RESUMEN
ZC3H11A (zinc finger CCCH domain-containing protein 11A) is a stress-induced mRNA-binding protein required for efficient growth of nuclear-replicating viruses. The cellular functions of ZC3H11A during embryonic development are unknown. Here, we report the generation and phenotypic characterization of Zc3h11a knockout (KO) mice. Heterozygous null Zc3h11a mice were born at the expected frequency without distinguishable phenotypic differences compared with wild-type mice. In contrast, homozygous null Zc3h11a mice were missing, indicating that Zc3h11a is crucial for embryonic viability and survival. Zc3h11a -/- embryos were detected at the expected Mendelian ratios up to late preimplantation stage (E4.5). However, phenotypic characterization at E6.5 revealed degeneration of Zc3h11a -/- embryos, indicating developmental defects around the time of implantation. Transcriptomic analyses documented a dysregulation of glycolysis and fatty acid metabolic pathways in Zc3h11a-/- embryos at E4.5. Proteomic analysis indicated a tight interaction between ZC3H11A and mRNA-export proteins in embryonic stem cells. CLIP-seq analysis demonstrated that ZC3H11A binds a subset of mRNA transcripts that are critical for metabolic regulation of embryonic cells. Furthermore, embryonic stem cells with an induced deletion of Zc3h11a display an impaired differentiation toward epiblast-like cells and impaired mitochondrial membrane potential. Altogether, the results show that ZC3H11A is participating in export and posttranscriptional regulation of selected mRNA transcripts required to maintain metabolic processes in embryonic cells. While ZC3H11A is essential for the viability of the early mouse embryo, inactivation of Zc3h11a expression in adult tissues using a conditional KO did not lead to obvious phenotypic defects.
Asunto(s)
Implantación del Embrión , Proteínas Nucleares , Proteómica , Proteínas de Unión al ARN , Animales , Femenino , Ratones , Embarazo , Implantación del Embrión/genética , Embrión de Mamíferos/metabolismo , Desarrollo Embrionario/genética , Regulación del Desarrollo de la Expresión Génica , Ratones Noqueados , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/genética , Proteínas Nucleares/genéticaRESUMEN
The biochemical pathway regulating the synthesis of yellow/red pheomelanin is less well characterized than the synthesis of black/brown eumelanin. Inhibitor of gold (IG phenotype) is a plumage colour variant in chicken that provides an opportunity to further explore this pathway since the recessive allele (IG) at this locus is associated with a defect in the production of pheomelanin. IG/IG homozygotes display a marked dilution of red pheomelanin pigmentation, whilst black pigmentation (eumelanin) is only slightly affected. Here we show that a 2-base pair insertion (frame-shift mutation) in the 5th exon of the Catechol-O-methyltransferase containing domain 1 gene (COMTD1), expected to cause a complete or partial loss-of-function of the COMTD1 enzyme, shows complete concordance with the IG phenotype within and across breeds. We show that the COMTD1 protein is localized to mitochondria in pigment cells. Knockout of Comtd1 in a mouse melanocytic cell line results in a reduction in pheomelanin metabolites and significant alterations in metabolites of glutamate/glutathione, riboflavin, and the tricarboxylic acid cycle. Furthermore, COMTD1 overexpression enhanced cellular proliferation following chemical-induced transfection, a potential inducer of oxidative stress. These observations suggest that COMTD1 plays a protective role for melanocytes against oxidative stress and that this supports their ability to produce pheomelanin.
Asunto(s)
Catecol O-Metiltransferasa , Pollos , Ratones , Animales , Pollos/genética , Catecol O-Metiltransferasa/genética , Ratones Noqueados , Melaninas/metabolismo , Pigmentación/genética , Mutación del Sistema de LecturaRESUMEN
The controlled release of mitochondrial content into the cytosol has emerged as one of the key steps in mitochondrial signaling. In particular, the release of mitochondrial DNA (mtDNA) into the cytosol has been shown to activate interferon beta (IFN-ß) gene expression to execute the innate immune response. In this report, we show that human adenovirus type 5 (HAdV-C5) infection induces the release of mtDNA into the cytosol. The release of mtDNA is mediated by the viral minor capsid protein VI (pVI), which localizes to mitochondria. The presence of the mitochondrial membrane proteins Bak and Bax are needed for the mtDNA release, whereas the viral E1B-19K protein blocked pVI-mediated mtDNA release. Surprisingly, the pVI-mediated mtDNA release did not increase but inhibited the IFN-ß gene expression. Notably, the pVI expression caused mitochondrial leakage of the HSP60 protein. The latter prevented specific phosphorylation of the interferon regulatory factor 3 (IRF3) needed for IFN-ß gene expression. Overall, we assign a new mitochondria and IFN-ß signaling-modulating function to the HAdV-C5 minor capsid protein VI. IMPORTANCE: Human adenoviruses (HAdVs) are common pathogens causing various self-limiting diseases, including conjunctivitis and the common cold. HAdVs need to interfere with multiple cellular signaling pathways during the infection to gain control over the host cell. In this study, we identified human adenovirus type 5 (HAdV-C5) minor capsid protein VI as a factor modulating mitochondrial membrane integrity and mitochondrial signaling. We show that pVI-altered mitochondrial signaling impedes the cell's innate immune response, which may benefit HAdV growth. Overall, our study provides new detailed insights into the HAdV-mitochondria interactions and signaling. This knowledge is helpful when developing new anti-viral treatments against pathogenic HAdV infections and improving HAdV-based therapeutics.
