RESUMEN
Campylobacter jejuni is a pathogenic bacterium that causes enteritis and Guillain-Barre syndrome in humans. To identify a protein target for the development of a new therapeutic against C. jejuni infection, each gene product of C. jejuni must be functionally characterized. The cj0554 gene of C. jejuni encodes a DUF2891 family protein with unknown functions. To provide functional insights into CJ0554, we determined and analyzed the crystal structure of the CJ0554 protein. CJ0554 adopts an (α/α)6-barrel structure, which consists of an inner α6 ring and an outer α6 ring. CJ0554 assembles into a dimer in a unique top-to-top orientation that is not observed in its structural homologs, N-acetylglucosamine 2-epimerase superfamily members. Dimer formation was verified by analyzing CJ0554 and its ortholog protein through gel-filtration chromatography. The top of the CJ0554 monomer barrel harbors a cavity, which is connected to that of the second subunit in the dimer structure, generating a larger intersubunit cavity. This elongated cavity accommodates extra nonproteinaceous electron density, presumably as a pseudosubstrate, and is lined with generally catalytically active histidine residues that are invariant in CJ0554 orthologs. Therefore, we propose that the cavity functions as the active site of CJ0554.
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Campylobacter jejuni , Enteritis , Humanos , Campylobacter jejuni/genética , Anticuerpos Antibacterianos , AcetilglucosaminaRESUMEN
BACKGROUND: Individualised positive end-expiratory pressure (PEEP) improves respiratory mechanics. However, whether PEEP reduces postoperative pulmonary complications (PPCs) remains unclear. We investigated whether driving pressure-guided PEEP reduces PPCs after laparoscopic/robotic abdominal surgery. METHODS: This single-centre, randomised controlled trial enrolled patients at risk for PPCs undergoing laparoscopic or robotic lower abdominal surgery. The individualised group received driving pressure-guided PEEP, whereas the comparator group received 5 cm H2O fixed PEEP during surgery. Both groups received a tidal volume of 8 ml kg-1 ideal body weight. The primary outcome analysed per protocol was a composite of pulmonary complications (defined by pre-specified clinical and radiological criteria) within 7 postoperative days after surgery. RESULTS: Some 384 patients (median age: 67 yr [inter-quartile range: 61-73]; 66 [18%] female) were randomised. Mean (standard deviation) PEEP in patients randomised to individualised PEEP (n=178) was 13.6 cm H2O (2.1). Individualised PEEP resulted in lower mean driving pressures (14.7 cm H2O [2.6]), compared with 185 patients randomised to standard PEEP (18.4 cm H2O [3.2]; mean difference: -3.7 cm H2O [95% confidence interval (CI): -4.3 to -3.1 cm H2O]; P<0.001). There was no difference in the incidence of pulmonary complications between individualised (25/178 [14.0%]) vs standard PEEP (36/185 [19.5%]; risk ratio [95% CI], 0.72 [0.45-1.15]; P=0.215). Pulmonary complications as a result of desaturation were less frequent in patients randomised to individualised PEEP (8/178 [4.5%], compared with standard PEEP (30/185 [16.2%], risk ratio [95% CI], 0.28 [0.13-0.59]; P=0.001). CONCLUSIONS: Driving pressure-guided PEEP did not decrease the incidence of pulmonary complications within 7 days of laparoscopic or robotic lower abdominal surgery, although uncertainty remains given the lower than anticipated event rate for the primary outcome. CLINICAL TRIAL REGISTRATION: KCT0004888 (http://cris.nih.go.kr, registration date: April 6, 2020).
