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1.
Acta Neurochir (Wien) ; 166(1): 383, 2024 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-39327320

RESUMEN

BACKGROUND: Surgical site infection (SSI) is the most consistently reported complication of cranioplasty. No material showed a categorical superiority in the incidence of infection. Porous polyethylene (PE) is considered a low risk material regarding SSI. However, the literature data are very limited. Thus, our objective was to verify the assumed low incidence of SSI after PE cranioplasty in patients at high risk of SSI. The primary objective was the infection rate, while secondary objectives were implant exposure, revision and cosmetic results. METHOD: Patients who underwent three-dimensional (3D) personalized PE cranioplasty in the period 2014-2023 were evaluated prospectively. Only patients with an increased risk of SSI, and a satisfactory clinical conditions were included in the study. RESULTS: Thirty procedures were performed in 30 patients. Cranioplasty was performed 23 times after hemispheric decompressive craniectomy, five times after limited size craniotomy and two times after bifrontal decompressive craniectomy. Risk factors for the development of infection were 18 previous SSIs, 16 previous repeated revision surgeries, four intraoperatively opened frontal sinuses and two times radiotherapy. Neither infection nor implant exposure was detected in any patient. All patients were satisfied with the aesthetic result. In two cases, a revision was performed due to postoperative epidural hematoma. CONCLUSIONS: Three-dimensional personalized PE cranioplasty is associated with an extremely low incidence of SSI even in high-risk patients. However, our conclusions can only be confirmed in larger studies.


Asunto(s)
Procedimientos de Cirugía Plástica , Infección de la Herida Quirúrgica , Humanos , Infección de la Herida Quirúrgica/epidemiología , Infección de la Herida Quirúrgica/etiología , Masculino , Femenino , Persona de Mediana Edad , Adulto , Anciano , Procedimientos de Cirugía Plástica/métodos , Procedimientos de Cirugía Plástica/efectos adversos , Polietileno , Factores de Riesgo , Cráneo/cirugía , Craniectomía Descompresiva/efectos adversos , Craniectomía Descompresiva/métodos , Porosidad , Estudios Prospectivos , Craneotomía/efectos adversos , Craneotomía/métodos
2.
Acta Neurochir (Wien) ; 165(12): 3825-3830, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37910307

RESUMEN

A 58-year-old patient presented with a severe neurological deficit due to a stroke caused by an occlusion of the left internal carotid artery siphon. Standard treatment failed and neurosurgical consult was delayed. Because of a favorable perfusion imaging finding, microsurgical revascularization via an extra-intracranial bypass (left superficial temporal artery - left middle cerebral artery) was performed 36 hours after the onset of the symptoms. The outcome of the patient was favorable. The authors want to emphasize the need to actively seek patients with a severe neurological deficit and still viable brain tissue. The time window and treatment alternatives are discussed.


Asunto(s)
Revascularización Cerebral , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Persona de Mediana Edad , Accidente Cerebrovascular Isquémico/complicaciones , Revascularización Cerebral/métodos , Resultado del Tratamiento , Arteria Carótida Interna/cirugía , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/cirugía , Perfusión/efectos adversos
3.
Int J Mol Sci ; 24(2)2023 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-36674559

RESUMEN

Cervical mucus (CM) is a viscous fluid that is produced by the cervical glands and functions as a uterine cervix plug. Its viscosity decreases during ovulation, providing a window for non-invasive sampling. This study focuses on proteomic characterization of CM to evaluate its potential as a non-invasively acquired source of biomarkers and in understanding of molecular (patho)physiology of the female genital tract. The first objective of this work was to optimize experimental workflow for CM processing and the second was to assess differences in the proteomic composition of CM during natural ovulatory cycles obtained from intrauterine insemination (IUI) cycles and in vitro fertilization (IVF) cycles with controlled ovarian hyperstimulation. Proteomic analysis of CM samples revealed 4370 proteins involved in processes including neutrophil degranulation, cellular stress responses, and hemostasis. Differential expression analysis revealed 199 proteins enriched in IUI samples and 422 enriched in IVF. The proteins enriched in IUI were involved in phosphatidic acid synthesis, responses to external stimulus, and neutrophil degranulation, while those enriched in IVF samples were linked to neutrophil degranulation, formation of a cornified envelope and hemostasis. Subsequent analyses clarified the protein composition of the CM and how it is altered by hormonal stimulation of the uterus.