Asunto(s)
Adenovirus Humanos , Proteínas de la Cápside , ADN Mitocondrial , Interferón beta , Mitocondrias , Transducción de Señal , Humanos , Adenovirus Humanos/fisiología , Adenovirus Humanos/genética , Adenovirus Humanos/metabolismo , Proteínas de la Cápside/metabolismo , Proteínas de la Cápside/genética , Mitocondrias/metabolismo , ADN Mitocondrial/metabolismo , ADN Mitocondrial/genética , Interferón beta/metabolismo , Interferón beta/genética , Inmunidad Innata , Factor 3 Regulador del Interferón/metabolismo , Factor 3 Regulador del Interferón/genética , Infecciones por Adenovirus Humanos/virología , Infecciones por Adenovirus Humanos/metabolismo , Membranas Mitocondriales/metabolismo , Células HEK293 , Fosforilación , Citosol/metabolismo , Citosol/virologíaRESUMEN
Nuclear mRNA metabolism is regulated by multiple proteins, which either directly bind to RNA or form multiprotein complexes. The RNA-binding protein ZC3H11A is involved in nuclear mRNA export, NF-κB signaling, and is essential during mouse embryo development. Furthermore, previous studies have shown that ZC3H11A is important for nuclear-replicating viruses. However, detailed biochemical characterization of the ZC3H11A protein has been lacking. In this study, we established the ZC3H11A protein interactome in human and mouse cells. We demonstrate that the nuclear poly(A)-binding protein PABPN1 interacts specifically with the ZC3H11A protein and controls ZC3H11A localization into nuclear speckles. We report that ZC3H11A specifically interacts with the human adenovirus type 5 (HAdV-5) capsid mRNA in a PABPN1-dependent manner. Notably, ZC3H11A uses the same zinc finger motifs to interact with PABPN1 and viral mRNA. Further, we demonstrate that the lack of ZC3H11A alters the polyadenylation of HAdV-5 capsid mRNA. Taken together, our results suggest that the ZC3H11A protein may act as a novel regulator of polyadenylation of nuclear mRNA.
Asunto(s)
Proteína I de Unión a Poli(A) , Poliadenilación , Animales , Humanos , Ratones , Proteína I de Unión a Poli(A)/genética , Proteína I de Unión a Poli(A)/metabolismo , Proteínas de Unión a Poli(A)/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismoRESUMEN
OBJECTIVES: Minimally invasive cardiac surgery techniques are increasingly used but have longer cardiopulmonary bypass time, which may increase inflammatory response and negatively affect coagulation. Our aim was to compare biomarkers of inflammation and coagulation as well as transfusion rates after minimally invasive mitral valve repair and mitral valve surgery using conventional sternotomy. DESIGN: A prospective non-randomized study was performed enrolling 71 patients undergoing mitral valve surgery (35 right mini-thoracotomy and 36 conventional sternotomy procedures). Blood samples were collected pre- and postoperatively to assess inflammatory response. Thromboelastometry (ROTEM) was performed to assess coagulation, and transfusion rates were monitored. RESULTS: The minimally invasive group had longer cardiopulmonary bypass times compared to the sternotomy group: 127 min ([115-146] vs 79 min [65-112], p < 0.001) and were cooled to a lower temperature during cardiopulmonary bypass, 34 °C vs 36 °C (p = 0.04). IL-6 was lower in the minimally invasive group compared to the conventional sternotomy group when measured at the end of the surgical procedure, (38 [23-69] vs 61[41-139], p = 0.008), but no differences were found at postoperative day 1 or postoperative day 3. The transfusion rate was lower in the minimally invasive group (14%) compared to full sternotomy (35%, p = 0.04) and the chest tube output was reduced, (395 ml [190-705] vs 570 ml [400-1040], p = 0.04). CONCLUSIONS: Our data showed that despite the longer use of extra corporal circulation during surgery, minimally invasive mitral valve repair is associated with reduced inflammatory response, lower rates of transfusion, and reduced chest tube output.