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Laparoscopía , Procedimientos Quirúrgicos Robotizados , Humanos , Femenino , Anciano , Masculino , Procedimientos Quirúrgicos Robotizados/efectos adversos , Procedimientos Quirúrgicos Robotizados/métodos , Pulmón , Respiración con Presión Positiva/métodos , Laparoscopía/efectos adversos , Laparoscopía/métodos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/prevención & control , Complicaciones Posoperatorias/etiología , Volumen de Ventilación PulmonarRESUMEN
BACKGROUND: Previous studies have consistently reported a slower recovery of consciousness following remimazolam-based total intravenous anesthesia without flumazenil than with propofol. This study aimed to compare the reversal effect of flumazenil on the recovery of consciousness after remimazolam-based total intravenous anesthesia with the propofol recovery profile. METHODS: This prospective, single-blinded, randomized trial included 57 patients undergoing elective open thyroidectomy at a tertiary university hospital. Patients were randomly allocated to receive either remimazolam- or propofol-based total intravenous anesthesia (remimazolam group: 28 patients, propofol group: 29 patients). The primary outcome was the time from the end of general anesthesia to first eye opening (min). The secondary outcomes were the time from the end of the general anesthesia to extubation (min), initial modified Aldrete score measured at the post-anesthesia care unit, length of stay at the post-anesthesia care unit (min), occurrence of postoperative nausea and vomiting during the first 24 h postoperatively, and Korean version of Quality of Recovery-15 score at 24 h postoperatively. RESULTS: The remimazolam group showed significantly faster first eye opening time (2.3 [interquartile range, IQR: 1.8-3.3] min vs. 5.0 [IQR: 3.5-7.8] min, median difference:-2.7 [95% confidence interval, CI: -3.7 to -1.5] min, P < 0.001) and extubation time (3.2 [IQR: 2.4-4.2] min vs. 5.7 [IQR: 4.7-8.3] min, median difference: -2.7 [97.5% CI: -5.0 to -1.6] min, P < 0.001). There were no significant differences in other postoperative outcomes. CONCLUSIONS: The planned incorporation of flumazenil with remimazolam-based total intravenous anesthesia provided rapid and reliable recovery of consciousness.
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Propofol , Humanos , Propofol/efectos adversos , Flumazenil , Anestésicos Intravenosos , Estudios Prospectivos , Tiroidectomía , Anestesia Intravenosa , Náusea y Vómito Posoperatorios/inducido químicamenteRESUMEN
BACKGROUND: Based on the controversy surrounding pulmonary artery catheterization (PAC) in surgical patients, we investigated the interchangeability of cardiac index (CI) and systemic vascular resistance (SVR) measurements between ClearSight™ and PAC during living-donor liver transplantation (LDLT). METHODS: This prospective study included consecutively selected LDLT patients. ClearSight™-based CI and SVR measurements were compared with those from PAC at seven LDLT-stage time points. ClearSight™-based systolic (SAP), mean (MAP), and diastolic (DAP) arterial pressures were also compared with those from femoral arterial catheterization (FAC). For the comparison and analysis of ClearSight™ and the reference method, Bland-Altman analysis was used to analyze accuracy while polar and four-quadrant plots were used to analyze the trending ability. RESULTS: From 27 patients, 189 pairs of ClearSight™ and reference values were analyzed. The CI and SVR performance errors (PEs) exhibited poor accuracy between the two methods (51.52 and 51.73%, respectively) in the Bland-Altman analysis. CI and SVR also exhibited unacceptable trending abilities in both the polar and four-quadrant plot analyses. SAP, MAP, and DAP PEs between the two methods displayed favorable accuracy (24.28, 21.18, and 26.26%, respectively). SAP and MAP exhibited acceptable trending ability in the four-quadrant plot between the two methods, but not in the polar plot analyses. CONCLUSIONS: During LDLT, CI and SVR demonstrated poor interchangeability, while SAP and MAP exhibited acceptable interchangeability between ClearSight™ and FAC.
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Trasplante de Hígado , Humanos , Trasplante de Hígado/métodos , Estudios Prospectivos , Gasto Cardíaco , Donadores Vivos , Resistencia Vascular , Termodilución/métodos , Reproducibilidad de los ResultadosRESUMEN
Helicobacter pylori is a pathogenic bacterium that causes gastric ulcers and cancer. Among the diverse virulence genes of H. pylori, the IceA gene was identified to be expressed upon adherence to host cells. The IceA gene has two alleles, iceA1 and iceA2, which encode completely different proteins. IceA1 protein was shown to exert endonuclease activity, whereas IceA2 has never been analyzed at the molecular level. Based on a sequence analysis, IceA2 proteins differ in length depending on the strain and are classified into five groups (A-E). To structurally characterize IceA2, we determined the crystal structure of group-D IceA2 (IceA2sD) and performed a modeling-based comparative analysis of IceA2 groups. IceA2sD consists of three ß-sheet repeats and serially arranges them like the ß-propeller structure of the WD40 domain. However, each ß-sheet of IceA2 is stabilized using a unique structural motif that is not observed in WD40. Moreover, IceA2sD lacks an additionally appended ß-strand and does not form the Velcro-like closure of WD40. Therefore, IceA2sD adopts a curved rod-like structure rather than an enclosed circular structure in WD40. IceA2 proteins contain 1-4 ß-sheet modules depending on the groups and are modeled to be highly diverse in size and shape.