Asunto(s)
Moco del Cuello Uterino , Inseminación Artificial , Humanos , Femenino , Proteoma , Proteómica , Fertilización In Vitro , Biomarcadores
4.
Ceska Gynekol ; 88(1): 4-12, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36858967

RESUMEN

Cervical mucus is a viscous fluid functioning as a cervix plug. Products of the endometrial and cervical glands can be detected in the cervical mucus. Cervical mucus is further enriched with transudate originating from the fallopian tubes and proteins originating from the ovaries, peritoneum and distant tissues. With increasing levels of ovarian estrogens, the properties of cervical mucus for possible collection and processing change appropriately. For these reasons, we chose a group of 10 patients treated in the center of assisted reproduction by controlled ovarian stimulation for in vitro fertilization. This study focuses on the proteomic characterization of cervical mucus and localizes the possible sources of the identified proteins. The most abundant proteins were extracellular proteins, mainly mucins; however, most of the identified proteins, present usually in lower quantities, were of intracellular origin. The tissue analysis revealed that proteins from female reproductive organs are also expressed in other tissues in addition to female reproductive organs, but also proteins specific to the testis, liver, placenta, retina, and cerebellum. This study confirms the suitability and high potential of cervical mucus as a source of proteomic bio-markers not only for the dia-gnosis of the female reproductive tract.


Asunto(s)
Moco del Cuello Uterino , Proteoma , Embarazo , Masculino , Humanos , Femenino , Proteómica , Ovario , Exudados y Transudados
5.
Rep Pract Oncol Radiother ; 28(6): 746-755, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38515821

RESUMEN

Background/Objective: Hormone receptor (HR) status is one of the key factors in determining the treatment of breast cancer. Previous studies suggested that HR status may change in metastatic tissue. However, available studies focused mainly on primary biopsies and there are only few trials comparing HR status in the primary tumour and the metastasis using material from complete resection. The aim of the study was to determine the frequency of HR alterations in metastatic breast cancer. Materials and methods: The study retrospectively examines a total of 50 patients who underwent brain, lung, or liver metastasectomy for metastatic breast cancer between January 2000 and January 2019. Results: HR conversion was observed in a total of 30 cases (60.0%), while HER-2/neu (human epidermal growth factor receptor 2) discrepancy surprisingly occurred only in one case (2.0%). A change in immunophenotype occurred in 28% of cases. Triple-negativity was more frequent in brain metastases (p = 0.039). Conclusions: We have confirmed that HR conversion between the primary tumour and its metastases occurs in a significant number of cases, which has important implications for further treatment decisions.

6.
J Enzyme Inhib Med Chem ; 36(1): 914-921, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33843395

RESUMEN

Pathogenic Candida albicans yeasts frequently cause infections in hospitals. Antifungal drugs lose effectiveness due to other Candida species and resistance. New medications are thus required. Secreted aspartic protease of C. parapsilosis (Sapp1p) is a promising target. We have thus solved the crystal structures of Sapp1p complexed to four peptidomimetic inhibitors. Three potent inhibitors (Ki: 0.1, 0.4, 6.6 nM) resembled pepstatin A (Ki: 0.3 nM), a general aspartic protease inhibitor, in terms of their interactions with Sapp1p. However, the weaker inhibitor (Ki: 14.6 nM) formed fewer nonpolar contacts with Sapp1p, similarly to the smaller HIV protease inhibitor ritonavir (Ki: 1.9 µM), which, moreover, formed fewer H-bonds. The analyses have revealed the structural determinants of the subnanomolar inhibition of C. parapsilosis aspartic protease. Because of the high similarity between Saps from different Candida species, these results can further be used for the design of potent and specific Sap inhibitor-based antimycotic drugs.