Asunto(s)
Biomarcadores , Coagulación Sanguínea , Transfusión Sanguínea , Puente Cardiopulmonar , Mediadores de Inflamación , Válvula Mitral , Esternotomía , Toracotomía , Humanos , Estudios Prospectivos , Femenino , Masculino , Biomarcadores/sangre , Persona de Mediana Edad , Válvula Mitral/cirugía , Válvula Mitral/fisiopatología , Mediadores de Inflamación/sangre , Puente Cardiopulmonar/efectos adversos , Anciano , Resultado del Tratamiento , Factores de Tiempo , Esternotomía/efectos adversos , Toracotomía/efectos adversos , Tromboelastografía , Interleucina-6/sangre , Inflamación/sangre , Inflamación/etiología , Inflamación/diagnóstico , Implantación de Prótesis de Válvulas Cardíacas/efectos adversos , Enfermedades de las Válvulas Cardíacas/cirugía , Enfermedades de las Válvulas Cardíacas/sangre , Factores de RiesgoRESUMEN
The mechanisms underlying sex determination are astonishingly plastic. Particularly the triggers for the molecular machinery, which recalls either the male or female developmental program, are highly variable and have evolved independently and repeatedly. Fish show a huge variety of sex determination systems, including both genetic and environmental triggers. The advent of sex chromosomes is assumed to stabilize genetic sex determination. However, because sex chromosomes are notoriously cluttered with repetitive DNA and pseudogenes, the study of their evolution is hampered. Here we reconstruct the birth of a Y chromosome present in the Atlantic herring. The region is tiny (230 kb) and contains only three intact genes. The candidate male-determining gene BMPR1BBY encodes a truncated form of a BMP1B receptor, which originated by gene duplication and translocation and underwent rapid protein evolution. BMPR1BBY phosphorylates SMADs in the absence of ligand and thus has the potential to induce testis formation. The Y region also contains two genes encoding subunits of the sperm-specific Ca2+ channel CatSper required for male fertility. The herring Y chromosome conforms with a characteristic feature of many sex chromosomes, namely, suppressed recombination between a sex-determining factor and genes that are beneficial for the given sex. However, the herring Y differs from other sex chromosomes in that suppression of recombination is restricted to an â¼500-kb region harboring the male-specific and sex-associated regions. As a consequence, any degeneration on the herring Y chromosome is restricted to those genes located in the small region affected by suppressed recombination.
Asunto(s)
Peces/genética , Cromosomas Sexuales/genética , Animales , Evolución Molecular , Femenino , Proteínas de Peces/genética , Peces/fisiología , Duplicación de Gen , Masculino , ReproducciónRESUMEN
In the disease familial amyloidosis, Finnish type (FAF), also known as AGel amyloidosis (AGel), the mechanism by which point mutations in the calcium-regulated actin-severing protein gelsolin lead to furin cleavage is not understood in the intact protein. Here, we provide a structural and biochemical characterization of the FAF variants. X-ray crystallography structures of the FAF mutant gelsolins demonstrate that the mutations do not significantly disrupt the calcium-free conformations of gelsolin. Small-angle X-ray-scattering (SAXS) studies indicate that the FAF calcium-binding site mutants are slower to activate, whereas G167R is as efficient as the wild type. Actin-regulating studies of the gelsolins at the furin cleavage pH (6.5) show that the mutant gelsolins are functional, suggesting that they also adopt relatively normal active conformations. Deletion of gelsolin domains leads to sensitization to furin cleavage, and nanobody-binding protects against furin cleavage. These data indicate instability in the second domain of gelsolin (G2), since loss or gain of G2-stabilizing interactions impacts the efficiency of cleavage by furin. To demonstrate this principle, we engineered non-FAF mutations in G3 that disrupt the G2-G3 interface in the calcium-activated structure. These mutants led to increased furin cleavage. We carried out molecular dynamics (MD) simulations on the FAF and non-FAF mutant G2-G3 fragments of gelsolin. All mutants showed an increase in the distance between the center of masses of the 2 domains (G2 and G3). Since G3 covers the furin cleavage site on G2 in calcium-activated gelsolin, this suggests that destabilization of this interface is a critical step in cleavage.