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Infecciones por Helicobacter , Helicobacter pylori , Antígenos Bacterianos , Proteínas de la Membrana Bacteriana Externa/genética , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Genotipo , Infecciones por Helicobacter/microbiología , Helicobacter pylori/metabolismo , Humanos , Virulencia/genéticaRESUMEN
BACKGROUND: Body temperature is a vital sign, and temperature monitoring during liver transplantation is important. Tracheal temperature can be measured via an endotracheal tube with a temperature sensor on the cuff of the tube. This study aimed to investigate the accuracy and trending ability of tracheal temperature measurement compared to those of the core temperature measured at the esophagus and pulmonary artery (PA) in living donor liver transplant recipients. METHODS: Twenty-two patients who underwent living donor liver transplantation (LDLT) were enrolled. Patients were intubated using an endotracheal tube with a temperature sensor placed on the inner surface of the tube cuff. Tracheal, esophageal, and PA temperatures were recorded at five time points corresponding to the different phases of liver transplantation. The tracheal and esophageal, tracheal and PA, and esophageal and PA temperatures were compared using Bland-Altman analysis, four-quadrant plot/concordance analysis, and polar plot analysis. RESULTS: Bland-Altman analysis showed an overall mean bias (95% limits of agreement) between tracheal and esophageal temperatures of -0.10 °C (-0.37 °C to 0.18 °C), with a percentage error of 0.27%; between tracheal and PA temperatures, -0.05 °C (-0.91 °C to 0.20 °C), with a percentage error of -0.15%; and between esophageal and PA temperatures, 0.04 °C (-0.27 °C to 0.35 °C), with a percentage error of 0.12%. The concordance rates between tracheal and esophageal temperatures, tracheal and PA temperatures, and esophageal and PA temperatures were 96.2%, 96.2%, and 94.94%, respectively. The polar plot analysis showed a mean angular bias (radial limits of agreement) of 4° (26°), -3° (13°), and 2° (21°). CONCLUSIONS: Monitoring core temperature at the inner surface of the endotracheal tube cuff is accurate in all phases of LDLT with good trending ability; thus, it can be an excellent alternative for monitoring during LDLTs.
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Temperatura Corporal , Trasplante de Hígado , Humanos , Donadores Vivos , Temperatura , TráqueaRESUMEN
NAD(H)/NADP(H)-dependent aldehyde/alcohol oxidoreductase (AAOR) participates in a wide range of physiologically important cellular processes by reducing aldehydes or oxidizing alcohols. Among AAOR substrates, furan aldehyde is highly toxic to microorganisms. To counteract the toxic effect of furan aldehyde, some bacteria have evolved AAOR that converts furan aldehyde into a less toxic alcohol. Based on biochemical and structural analyses, we identified Bacillus subtilis YugJ as an atypical AAOR that reduces furan aldehyde. YugJ displayed high substrate specificity toward 5-hydroxymethylfurfural (HMF), a furan aldehyde, in an NADPH- and Ni2+-dependent manner. YugJ folds into a two-domain structure consisting of a Rossmann-like domain and an α-helical domain. YugJ interacts with NADP and Ni2+ using the interdomain cleft of YugJ. A comparative analysis of three YugJ structures indicated that NADP(H) binding plays a key role in modulating the interdomain dynamics of YugJ. Noticeably, a nitrate ion was found in proximity to the nicotinamide ring of NADP in the YugJ structure, and the HMF-reducing activity of YugJ was inhibited by nitrate, providing insights into the substrate-binding mode of YugJ. These findings contribute to the characterization of the YugJ-mediated furan aldehyde reduction mechanism and to the rational design of improved furan aldehyde reductases for the biofuel industry.