Asunto(s)
Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Candida parapsilosis/enzimología , Proteínas Fúngicas/antagonistas & inhibidores , Peptidomiméticos/farmacología , Inhibidores de Proteasas/farmacología , Ácido Aspártico Endopeptidasas/metabolismo , Relación Dosis-Respuesta a Droga , Proteínas Fúngicas/metabolismo , Modelos Moleculares , Estructura Molecular , Peptidomiméticos/síntesis química , Peptidomiméticos/química , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/química , Relación Estructura-Actividad
7.
Int J Mol Sci ; 21(3)2020 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-32013007

RESUMEN

Pathogenic yeasts Candida albicans and Candida parapsilosis possess a ß-type carbonic anhydrase Nce103p, which is involved in CO2 hydration and signaling. C. albicans lacking Nce103p cannot survive in low CO2 concentrations, e.g., in atmospheric growth conditions. Candida carbonic anhydrases are orthologous to the Saccharomyces cerevisiae enzyme, which had originally been detected as a substrate of a non-classical export pathway. However, experimental evidence on localization of C. albicans and C. parapsilosis carbonic anhydrases has not been reported to date. Immunogold labeling and electron microscopy used in the present study showed that carbonic anhydrases are localized in the cell wall and plasmatic membrane of both Candida species. This localization was confirmed by Western blot and mass spectrometry analyses of isolated cell wall and plasma membrane fractions. Further analysis of C. albicans and C. parapsilosis subcellular fractions revealed presence of carbonic anhydrases also in the cytosolic and mitochondrial fractions of Candida cells cultivated in shaken liquid cultures, under the atmospheric conditions.


Asunto(s)
Candida albicans/crecimiento & desarrollo , Candida parapsilosis/crecimiento & desarrollo , Anhidrasas Carbónicas/metabolismo , Técnicas de Cultivo Celular por Lotes , Candida albicans/enzimología , Candida parapsilosis/enzimología , Membrana Celular/enzimología , Pared Celular/enzimología , Citosol/enzimología , Proteínas Fúngicas/metabolismo , Espectrometría de Masas , Microscopía Electrónica , Mitocondrias/enzimología
8.
BMC Struct Biol ; 18(1): 14, 2018 10 26.
Artículo en Inglés | MEDLINE | ID: mdl-30367660

RESUMEN

BACKGROUND: The pathogenic yeast Candida albicans can proliferate in environments with different carbon dioxide concentrations thanks to the carbonic anhydrase CaNce103p, which accelerates spontaneous conversion of carbon dioxide to bicarbonate and vice versa. Without functional CaNce103p, C. albicans cannot survive in atmospheric air. CaNce103p falls into the ß-carbonic anhydrase class, along with its ortholog ScNce103p from Saccharomyces cerevisiae. The crystal structure of CaNce103p is of interest because this enzyme is a potential target for surface disinfectants. RESULTS: Recombinant CaNce103p was prepared in E. coli, and its crystal structure was determined at 2.2 Å resolution. CaNce103p forms a homotetramer organized as a dimer of dimers, in which the dimerization and tetramerization surfaces are perpendicular. Although the physiological role of CaNce103p is similar to that of ScNce103p from baker's yeast, on the structural level it more closely resembles carbonic anhydrase from the saprophytic fungus Sordaria macrospora, which is also tetrameric. Dimerization is mediated by two helices in the N-terminal domain of the subunits. The N-terminus of CaNce103p is flexible, and crystals were obtained only upon truncation of the first 29 amino acids. Analysis of CaNce103p variants truncated by 29, 48 and 61 amino acids showed that residues 30-48 are essential for dimerization. Each subunit contains a zinc atom in the active site and displays features characteristic of type I ß-carbonic anhydrases. Zinc is tetrahedrally coordinated by one histidine residue, two cysteine residues and a molecule of ß-mercaptoethanol originating from the crystallization buffer. The active sites are accessible via substrate tunnels, which are slightly longer and narrower than those observed in other fungal carbonic anhydrases. CONCLUSIONS: CaNce103p is a ß-class homotetrameric metalloenzyme composed of two homodimers. Its structure closely resembles those of other ß-type carbonic anhydrases, in particular CAS1 from Sordaria macrospora. The main differences occur in the N-terminal part and the substrate tunnel. Detailed knowledge of the CaNce103p structure and the properties of the substrate tunnel in particular will facilitate design of selective inhibitors of this enzyme.