Asunto(s)
Amiloidosis/genética , Distrofias Hereditarias de la Córnea/genética , Furina/química , Gelsolina/química , Conformación Proteica , Actinas/química , Actinas/genética , Amiloidosis/patología , Sitios de Unión/genética , Calcio/química , Distrofias Hereditarias de la Córnea/patología , Cristalografía por Rayos X , Furina/genética , Gelsolina/genética , Gelsolina/ultraestructura , Predisposición Genética a la Enfermedad , Humanos , Simulación de Dinámica Molecular , Mutación/genética , Unión Proteica/genética , Dominios Proteicos/genéticaRESUMEN
The transcription factor ZBED6 acts as a repressor of Igf2 and affects directly or indirectly the transcriptional regulation of thousands of genes. Here, we use gene editing in mouse C2C12 myoblasts and show that ZBED6 regulates Igf2 exclusively through its binding site 5'-GGCTCG-3' in intron 1 of Igf2. Deletion of this motif (Igf2ΔGGCT ) or complete ablation of Zbed6 leads to ~20-fold upregulation of the IGF2 protein. Quantitative proteomics revealed an activation of Ras signaling pathway in both Zbed6-/- and Igf2ΔGGCT myoblasts, and a significant enrichment of mitochondrial membrane proteins among proteins showing altered expression in Zbed6-/- myoblasts. Both Zbed6-/- and Igf2ΔGGCT myoblasts showed a faster growth rate and developed myotube hypertrophy. These cells exhibited an increased O2 consumption rate, due to IGF2 upregulation. Transcriptome analysis revealed ~30% overlap between differentially expressed genes in Zbed6-/- and Igf2ΔGGCT myotubes, with an enrichment of upregulated genes involved in muscle development. In contrast, ZBED6-overexpression in myoblasts led to cell apoptosis, cell cycle arrest, reduced mitochondrial activities, and ceased myoblast differentiation. The similarities in growth and differentiation phenotypes observed in Zbed6-/- and Igf2ΔGGCT myoblasts demonstrates that ZBED6 affects mitochondrial activity and myogenesis largely through its regulation of IGF2 expression. This study adds new insights how the ZBED6-Igf2 axis affects muscle metabolism.
Asunto(s)
Factor II del Crecimiento Similar a la Insulina/metabolismo , Mioblastos/metabolismo , Proteínas Represoras/metabolismo , Animales , Apoptosis/genética , Puntos de Control del Ciclo Celular/genética , Diferenciación Celular/genética , Línea Celular , Regulación de la Expresión Génica/genética , Factor II del Crecimiento Similar a la Insulina/genética , Ratones , Mitocondrias/genética , Fibras Musculares Esqueléticas/metabolismo , Proteínas Represoras/genética , Transducción de Señal/genética , Transcripción Genética/genética , Transcriptoma/genética , Regulación hacia Arriba/genéticaRESUMEN
Sex-linked barring is a fascinating plumage pattern in chickens recently shown to be associated with two non-coding and two missense mutations affecting the ARF transcript at the CDKN2A tumor suppressor locus. It however remained a mystery whether all four mutations are indeed causative and how they contribute to the barring phenotype. Here, we show that Sex-linked barring is genetically heterogeneous, and that the mutations form three functionally different variant alleles. The B0 allele carries only the two non-coding changes and is associated with the most dilute barring pattern, whereas the B1 and B2 alleles carry both the two non-coding changes and one each of the two missense mutations causing the Sex-linked barring and Sex-linked dilution phenotypes, respectively. The data are consistent with evolution of alleles where the non-coding changes occurred first followed by the two missense mutations that resulted in a phenotype more appealing to humans. We show that one or both of the non-coding changes are cis-regulatory mutations causing a higher CDKN2A expression, whereas the missense mutations reduce the ability of ARF to interact with MDM2. Caspase assays for all genotypes revealed no apoptotic events and our results are consistent with a recent study indicating that the loss of melanocyte progenitors in Sex-linked barring in chicken is caused by premature differentiation and not apoptosis. Our results show that CDKN2A is a major locus driving the differentiation of avian melanocytes in a temporal and spatial manner.
Asunto(s)
Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Evolución Molecular , Ligamiento Genético , Pigmentación/genética , Alelos , Animales , Diferenciación Celular/genética , Pollos , Plumas/crecimiento & desarrollo , Plumas/metabolismo , Femenino , Genotipo , Mutación , FenotipoRESUMEN
OBJECTIVE: To evaluate the hemostatic system in patients undergoing surgery for acute type A aortic dissection (ATAAD) compared with those undergoing elective aortic procedures. DESIGN: This was a prospective, observational study. SETTING: The study was performed at a single university hospital. PARTICIPANTS: Twenty-five patients with ATAAD were compared with 20 control patients undergoing elective surgery of the ascending aorta or the aortic root. INTERVENTIONS: No interventions were performed. MEASUREMENTS AND MAIN RESULTS: Platelet count and levels of fibrinogen, D-dimer, prothrombin time/international normalized ratio, activated partial thromboplastin time, and antithrombin were analyzed perioperatively and compared between the 2 groups. Patients with ATAAD had lower preoperative levels of platelets (188 [156-217]â¯×â¯109/L v 221 [196-240]â¯×â¯109/L; pâ¯=â¯0.018), fibrinogen (1.9 [1.6-2.4] g/L v 2.8 [2.2-3.0] g/L; pâ¯=â¯0.003), and antithrombin (0.81 [0.73-0.94] kIU/L v 0.96 [0.92-1.00] kIU/L; pâ¯=â¯0.003) and significantly higher levels of D-dimer (2.9 [1.7-9.7] mg/L v 0.1 [0.1-0.2] mg/L; p < 0.001) and prothrombin time/international normalized ratio (1.15 [1.1-1.2] v 1.0 [0.93-1.0]; pâ¯=â¯0.001). Surgery caused significant changes of the coagulation system in both groups. Intraoperative bleeding volumes were larger in the ATAAD group (2,407 [1,804-3,209] mL v 1,212 [917-1,920] mL; p < 0.001), and patients undergoing ATAAD surgery received significantly more transfusions of red blood cells (2.5 [0.25-4.75] U v 0 [0-2.75] U; pâ¯=â¯0.022), platelets (4 [3.25-6] U v 2 [2-4] U; pâ¯=â¯0.002), and plasma (2 [0-4] U v 0 [0-0] U; pâ¯=â¯0.004) compared with the elective group. CONCLUSIONS: This study demonstrates that ATAAD is associated with a coagulopathic state. Surgery causes additional damage to the hemostatic system in ATAAD patients, but also in patients undergoing elective surgery of the ascending aorta or the aortic root.