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Aldehído Reductasa/química , Aldehído Reductasa/metabolismo , Bacillus subtilis/enzimología , Furaldehído/análogos & derivados , NADP/metabolismo , Níquel/metabolismo , Aldehído Reductasa/genética , Bacillus subtilis/genética , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Clonación Molecular , Cristalografía por Rayos X , Furaldehído/metabolismo , Modelos Moleculares , Unión Proteica , Conformación Proteica , Dominios Proteicos , Pliegue de Proteína , Especificidad por SustratoRESUMEN
Although epigenetic mechanisms of gene expression regulation have recently been implicated in memory consolidation and persistence, the role of nucleosome-remodeling is largely unexplored. Recent studies show that the functional loss of BAF53b, a postmitotic neuron-specific subunit of the BAF nucleosome-remodeling complex, results in the deficit of consolidation of hippocampus-dependent memory and cocaine-associated memory in the rodent brain. However, it is unclear whether BAF53b expression is regulated during memory formation and how BAF53b regulates fear memory in the amygdala, a key brain site for fear memory encoding and storage. To address these questions, we used viral vector approaches to either decrease or increase BAF53b function specifically in the lateral amygdala of adult mice in auditory fear conditioning paradigm. Knockdown of Baf53b before training disrupted long-term memory formation with no effect on short-term memory, basal synaptic transmission, and spine structures. We observed in our qPCR analysis that BAF53b was induced in the lateral amygdala neurons at the late consolidation phase after fear conditioning. Moreover, transient BAF53b overexpression led to persistently enhanced memory formation, which was accompanied by increase in thin-type spine density. Together, our results provide the evidence that BAF53b is induced after learning, and show that such increase of BAF53b level facilitates memory consolidation likely by regulating learning-related spine structural plasticity.SIGNIFICANCE STATEMENT Recent works in the rodent brain begin to link nucleosome remodeling-dependent epigenetic mechanism to memory consolidation. Here we show that BAF53b, an epigenetic factor involved in nucleosome remodeling, is induced in the lateral amygdala neurons at the late phase of consolidation after fear conditioning. Using specific gene knockdown or overexpression approaches, we identify the critical role of BAF53b in the lateral amygdala neurons for memory consolidation during long-term memory formation. Our results thus provide an idea about how nucleosome remodeling can be regulated during long-term memory formation and contributes to the permanent storage of associative fear memory in the lateral amygdala, which is relevant to fear and anxiety-related mental disorders.
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Actinas/metabolismo , Amígdala del Cerebelo/fisiología , Proteínas Cromosómicas no Histona/metabolismo , Proteínas de Unión al ADN/metabolismo , Miedo/fisiología , Consolidación de la Memoria/fisiología , Neuronas/metabolismo , Nucleosomas/metabolismo , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Plasticidad Neuronal/fisiologíaRESUMEN
BACKGROUND: Recent studies have suggested that the activation of mammalian target of rapamycin (mTOR) signaling may be related to antidepressant action. Therefore, the present study evaluated whether antidepressant drugs would exert differential effects on mTOR signaling in the rat hippocampus under conditions of chronic restraint stress. Male Sprague-Dawley rats were subjected to restraint stress for 6 h/days for 21 days with either escitalopram (10 mg/kg) or paroxetine (10 mg/kg) administered after the chronic stress procedure. Western blot analyses were used to assess changes in the levels of phospho-Ser2448-mTOR, phospho-Thr37/46-4E-BP-1, phospho-Thr389-p70S6 K, phospho-Ser422-eIF4B, phospho-Ser240/244-S6, phospho-Ser473-Akt, and phospho-Thr202/Tyr204-ERK in the hippocampus. RESULTS: Chronic restraint stress significantly decreased the levels of phospho-mTOR complex 1 (mTORC1), phospho-4E-BP-1, phospho-p70S6 K, phospho-eIF4B, phospho-S6, phospho-Akt, and phospho-ERK (p < 0.05); the administration of escitalopram and paroxetine increased the levels of all these proteins (p < 0.05 or 0.01). Additionally, chronic restraint stress reduced phospho-mTORC1 signaling activities in general, while escitalopram and paroxetine prevented these changes in phospho-mTORC1 signaling activities. CONCLUSION: These findings provide further data that contribute to understanding the possible relationships among mTOR activity, stress, and antidepressant drugs.
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Antidepresivos de Segunda Generación/farmacología , Citalopram/farmacología , Hipocampo/efectos de los fármacos , Diana Mecanicista del Complejo 1 de la Rapamicina/efectos de los fármacos , Paroxetina/farmacología , Estrés Psicológico/metabolismo , Animales , Hipocampo/metabolismo , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratas , Ratas Sprague-Dawley , Restricción Física/efectos adversos , Transducción de Señal/efectos de los fármacosRESUMEN
The dentate gyrus (DG) of the hippocampus is essential for contextual and spatial memory processing. While lesion or silencing of the DG impairs contextual memory encoding and recall, overly activated DG also prevents proper memory retrieval. Abnormally elevated activity in the DG is repeatedly reported in amnesic mild cognitive impairment (aMCI) patients or aged adults. Although the correlation between memory failure and abnormally active hippocampus is clear, their causal relationship or the underlying nature of such interfering activity is not well understood. Using optogenetics aided by a carefully controlled adeno-associated virus infection system, we were able to examine the differential effects of abnormally activated hippocampus on mice motor behavior and memory function, depending on the extent of the stimulation. Optogenetic stimulation of massive proportion of dorsal DG cells resulted in memory retrieval impairment, but also induced increase in general locomotion. Random additional activity in a sparse population of dorsal DG neurons, however, interfered with contextual memory recall without inducing hyperactivity. Our findings thus establish the causal role of elevated DG activity on memory recall failure, suggesting such aberrant DG activity may contribute to amnesic symptoms in aMCI patients and aged adults.