Asunto(s)
Candida albicans/enzimología , Anhidrasas Carbónicas/química , Secuencia de Aminoácidos , Dominio Catalítico , Cristalografía por Rayos X , Modelos Moleculares , Multimerización de Proteína , Estructura Cuaternaria de Proteína
9.
Retrovirology ; 13: 2, 2016 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-26728401

RESUMEN

BACKGROUND: Myristoylation of the matrix (MA) domain mediates the transport and binding of Gag polyproteins to the plasma membrane (PM) and is required for the assembly of most retroviruses. In betaretroviruses, which assemble immature particles in the cytoplasm, myristoylation is dispensable for assembly but is crucial for particle transport to the PM. Oligomerization of HIV-1 MA stimulates the transition of the myristoyl group from a sequestered to an exposed conformation, which is more accessible for membrane binding. However, for other retroviruses, the effect of MA oligomerization on myristoyl group exposure has not been thoroughly investigated. RESULTS: Here, we demonstrate that MA from the betaretrovirus mouse mammary tumor virus (MMTV) forms dimers in solution and that this process is stimulated by its myristoylation. The crystal structure of N-myristoylated MMTV MA, determined at 1.57 Å resolution, revealed that the myristoyl groups are buried in a hydrophobic pocket at the dimer interface and contribute to dimer formation. Interestingly, the myristoyl groups in the dimer are mutually swapped to achieve energetically stable binding, as documented by molecular dynamics modeling. Mutations within the myristoyl binding site resulted in reduced MA dimerization and extracellular particle release. CONCLUSIONS: Based on our experimental, structural, and computational data, we propose a model for dimerization of MMTV MA in which myristoyl groups stimulate the interaction between MA molecules. Moreover, dimer-forming MA molecules adopt a sequestered conformation with their myristoyl groups entirely buried within the interaction interface. Although this differs from the current model proposed for lentiviruses, in which oligomerization of MA triggers exposure of myristoyl group, it appears convenient for intracellular assembly, which involves no apparent membrane interaction and allows the myristoyl group to be sequestered during oligomerization.


Asunto(s)
Virus del Tumor Mamario del Ratón/química , Virus del Tumor Mamario del Ratón/fisiología , Multimerización de Proteína , Procesamiento Proteico-Postraduccional , Proteínas de la Matriz Viral/química , Proteínas de la Matriz Viral/metabolismo , Animales , Línea Celular , Cristalografía por Rayos X , Humanos , Modelos Biológicos , Modelos Moleculares , Simulación de Dinámica Molecular , Ratas
10.
J Biol Chem ; 289(19): 13066-78, 2014 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-24659783

RESUMEN

Tuberculosis remains a major health concern worldwide. Eradication of its causative agent, the bacterial pathogen Mycobacterium tuberculosis, is particularly challenging due to a vast reservoir of latent carriers of the disease. Despite the misleading terminology of a so-called dormant state associated with latent infections, the bacteria have to maintain basic metabolic activities. Hypoxic conditions have been widely used as an in vitro system to study this dormancy. Such studies identified a rearrangement of central carbon metabolism to exploit fermentative processes caused by the lack of oxygen. Phosphoenolpyruvate carboxykinase (Pck; EC 4.1.1.32) is the enzyme at the center of these metabolic rearrangements. Although Pck is associated with gluconeogenesis under standard growth conditions, the enzyme can catalyze the reverse reaction, supporting anaplerosis of the tricarboxylic acid cycle, under conditions leading to slowed or stopped bacterial replication. To study the mechanisms that regulate the switch between two Pck functions, we systematically investigated factors influencing the gluconeogenic and anaplerotic reaction kinetics. We demonstrate that a reducing environment, as found under hypoxia-triggered non-replicating conditions, accelerates the reaction in the anaplerotic direction. Furthermore, we identified proteins that interact with Pck. The interaction between Pck and the reduced form of mycobacterial thioredoxin, gene expression of which is increased under hypoxic conditions, also increased the Pck anaplerotic activity. We thus propose that a reducing environment and the protein-protein interaction with thioredoxin in particular enable the Pck anaplerotic function under fermentative growth conditions.