Asunto(s)
Aneurisma de la Aorta Torácica/cirugía , Disección Aórtica/cirugía , Trastornos de la Coagulación Sanguínea/etiología , Injerto Vascular/efectos adversos , Enfermedad Aguda , Anciano , Disección Aórtica/sangre , Aorta/cirugía , Aneurisma de la Aorta Torácica/sangre , Trastornos de la Coagulación Sanguínea/sangre , Pruebas de Coagulación Sanguínea/métodos , Pérdida de Sangre Quirúrgica , Transfusión Sanguínea/métodos , Transfusión Sanguínea/estadística & datos numéricos , Estudios de Casos y Controles , Femenino , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Fibrinógeno/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Recuento de Plaquetas , Complicaciones Posoperatorias/sangre , Complicaciones Posoperatorias/etiología , Estudios Prospectivos , Injerto Vascular/métodosRESUMEN
Here we report the discovery of a bacterial DNA-segregating actin-like protein (BtParM) from Bacillus thuringiensis, which forms novel antiparallel, two-stranded, supercoiled, nonpolar helical filaments, as determined by electron microscopy. The BtParM filament features of supercoiling and forming antiparallel double-strands are unique within the actin fold superfamily, and entirely different to the straight, double-stranded, polar helical filaments of all other known ParMs and of eukaryotic F-actin. The BtParM polymers show dynamic assembly and subsequent disassembly in the presence of ATP. BtParR, the DNA-BtParM linking protein, stimulated ATP hydrolysis/phosphate release by BtParM and paired two supercoiled BtParM filaments to form a cylinder, comprised of four strands with inner and outer diameters of 57 Å and 145 Å, respectively. Thus, in this prokaryote, the actin fold has evolved to produce a filament system with comparable features to the eukaryotic chromosome-segregating microtubule.
Asunto(s)
Actinas/metabolismo , Bacillus thuringiensis/metabolismo , ADN Bacteriano/metabolismo , Nanotubos , Plásmidos , Bacillus thuringiensis/genética , Proteínas Fluorescentes Verdes/genéticaRESUMEN
OBJECTIVE: In patients presenting with acute type-A aortic dissection (aTAAD), lactic acid measurement is a frequently used analysis for diagnosis of acute ischemia, which may have a dismal prognosis. The aim of the current study was to determine the performance of perioperative arterial lactic acid measurements in predicting outcome in aTAAD patients. DESIGN: Retrospective, observational study. SETTING: Cardiothoracic surgery unit at a tertiary-level hospital. PARTICIPANTS: The study involved 285 consecutive patients undergoing surgery for aTAAD. INTERVENTIONS: Preoperative and postoperative lactic acid levels were measured and evaluated together with clinical data related to outcome, including in-hospital and 1-year mortality. MEASUREMENTS AND MAIN RESULTS: Altogether, 37 patients (13%) died during the index hospital admission, and survival was 84.4 ± 2.2 at 1 year. Preoperative cardiac malperfusion (odds ratio [OR] 3.1; 95% confidence interval [CI] 1.3-7.3) and cerebral malperfusion (OR 2.6; 95% CI 1.2-5.6) were associated significantly with poorer 1-year survival. The area under the curve (AUC) for in-hospital and 1-year mortality in relation to preoperative lactic acid levels was 0.684 and 0.673, respectively, corresponding to a lactic acid cut-off for in-hospital mortality of 2.75 mmol/L (sensitivity 56%; specificity 72%) and a cut-off for 1-year mortality of 2.85 mmol/L (sensitivity 48%; specificity 74%). The AUC for in-hospital and 1-year mortality in relation to lactic acid levels measured postoperatively on arrival at the intensive care unit was 0.582 and 0.498, respectively. CONCLUSION: Although hyperlactemia in aTAAD indicates an increased risk of postoperative mortality, the sole use of lactic acid levels as a tool for accurate assessment of postoperative mortality is inadvisable due to its poor discriminatory performance.