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Giro Dentado/fisiología , Recuerdo Mental/fisiología , Estimulación Acústica , Adenoviridae/fisiología , Animales , Condicionamiento Clásico , Miedo , Ratones Endogámicos C57BL , Actividad Motora , Neuronas/fisiología , OptogenéticaRESUMEN
OBJECTIVES: Mood-stabilizing drugs, such as lithium (Li) and valproate (VPA), are widely used for the treatment of bipolar disorder, a disease marked by recurrent episodes of mania and depression. Growing evidence suggests that Li exerts neurotrophic and neuroprotective effects, leading to an increase in neural plasticity. The present study investigated whether other mood-stabilizing drugs produce similar effects in primary hippocampal neurons. METHODS: The effects of the mood-stabilizing drugs Li, VPA, carbamazepine (CBZ), and lamotrigine (LTG) on hippocampal dendritic outgrowth were examined. Western blotting analysis was used to measure the expression of synaptic proteins - that is, brain-derived neurotrophic factor (BDNF), postsynaptic density protein-95 (PSD-95), neuroligin 1 (NLG1), ß-neurexin, and synaptophysin (SYP). To determine neuroprotective effects, we used a B27-deprivation cytotoxicity model which causes hippocampal cell death upon removal of B27 from the culture medium. RESULTS: Li (0.5-2.0 mM), VPA (0.5-2.0 mM), CBZ (0.01-0.10 mM), and LTG (0.01-0.10 mM) significantly increased dendritic outgrowth. The neurotrophic effect of Li and VPA was blocked by inhibition of phosphatidylinositol 3-kinase, extracellular signal-regulated kinase, and protein kinase A signaling; the effects of CBZ and LTG were not affected by inhibition of these signaling pathways. Li, VPA, and CBZ prevented B27 deprivation-induced decreases in BDNF, PSD-95, NLG1, ß-neurexin, and SYP levels, whereas LTG did not. CONCLUSIONS: These results suggest that Li, VPA, CBZ, and LTG exert neurotrophic effects by promoting dendritic outgrowth; however, the mechanism of action differs. Furthermore, certain mood-stabilizing drugs may exert neuroprotective effects by enhancing synaptic protein levels against cytotoxicity in hippocampal cultures.
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Antimaníacos/farmacología , Trastorno Bipolar , Dendritas/efectos de los fármacos , Compuestos de Litio/farmacología , Neuronas/efectos de los fármacos , Triazinas/farmacología , Ácido Valproico/farmacología , Animales , Factor Neurotrófico Derivado del Encéfalo/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Moléculas de Adhesión Celular Neuronal/efectos de los fármacos , Moléculas de Adhesión Celular Neuronal/metabolismo , Homólogo 4 de la Proteína Discs Large , Hipocampo/citología , Péptidos y Proteínas de Señalización Intracelular/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Lamotrigina , Proteínas de la Membrana/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Fármacos Neuroprotectores , Fosfatidilinositol 3-Quinasas , Ratas , Sinaptofisina/efectos de los fármacos , Sinaptofisina/metabolismoRESUMEN
Recent studies suggest that ketamine produces antidepressant actions via stimulation of mammalian target of rapamycin (mTOR), leading to increased levels of synaptic proteins in the prefrontal cortex. Thus, mTOR activation may be related to antidepressant action. However, the mTOR signalling underlying antidepressant drug action has not been well investigated. The aim of the present study was to determine whether alterations in mTOR signalling were observed following treatment with antidepressant drugs, using ketamine as a positive control. Using Western blotting, we measured changes in the mTOR-mediated proteins and synaptic proteins in rat hippocampal cultures. Dendritic outgrowth was determined by neurite assay. Our findings demonstrated that escitalopram, paroxetine and tranylcypromine significantly increased levels of phospho-mTOR and its down-stream regulators (phospho-4E-BP-1 and phospho-p70S6K); fluoxetine, sertraline and imipramine had no effect. All drugs tested increased up-stream regulators (phospho-Akt and phospho-ERK) levels. Increased phospho-mTOR induced by escitalopram, paroxetine or tranylcypromine was significantly blocked in the presence of specific PI3K, MEK or mTOR inhibitors, respectively. All drugs tested also increased hippocampal dendritic outgrowth and synaptic proteins levels. The mTOR inhibitor, rapamycin, significantly blocked these effects on escitalopram, paroxetine and tranylcypromine whereas fluoxetine, sertraline and imipramine effects were not affected. The effects of escitalopram, paroxetine and tranylcypromine paralleled those of ketamine. This study presents novel in vitro evidence indicating that some antidepressant drugs promote dendritic outgrowth and increase synaptic protein levels through mTOR signalling; however, other antidepressant drugs seem to act via a different pathway. mTOR signalling may be a promising target for the development of new antidepressant drugs.