Asunto(s)
Proteínas Bacterianas/metabolismo , Mycobacterium tuberculosis/enzimología , Fosfoenolpiruvato Carboxiquinasa (ATP)/metabolismo , Tiorredoxinas/metabolismo , Proteínas Bacterianas/genética , Ciclo del Ácido Cítrico/fisiología , Regulación Bacteriana de la Expresión Génica/fisiología , Regulación Enzimológica de la Expresión Génica/fisiología , Mycobacterium tuberculosis/genética , Oxidación-Reducción , Fosfoenolpiruvato Carboxiquinasa (ATP)/genética , Tiorredoxinas/genética
11.
Acta Crystallogr D Biol Crystallogr ; 71(Pt 12): 2494-504, 2015 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-26627656

RESUMEN

The virulence of the Candida pathogens is enhanced by the production of secreted aspartic proteases, which therefore represent possible targets for drug design. Here, the crystal structure of the secreted aspartic protease Sapp2p from Candida parapsilosis was determined. Sapp2p was isolated from its natural source and crystallized in complex with pepstatin A, a classical aspartic protease inhibitor. The atomic resolution of 0.83 Šallowed the protonation states of the active-site residues to be inferred. A detailed comparison of the structure of Sapp2p with the structure of Sapp1p, the most abundant C. parapsilosis secreted aspartic protease, was performed. The analysis, which included advanced quantum-chemical interaction-energy calculations, uncovered molecular details that allowed the experimentally observed equipotent inhibition of both isoenzymes by pepstatin A to be rationalized.


Asunto(s)
Proteasas de Ácido Aspártico/química , Candida/química , Proteínas Fúngicas/química , Pepstatinas/química , Inhibidores de Proteasas/química , Secuencia de Aminoácidos , Proteasas de Ácido Aspártico/genética , Proteasas de Ácido Aspártico/aislamiento & purificación , Proteasas de Ácido Aspártico/metabolismo , Candida/enzimología , Candida/genética , Dominio Catalítico , Cristalografía por Rayos X , Proteínas Fúngicas/genética , Proteínas Fúngicas/aislamiento & purificación , Proteínas Fúngicas/metabolismo , Expresión Génica , Isoenzimas/química , Isoenzimas/genética , Isoenzimas/aislamiento & purificación , Isoenzimas/metabolismo , Cinética , Modelos Moleculares , Datos de Secuencia Molecular , Unión Proteica , Estructura Secundaria de Proteína , Teoría Cuántica , Alineación de Secuencia , Homología Estructural de Proteína , Especificidad por Sustrato , Termodinámica
12.
J Theor Biol ; 382: 178-86, 2015 Oct 07.
Artículo en Inglés | MEDLINE | ID: mdl-26164060

RESUMEN

Multitemplate polymerase chain reaction (PCR) is used for preparative and analytical applications in diagnostics and research. Classical PCR and qPCR are two basic setups with many possible experimental modifications. Classical PCR is a method of choice to obtain enough material for subsequent sophisticated applications such as construction of libraries for next-generation sequencing or high-throughput screening. Sequencing and Single Nucleotide Primer Extension (SNuPE) employ one-strand synthesis and represent a distinct variant of analytical DNA synthesis. In all these applications, maintaining the initial ratio of templates and avoiding underestimation of minority templates is desired. Here, we demonstrate that different templates can amplify independently at low template concentrations (typical in qPCR setups, in which the polymerase concentration is usually several orders of magnitude higher than the template concentration). However, rare templates can be diluted in an effort to keep DNA amplification in the exponential phase, or template concentration can be biased by differences in amplification efficiency. Moreover, amplification of templates present in low concentrations is more vulnerable to stochastic events that lead to proportional changes in the product ratio, as well as by incomplete amplification leading to chimera formation. These undesired effects can be compensated for by using highly processive polymerases with high and equal affinity to different primer-template complexes. Novel enhanced polymerases are desired. With increasing concentration of a primer-template of interest, the system becomes more deterministic. Nevertheless, marked deviation from independent exponential amplification occurs when the total template concentration starts to approach the polymerase concentration. The primer-template complexes compete for enzyme molecules, and the amount of products grows arithmetically-the system starts to obey Michaelis-Menten kinetics. Synthesis of rare products in a multitemplate mixture can run more easily under the detection limit in such conditions, although it would be unequivocally detectable in a single template assay. When fishing out rare template variants, the best processive polymerases should be used to decrease both amplification and detection limits. The possibility of stochastic events, should be taken into account to correctly interpret the obtained data.