Asunto(s)
Aneurisma de la Aorta Torácica/sangre , Disección Aórtica/sangre , Hiperlactatemia/sangre , Procedimientos Quirúrgicos Vasculares , Enfermedad Aguda , Disección Aórtica/mortalidad , Disección Aórtica/cirugía , Aneurisma de la Aorta Torácica/mortalidad , Aneurisma de la Aorta Torácica/cirugía , Biomarcadores/sangre , Femenino , Estudios de Seguimiento , Humanos , Hiperlactatemia/epidemiología , Hiperlactatemia/etiología , Incidencia , Ácido Láctico/sangre , Masculino , Persona de Mediana Edad , Periodo Perioperatorio , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Suecia/epidemiología , Factores de TiempoRESUMEN
BACKGROUND: To date, there are no known methods for preventing acute kidney injury after cardiac surgery. Increasing evidence suggests that erythropoietin has renal antiapoptotic and tissue protective effects. However, recent human studies have shown conflicting results. The authors aimed to study the effect of a single high-dose erythropoietin preoperatively on renal function after coronary artery bypass grafting in patients with preoperative impaired renal function. METHODS: This single-center, randomized, double-blind, placebo-controlled study included 75 patients scheduled for coronary artery bypass grafting with preexisting renal impairment estimated glomerular filtration rate based on p-cystatin C (<60 and >15 ml/min). The patients either received a single high-dose erythropoietin (400 IU/kg) or placebo preoperatively. The primary endpoint was renal protection evaluated by p-cystatin C at the third postoperative day compared to the preoperative values. Incidence of acute kidney injury and other renal biomarker changes were among secondary endpoints. RESULTS: There was no statistically significant difference on the third postoperative day for relative p-cystatin C level changes from baseline between the groups, 131 ± 31% (mean ± SD) for the study group and 125 ± 24% for the control group (P = 0.31; 95% CI, -0.6 to 20% for the difference). There were no statistically significant differences in other renal biomarkers or measures between the groups (p-neutrophil gelatinase-associated lipocalin, p-creatinine, p-urea, and estimated glomerular filtration rate). There were no other differences in outcome variables between the groups. CONCLUSION: Intravenous administration of a single high-dose (400 IU/kg) erythropoietin did not have a renal protective effect on patients with reduced kidney function undergoing coronary artery bypass surgery.
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Lesión Renal Aguda/prevención & control , Puente de Arteria Coronaria/efectos adversos , Eritropoyetina/uso terapéutico , Anciano , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Proteínas Recombinantes/uso terapéuticoRESUMEN
Corynebacterium is a skin commensal bacterium that can contaminate blood cultures. It is however also a rare cause of infective endocarditis (IE). Here we report a case of Corynebacterium kroppenstedtii aortic prosthesis IE in a 76-year-old man where only a single blood culture bottle was positive initially. C. kroppenstedtii is a very rare cause of IE, only reported two times previously. The diagnosis in our case was confirmed by repeated blood culture positivity and eventually by detection of DNA from C. kroppenstedtii on heart valves after valve exchange surgery. At surgery an aortic root abscess was detected and the valve was replaced by a homograft. Recovery was complicated by antibiotic-induced nephrotoxicity and treatment was concluded with moxifloxacin in combination with rifampicin. Recovery was uneventful. This case demonstrates that growth in even a single blood culture bottle may be important in patients with prosthetic heart valves.
RESUMEN
BACKGROUND: To assess whether retrograde cerebral perfusion reduces neurological injury and mortality in patients undergoing surgery for acute type A aortic dissection. METHODS: Single-center, retrospective, observational study including all patients undergoing acute type A aortic dissection repair with deep hypothermic circulatory arrest between January 1998 and December 2022 with or without the adjunct of retrograde cerebral perfusion. 515 patients were included: 257 patients with hypothermic circulatory arrest only and 258 patients with hypothermic circulatory arrest and retrograde cerebral perfusion. The primary endpoints were clinical neurological injury, embolic lesions, and watershed lesions. Multivariable logistic regression was performed to identify independent predictors of the primary outcomes. Survival analysis was performed using Kaplan-Meier estimates. RESULTS: Clinical neurological injury and embolic lesions were less frequent in patients with retrograde cerebral perfusion (20.2% vs. 28.4%, p = 0.041 and 13.7% vs. 23.4%, p = 0.010, respectively), but there was no significant difference in the occurrence of watershed lesions (3.0% vs. 6.1%, p = 0.156). However, after multivariable logistic regression, retrograde cerebral perfusion was associated with a significant reduction of clinical neurological injury (OR: 0.60; 95% CI 0.36-0.995, p = 0.049), embolic lesions (OR: 0.55; 95% CI 0.31-0.97, p = 0.041), and watershed lesions (OR: 0.25; 95%CI 0.07-0.80, p = 0.027). There was no significant difference in 30-day mortality (12.8% vs. 11.7%, p = ns) or long-term survival between groups. CONCLUSION: In this study, we showed that the addition of retrograde cerebral perfusion during hypothermic circulatory arrest in the setting of acute type A aortic dissection repair reduced the risk of clinical neurological injury, embolic lesions, and watershed lesions.