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Antidepresivos/farmacología , Hipocampo/citología , Neuronas/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Animales , Proteínas Portadoras/metabolismo , Células Cultivadas , Relación Dosis-Respuesta a Droga , Embrión de Mamíferos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular , Neuritas/efectos de los fármacos , Neuronas/citología , Proteína Oncogénica v-akt/metabolismo , Fosfoproteínas/metabolismo , Fosforilación/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismoRESUMEN
In bacteria, NarJ plays an essential role as a redox enzyme maturation protein in the assembly of the nitrate reductase NarGHI by interacting with the N-terminal signal peptide of NarG to facilitate cofactor incorporation into NarG. The purpose of our research was to elucidate the exact mechanism of NarG signal peptide recognition by NarJ. We determined the structures of NarJ alone and in complex with the signal peptide of NarG via X-ray crystallography and verified the NarJ-NarG interaction through mutational, binding, and molecular dynamics simulation studies. NarJ adopts a curved α-helix bundle structure with a U-shaped hydrophobic groove on its concave side. This groove accommodates the signal peptide of NarG via a dual binding mode in which the left and right parts of the NarJ groove each interact with two consecutive hydrophobic residues from the N- and C-terminal regions of the NarG signal peptide, respectively, through shape and chemical complementarity. This binding is accompanied by unwinding of the helical structure of the NarG signal peptide and by stabilization of the NarG-binding loop of NarJ. We conclude that NarJ recognizes the NarG signal peptide through a complementary hydrophobic interaction mechanism that mediates a structural rearrangement.
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Escherichia coli , Señales de Clasificación de Proteína , Nitrato-Reductasa/química , Nitrato-Reductasa/metabolismo , Escherichia coli/metabolismo , Oxidación-Reducción , Interacciones Hidrofóbicas e HidrofílicasRESUMEN
Recent evidence has suggested that atypical antipsychotic drugs regulate synaptic plasticity. We investigated whether some atypical antipsychotic drugs (olanzapine, aripiprazole, quetiapine, and ziprasidone) altered the expression of synapse-associated proteins in rat hippocampal neuronal cultures under toxic conditions induced by B27 deprivation. A typical antipsychotic, haloperidol, was used for comparison. We measured changes in the expression of various synaptic proteins including postsynaptic density protein-95 (PSD-95), brain-derived neurotrophic factor (BDNF), and synaptophysin (SYP). Then we examined whether these drugs affected the dendritic morphology of hippocampal neurons. We found that olanzapine, aripiprazole, and quetiapine, but not haloperidol, significantly hindered the B27 deprivation-induced decrease in the levels of these synaptic proteins. Ziprasidone did not affect PSD-95 or BDNF levels, but significantly increased the levels of SYP under B27 deprivation conditions. Moreover, olanzapine and aripiprazole individually significantly increased the levels of PSD-95 and BDNF, respectively, even under normal conditions, whereas haloperidol decreased the levels of PSD-95. These drugs increased the total outgrowth of hippocampal dendrites via PI3K signaling, whereas haloperidol had no effect in this regard. Together, these results suggest that the up-regulation of synaptic proteins and dendritic outgrowth may represent key effects of some atypical antipsychotic drugs but that haloperidol may be associated with distinct actions.
