched polyester added, the tensile strength and elongation at break of PEG polyurethane elastomer are improved obviously. When the content of hyperbranched polyester of the third generation is 0.4%, the resultant elastomer has the best tensile strength, which increases 2.53 times. When the content of hyperbranched polyester of the first generation rises up to 1.6%, the resultant elastomer has the best elongation at break, which increases 1.43 times. The degree of the total hydrogen bonding and the degree of microphase separation are increased, which enhance the mechanical properties of PEG polyurethane elastomer.
RESUMEN
BACKGROUND: CRISPR-Cas9 has been developed as a therapeutic agent for various infectious and genetic diseases. In many clinically relevant applications, constitutively active CRISPR-Cas9 is delivered into human cells without a temporal control system. Excessive and prolonged expression of CRISPR-Cas9 can lead to elevated off-target cleavage. The need for modulating CRISPR-Cas9 activity over time and dose has created the demand of developing CRISPR-Cas off switches. Protein and small molecule-based CRISPR-Cas inhibitors have been reported in previous studies. RESULTS: We report the discovery of Cas9-inhibiting peptides from inoviridae bacteriophages. These peptides, derived from the periplasmic domain of phage major coat protein G8P (G8PPD), can inhibit the in vitro activity of Streptococcus pyogenes Cas9 (SpCas9) proteins in an allosteric manner. Importantly, the inhibitory activity of G8PPD on SpCas9 is dependent on the order of guide RNA addition. Ectopic expression of full-length G8P (G8PFL) or G8PPD in human cells can inactivate the genome-editing activity of SpyCas9 with minimum alterations of the mutation patterns. Furthermore, unlike the anti-CRISPR protein AcrII4A that completely abolishes the cellular activity of CRISPR-Cas9, G8P co-transfection can reduce the off-target activity of co-transfected SpCas9 while retaining its on-target activity. CONCLUSION: G8Ps discovered in the current study represent the first anti-CRISPR peptides that can allosterically inactivate CRISPR-Cas9. This finding may provide insights into developing next-generation CRISPR-Cas inhibitors for precision genome engineering.
Asunto(s)
Proteína 9 Asociada a CRISPR/antagonistas & inhibidores , Sistemas CRISPR-Cas , Fragmentos de Péptidos/metabolismo , Regulación Alostérica , Bacteriófago M13 , Proteína 9 Asociada a CRISPR/metabolismo , Proteínas de la Cápside/química , Edición Génica/métodos , Células HEK293 , Humanos , Células K562 , Fragmentos de Péptidos/química , Fragmentos de Péptidos/genéticaRESUMEN
The purpose of this study was to investigate the effectiveness and practicality of 3D-printed model-guided endoscopic surgery for the treatment of basal ganglia hemorrhage. The authors retrospectively analyzed the data of all patients who underwent endoscopic evacuation of basal ganglia hemorrhage in the Department of Neurosurgery at Dalang Hospital and Shipai Hospital between December 2017 and February 2019. Twelve patients, in whom the 3D-printed model guidance was used for endoscopic evacuation, were included in this investigation. Using 3D reconstructed technology, we designed the appropriate surgical approach. Then, an individualized facial model with the guide orifice was printed by a 3D printer. Further, the 3D-printed model was employed to guide the insertion of the endoscope sheath. As a result, the average evacuation rate was 97.2% (range 90.1-100.0%). The GCS and mRS score were improved in each patient from admission to discharge examination. All patients had a good prognosis based on their functional independence measure (FIM) scores at the 6-month follow-up. The 3D-printed model-guided endoscopic evacuation was effective and safe for basal ganglia hemorrhage. This technique deserves further investigation to determine its role in intracerebral hemorrhage management.