Asunto(s)
Disección Aórtica , Circulación Cerebrovascular , Paro Circulatorio Inducido por Hipotermia Profunda , Perfusión , Humanos , Disección Aórtica/cirugía , Femenino , Masculino , Paro Circulatorio Inducido por Hipotermia Profunda/métodos , Estudios Retrospectivos , Persona de Mediana Edad , Perfusión/métodos , Circulación Cerebrovascular/fisiología , Anciano , Complicaciones Posoperatorias/prevención & control , Aneurisma de la Aorta Torácica/cirugíaRESUMEN
OBJECTIVES: It has been commonly accepted that untreated acute type A aortic dissection (ATAAD) results in an hourly mortality rate of 1-2% during the 1st 24 h after symptom onset. The data to support this statement rely solely on patients who have been denied surgical treatment after reaching surgical centres. The objective was to perform a total review of non-surgically treated (NST) ATAAD and provide contemporary mortality data. METHODS: This was a regional, retrospective, observational study. All patients receiving one of the following diagnoses: International Classification of Diseases (ICD)-9 4410, 4411, 4415, 4416 or ICD-10 I710, I711, I715, I718 in an area of 1.9 million inhabitants in Southern Sweden during a period of 23 years (January 1998 to November 2021) were retrospectively screened. The search was conducted using all available medical registries so that every patient diagnosed with ATAAD in our region was identified. The charts and imaging of each screened patient were subsequently reviewed to confirm or discard the diagnosis of ATAAD. RESULTS: Screening identified 2325 patients, of whom 184 NST ATAAD patients were included. The mortality of NST ATAAD was 47.3 ± 4.4%, 55.0 ± 4.4%, 76.7 ± 3.7% and 83.9 ± 4.3% at 24 h, 48 h, 14 days and 1 year, respectively. The hourly mortality rate during the 1st 24 h after symptom onset was 2.6%. CONCLUSIONS: This study observed higher mortality than has previously been reported. It emphasizes the need for timely diagnosis, swift management and emergent surgical treatment for patients suffering an acute type A aortic dissection.
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Aneurisma de la Aorta Torácica , Disección Aórtica , Humanos , Estudios Retrospectivos , Disección Aórtica/cirugía , Resultado del Tratamiento , Factores de Tiempo , Sistema de Registros , Enfermedad Aguda , Aneurisma de la Aorta Torácica/diagnóstico , Aneurisma de la Aorta Torácica/cirugíaRESUMEN
Krill are vital as food for many marine animals but also impacted by global warming. To learn how they and other zooplankton may adapt to a warmer world we studied local adaptation in the widespread Northern krill (Meganyctiphanes norvegica). We assemble and characterize its large genome and compare genome-scale variation among 74 specimens from the colder Atlantic Ocean and warmer Mediterranean Sea. The 19 Gb genome likely evolved through proliferation of retrotransposons, now targeted for inactivation by extensive DNA methylation, and contains many duplicated genes associated with molting and vision. Analysis of 760 million SNPs indicates extensive homogenizing gene-flow among populations. Nevertheless, we detect signatures of adaptive divergence across hundreds of genes, implicated in photoreception, circadian regulation, reproduction and thermal tolerance, indicating polygenic adaptation to light and temperature. The top gene candidate for ecological adaptation was nrf-6, a lipid transporter with a Mediterranean variant that may contribute to early spring reproduction. Such variation could become increasingly important for fitness in Atlantic stocks. Our study underscores the widespread but uneven distribution of adaptive variation, necessitating characterization of genetic variation among natural zooplankton populations to understand their adaptive potential, predict risks and support ocean conservation in the face of climate change.