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Antipsicóticos/farmacología , Dendritas/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Hipocampo/citología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas de la Membrana/metabolismo , Sinaptofisina/metabolismo , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Células Cultivadas , Dendritas/metabolismo , Homólogo 4 de la Proteína Discs Large , Hipocampo/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas de la Membrana/genética , Ratas , Ratas Sprague-Dawley , Sinaptofisina/genética , Regulación hacia ArribaRESUMEN
BACKGROUND: The Hypotension Prediction Index (HPI) was recently introduced and clinically validated in different surgical conditions. This prospective observational study evaluated HPI's performance in living donor liver transplant recipients under the hypothesis that HPI would be inferior to the previously reported predictability in major surgery due to the surgical characteristics of liver transplantation. METHODS: Twenty adult patients undergoing living donor liver transplantation were enrolled. HPI was monitored during the surgery with the attending anesthesiologist blinded to the HPI. The mean arterial pressure and HPI were recorded at 1-minute intervals. The area under the curve (AUC) of the receiver operating characteristic curve was calculated for the whole dataset and at each phase of liver transplantation at five, 10, and 15 minutes to analyze HPI's performance. RESULTS: A total of 9173 data points were analyzed. The AUC for predicting hypotension at five minutes was 0.810 (95% confidence interval [CI]: 0.780-0.840). The AUCs for predicting hypotension at 10 and 15 minutes were 0.726 (95% CI: 0.681-0.772) and 0.689 (95% CI: 0.642-0.737), respectively. The AUCs for predicting hypotension at five minutes in the preanhepatic, anhepatic, and neohepatic phase were 0.795 (95% CI: 0.711-0.876), 0.728 (95% CI: 0.638-0.819), and 0.837 (95% CI: 0.802-0.873), respectively. The HPI's performance was inferior to that previously reported in major surgery. CONCLUSIONS: HPI in this observational study in living donor liver transplantation predicted hypotension with moderate-to-low accuracy, its predictive value being highest in the neohepatic phase and lowest in the anhepatic phase.
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Hipotensión , Trasplante de Hígado , Adulto , Humanos , Donadores Vivos , Hipotensión/diagnóstico , Hipotensión/etiología , Presión Arterial , Estudios ProspectivosRESUMEN
Background: The modified thoracoabdominal nerve block through the perichondral approach (M-TAPA) is a novel regional analgesic technique that can provide analgesia for both the lateral and anterior abdominal walls. This study aimed to compare the analgesic effect of M-TAPA with that of the subcostal transversus abdominis plane block (TAPB) in patients undergoing laparoscopic cholecystectomy (LC). Methods: Sixty patients scheduled to undergo elective LC were randomly assigned to receive either M-TAPA or subcostal TAPB during anesthesia induction. The primary outcome was the maximum pain intensity during movement within the first 12 hours postoperatively, measured using an 11-point numeric rating scale (NRS). Secondary outcomes included changes in NRS scores during rest, coughing, and movement, which were assessed at 1, 2, 4, 6, and 12 hours postoperatively and immediately before discharge. Additionally, postoperative nausea and vomiting, and patient satisfaction were recorded as secondary outcomes. Results: Data from 56 patients were analyzed, and no significant difference was observed in the primary outcome between the two groups (M-TAPA: 5.5 [interquartile range (IQR): 5-7] vs . subcostal TAPB: 5 [IQR: 4-7], median difference: 0, 95% confidence interval: -1 to 1, P = 0.580). Furthermore, no significant differences in secondary outcomes were observed between the two groups. Conclusions: No significant difference was observed in the analgesic effect between the two techniques. Consequently, further research is necessary to compare the efficacy of M-TAPA with other well-established regional analgesic techniques.
RESUMEN
We aimed to compare the effect of sugammadex to that of neostigmine with respect to the occurrence of postoperative nausea and vomiting (PONV) during the first 24 h following general anesthesia. This retrospective cohort study included patients who underwent elective surgery under general anesthesia in 2020 at an academic medical center in Seoul, South Korea. The exposure groups were determined according to whether the patient received sugammadex or neostigmine as a reversal agent. The primary outcome was PONV occurrence during the first 24 h postoperatively (overall). The association between the type of reversal agent and primary outcome was investigated using logistic regression while adjusting for confounding variables using stabilized inverse probability of treatment weighting (sIPTW). Of the 10,912 patients included in this study, 5,918 (54.2%) received sugammadex. Sugammadex was associated with a significantly lower incidence of overall PONV (15.8% vs. 17.7%; odds ratio, 0.87; 95% confidence interval [CI], 0.79-0.97; P = 0.010) after sIPTW. In conclusion, compared with neostigmine/glycopyrrolate, sugammadex use has a lower risk of PONV during the first 24 h following general anesthesia.