Asunto(s)
Enzimas/metabolismo , Reacción en Cadena de la Polimerasa/métodos , Moldes Genéticos , Simulación por Computador , Cartilla de ADN , Procesos Estocásticos
13.
Artículo en Inglés | MEDLINE | ID: mdl-39151915

RESUMEN

INTRODUCTION Microvascular anastomosis using interrupted suture is a widely accepted standard technique. Continuous suture is less common due to the presumption that its firmness can negatively affect anastomosis maturation. The purpose of this study was to determine whether the use of continuous suture allows maturation of the microanastomosis site. MATERIAL AND METHODS A rat common carotid artery (CCA) end-to-end microanastomosis model was utilized, with 19 Long-Evans rats in the interrupted sutures group and 13 in the continuous suture group. Immediate blood flow of the operated and contralateral intact CCAs was compared before clamping, at the completion of the anastomosis and after 14 days. Quantitative transit time flowmetry measurement and histological examination were employed. RESULTS Initial blood flow in both intact CCAs was similar across all animals (p = .004). In the interrupted suture group, median anastomosis blood flow was 88.9% of the contralateral CCA blod flow, with a median suture time of 46 minutes. After two weeks, blood flow increased to 96.1%. In the continuous suture group, median anastomosis blood flow was 88.3% of the contralateral CCA blood flow, with a median suture time of 30 minutes. After two weeks, blood flow increased to 100.0%. The reduction in suture time achieved with continuous suture was 34.8% (p < .001). Histological examination confirmed scar maturity. CONCLUSIONS The maturation rates of continuous and interrupted suture microanastomosis were comparable in our study, implying that concerns about the suture restricting maturation may be unwarranted. Additional finding is the potential for a reduction in microanastomosis time when using the continuous suture technique.

14.
Front Cardiovasc Med ; 11: 1443214, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39238502

RESUMEN

Introduction: Human diving reflex is a well-studied phenomenon. However, very little is known about the possible relationship between augmented diving reflex and autonomic dysfunction. Methods: We retrospectively studied a group of four swimmers who underwent a diving reflex test as part of the examination due to symptoms related to autonomic dysfunction during swimming. The control group comprised 11 healthy swimmers with no history of these symptoms. A standardized diving reflex test was performed for each athlete in both groups. Hemodynamic profiles, including heart rate, stroke volume, and cardiac output, were recorded. Results: There were no statistically significant differences between the groups in any of the three parameters measured before the test. However, at the end of the test, each parameter (heart rate, stroke volume, and cardiac output) was significantly lower in the swimmers who presented with clinical symptoms related to autonomic dysfunction than in the control group. Conclusion: This observation could shed light on autonomic dysfunction as a possible cause of sudden cardiac death in swimming athletes. It also demonstrated that autonomic dysfunction is presented not only by decreased heart rate but also by stroke volume, causing a drop in cardiac output to the level of hemodynamic collapse.

15.
Mol Oncol ; 17(12): 2565-2583, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37408496

RESUMEN

Mutations in the splicing factor 3b subunit 1 (SF3B1) gene are frequent in myelodysplastic neoplasms (MDS). Because the splicing process is involved in the production of circular RNAs (circRNAs), we investigated the impact of SF3B1 mutations on circRNA processing. Using RNA sequencing, we measured circRNA expression in CD34+ bone marrow MDS cells. We defined circRNAs deregulated in a heterogeneous group of MDS patients and described increased circRNA formation in higher-risk MDS. We showed that the presence of SF3B1 mutations did not affect the global production of circRNAs; however, deregulation of specific circRNAs was observed. Particularly, we demonstrated that strong upregulation of circRNAs processed from the zinc finger E-box binding homeobox 1 (ZEB1) transcription factor; this upregulation was exclusive to SF3B1-mutated patients and was not observed in those with mutations in other splicing factors or other recurrently mutated genes, or with other clinical variables. Furthermore, we focused on the most upregulated ZEB1-circRNA, hsa_circ_0000228, and, by its knockdown, we demonstrated that its expression is related to mitochondrial activity. Using microRNA analyses, we proposed miR-1248 as a direct target of hsa_circ_0000228. To conclude, we demonstrated that mutated SF3B1 leads to deregulation of ZEB1-circRNAs, potentially contributing to the defects in mitochondrial metabolism observed in SF3B1-mutated MDS.