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Adaptación Fisiológica , Euphausiacea , Genómica , Animales , Euphausiacea/genética , Océano Atlántico , Adaptación Fisiológica/genética , Mar Mediterráneo , Polimorfismo de Nucleótido Simple , Genoma , Zooplancton/genética , Flujo Génico , Variación GenéticaRESUMEN
In preparation for mammalian cell division, microtubules repeatedly probe the cytoplasm to capture chromosomes and assemble the mitotic spindle. Critical features of this microtubule system are the formation of radial arrays centered at the centrosomes and dynamic instability, leading to persistent cycles of polymerization and depolymerization. Here, we show that actin homolog, ParM-R1 that drives segregation of the R1 multidrug resistance plasmid from Escherichia coli, can also self-organize in vitro into asters, which resemble astral microtubules. ParM-R1 asters grow from centrosome-like structures consisting of interconnected nodes related by a pseudo 8-fold symmetry. In addition, we show that ParM-R1 is able to perform persistent microtubule-like oscillations of assembly and disassembly. In vitro, a whole population of ParM-R1 filaments is synchronized between phases of growth and shrinkage, leading to prolonged synchronous oscillations even at physiological ParM-R1 concentrations. These results imply that the selection pressure to reliably segregate DNA during cell division has led to common mechanisms within diverse segregation machineries.
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Actinas/química , Proteínas de Escherichia coli/química , Escherichia coli , Microtúbulos/química , Actinas/genética , Actinas/ultraestructura , Adenosina Trifosfato/química , Sustitución de Aminoácidos , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/ultraestructura , Análisis de Fourier , Guanosina Trifosfato/química , Hidrólisis , Luz , Mutagénesis Sitio-Dirigida , Multimerización de Proteína , Estructura Cuaternaria de Proteína , Dispersión de RadiaciónRESUMEN
To investigate mortality and reoperation rates following limited distal repair after acute type A aortic dissection (ATAAD) at a single medium volume institution. We analyzed all patients that underwent limited distal repair (ascending aortic or hemiarch replacement) following ATAAD between January 1998 and April 2020 at our institution. During the study period, 489 patients underwent ATAAD surgery, of which 457 (94%) underwent limited distal repair with a 30-day mortality of 12.9%. Among 30-day survivors, late follow-up was 97.7% complete with a mean follow-up of 6.0 ± 5.5 years. In all, 50 patients (11%) required a reoperation during the study period at a mean of 3.4 ± 3.4 years after initial repair, with a 30-day mortality of 12%. An aortic reoperation was required in 4.1 (2.0-6.1)%, 10.3 (7.1-13.6)%, 15.1 (10.9-19.4)%, and 18.0 (13.0-22.9)% of patients at 1, 5, 10, and 15 years. A distal reoperation was required in 3.0 (1.2-4.7)%, 8.0 (5.1-10.9)%, 10.3 (6.8-13.8)%, and 12.4 (8.2-16.5)% of patients and 4.4 (2.3-6.4)%, 10.4 (7.1-13.7)%, 13.9 (9.8-18.0)%, and 16.9 (12.0-21.9)% of patents had a distal event at 1, 5, 10, and 15 years, respectively. Limited distal repair with an ascending aortic or hemiarch replacement was associated with acceptable survival and rates of reoperations and distal events. Limited distal repair is a safe and feasible standard approach to ATAAD surgery at a medium-volume center.
Asunto(s)
Disección Aórtica , Humanos , Resultado del Tratamiento , Aorta , Reoperación , ReimplantaciónRESUMEN
BACKGROUND: Neurological injuries are frequent following Acute Type A Aortic Dissection (ATAAD) repair occurring in 4-30% of all patients. Our objective was to study whether S100B can predict neurological injury following ATAAD repair. METHODS: This was a single-center, retrospective, observational study. The study included all patients that underwent ATAAD repair at our institution between Jan 1998 and Dec 2021 and had recorded S100B-values. The primary outcome measure was neurological injury, defined as focal neurological deficit or coma diagnosed by clinical assessment with or without radiological confirmation and with a symptom duration of more than 24 h. Secondary outcome measure was 30-day mortality. RESULTS: 538 patients underwent surgery during the study period and 393 patients, had recorded S100B-values. The patients had a mean age of 64.4 ± 11.1 years and 34% were female. Receiver operating characteristic curve for S100B 24 h postoperatively yielded area under the curve 0.687 (95% CI 0.615-0.759) and best Youden's index corresponded to S100B 0.225 which gave a sensitivity of 60% and specificity of 75%. Multivariable logistic regression identified S100B ≥ 0.23 µg/l at 24 h as an independent predictor for neurological injury (OR 4.71, 95% CI 2.59-8.57; p < 0.01) along with preoperative cerebral malperfusion (OR 4.23, 95% CI 2.03-8.84; p < 0.01) as well as an independent predictor for 30-day mortality (OR 4.57, 95% CI 1.18-11.70; p < 0.01). CONCLUSIONS: We demonstrated that S100B, 24 h after surgery is a strong independent predictor for neurological injury and 30-day mortality after ATAAD repair. TRIAL REGISTRATION: As this was a retrospective observational study it was not registered.