Asunto(s)
Neostigmina , Bloqueo Neuromuscular , Humanos , Adulto , Sugammadex , Náusea y Vómito Posoperatorios/tratamiento farmacológico , Estudios Retrospectivos , Bloqueo Neuromuscular/métodos , Anestesia General/efectos adversos , Anestesia General/métodos , Inhibidores de la Colinesterasa/uso terapéuticoRESUMEN
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of motor neurons in the spinal cord. Although the disease's pathophysiological mechanism remains poorly understood, multifactorial mechanisms affecting motor neuron loss converge to worsen the disease. Although two FDA-approved drugs, riluzole and edaravone, targeting excitotoxicity and oxidative stress, respectively, are available, their efficacies are limited to extending survival by only a few months. Here, we developed combinatorial drugs targeting multifactorial mechanisms underlying key components in ALS disease progression. Using data analysis based on the genetic information of patients with ALS-derived cells and pharmacogenomic data of the drugs, a combination of nebivolol and donepezil (nebivolol-donepezil) was identified for ALS therapy. Here, nebivolol-donepezil markedly reduced the levels of cytokines in the microglial cell line, inhibited nuclear factor-κB (NF-κB) nucleus translocation in the HeLa cell and substantially protected against excitotoxicity-induced neuronal loss by regulating the PI3K-Akt pathway. Nebivolol-donepezil significantly promoted the differentiation of neural progenitor cells (NPC) into motor neurons. Furthermore, we verified the low dose efficacy of nebivolol-donepezil on multiple indices corresponding to the quality of life of patients with ALS in vivo using SOD1G93A mice. Nebivolol-donepezil delayed motor function deterioration and halted motor neuronal loss in the spinal cord. Drug administration effectively suppressed muscle atrophy by mitigating the proportion of smaller myofibers and substantially reducing phospho-neurofilament heavy chain (pNF-H) levels in the serum, a promising ALS biomarker. High-dose nebivolol-donepezil significantly prolonged survival and delayed disease onset compared with vehicle-treated mice. These results indicate that the combination of nebivolol-donepezil efficiently prevents ALS disease progression, benefiting the patients' quality of life and life expectancy.
Asunto(s)
Esclerosis Amiotrófica Lateral , Humanos , Ratones , Animales , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , Donepezilo/uso terapéutico , Nebivolol/uso terapéutico , Nebivolol/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Células HeLa , Calidad de Vida , Médula Espinal/metabolismo , Progresión de la Enfermedad , Modelos Animales de Enfermedad , Ratones Transgénicos , Superóxido Dismutasa/genética , Superóxido Dismutasa-1/genéticaRESUMEN
Taste receptor cells are taste bud epithelial cells that are dependent upon the innervating nerve for continuous renewal and are maintained by resident tissue stem/progenitor cells. Transection of the innervating nerve causes degeneration of taste buds and taste receptor cells. However, a subset of the taste receptor cells is maintained without nerve contact after glossopharyngeal nerve transection in the circumvallate papilla in adult mice. Here, we revealed that injury caused by glossopharyngeal nerve transection triggers the remaining differentiated K8-positive taste receptor cells to dedifferentiate and acquire transient progenitor cell-like states during regeneration. Dedifferentiated taste receptor cells proliferate, express progenitor cell markers (K14, Sox2, PCNA) and form organoids in vitro. These data indicate that differentiated taste receptor cells can enter the cell cycle, acquire stemness, and participate in taste bud regeneration. We propose that dedifferentiated taste receptor cells in combination with stem/progenitor cells enhance the regeneration of taste buds following nerve injury.
Asunto(s)
Traumatismos del Nervio Glosofaríngeo , Papilas Gustativas , Ratones , Animales , Papilas Gustativas/metabolismo , Gusto , Células Madre , Células EpitelialesRESUMEN
BACKGROUND: Due to its abuse potential, propofol has been classified as a controlled substance since February 2011 in South Korea. Healthcare workers are exposed to propofol abuse considering their easy access to this substance in hospitals. Therefore, we aimed to investigate propofol abuse among healthcare workers through the database of the Supreme Court in South Korea. METHODS: We retrospectively analyzed adjudicated criminal cases related to propofol abuse among healthcare workers from January 1, 2013, to December 31, 2020, using the database of the Supreme Court of South Korea's judgments. We collected the clinical characteristics and punishment-related information of healthcare workers who abused propofol. RESULTS: Of the 194 cases collected using the search term 'propofol,' 20 were included in the final analysis. The most common healthcare workers who abused propofol were nursing aides (n = 15). Among them, 40% (n = 8) of the defendants had previously been punished for substance abuse, and 35% (n = 7) had a history of psychological disease. Of the defendants, 65% (n = 13) self-administered propofol more than twice, and the median number of self-administrations was three. Except for two, the defendants were sentenced to imprisonment, including suspended sentences, and the median values of their duration of prison and probation were 9 months and 24 months. CONCLUSIONS: Despite propofol being strongly regulated as a controlled substance in South Korea, its abuse among healthcare workers remains. Healthcare workers should be vigilant against its abuse among themselevs.