Asunto(s)
Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Humanos , Factores de Empalme de ARN/genética , ARN Circular/genética , Síndromes Mielodisplásicos/genética , Mutación/genética , Factores de Transcripción/genética , Fosfoproteínas/genética
16.
J Enzyme Inhib Med Chem ; 27(1): 160-5, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22146051

RESUMEN

Secreted aspartic proteases (Saps) are extracellular proteolytic enzymes that enhance the virulence of Candida pathogens. These enzymes therefore represent possible targets for therapeutic drug design. Saps are inhibited by nanomolar concentrations of the classical inhibitor of aspartic proteases pepstatin A and also by the inhibitors of the HIV protease, but with the K(i) of micromolar values or higher. To contribute to the discussion regarding whether HIV protease inhibitors can act against opportunistic mycoses by the inhibition of Saps, we determined the structure of Sapp1p from Candida parapsilosis in complex with ritonavir (RTV), a clinically used inhibitor of the HIV protease. The crystal structure refined at resolution 2.4 Å proved binding of RTV into the active site of Sapp1p and provided the structural information necessary to evaluate the stability and specificity of the protein-inhibitor interaction.


Asunto(s)
Ácido Aspártico Endopeptidasas/química , Candida/enzimología , Proteínas Fúngicas/química , Inhibidores de la Proteasa del VIH/química , Ritonavir/química , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Cristalografía por Rayos X , Proteínas Fúngicas/antagonistas & inhibidores , Inhibidores de la Proteasa del VIH/farmacología , Modelos Moleculares , Ritonavir/farmacología , Relación Estructura-Actividad
17.
J Neurol Surg A Cent Eur Neurosurg ; 82(5): 437-445, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-33618416

RESUMEN

BACKGROUND: Decompressive craniectomy (DC) has become the definitive surgical procedure to manage a medically intractable rise in intracranial pressure. DC is a life-saving procedure resulting in lower mortality but also higher rates of severe disability. Although technically straightforward, DC is accompanied by many complications. It has been reported that complications are associated with worse outcome. We reviewed a series of patients who underwent DC at our department to establish the incidence and types of complications. METHODS: We retrospectively evaluated the incidence of complications after DC performed in 135 patients during the time period from January 2013 to December 2018. Postoperative complications were evaluated using clinical status and CT during 6 months of follow-up. In addition, the impact of potential risk factors on the incidence of complications and the impact of complications on outcome were assessed. RESULTS: DC was performed in 135 patients, 93 of these for trauma, 22 for subarachnoid hemorrhage, 13 for malignant middle cerebral artery infarction, and 7 for intracerebral hemorrhage. Primary DC was performed in 120 patients and secondary DC in 15 patients. At least 1 complication occurred in each of 100 patients (74%), of which 22 patients (22%) were treated surgically. The following complications were found: edema or hematoma of the temporal muscle (34 times), extracerebral hematoma (33 times), extra-axial fluid collection (31 times), hemorrhagic progression of contusions (19 times), hydrocephalus (12 times), intraoperative malignant brain edema (10 times), temporal muscle atrophy (7 times), significant intraoperative blood loss (6 times), epileptic seizures (5 times), and skin necrosis (4 times). Trauma (p = 0.0006), coagulopathy (p = 0.0099), and primary DC (p = 0.0252) were identified as risk factors for complications. There was no significant impact of complications on outcome. CONCLUSIONS: The incidence of complications following DC is high. However, we did not confirm a significant impact of complications on outcome. We emphasize that some phenomena are so frequent that they can be considered a consequence of primary injury or natural sequelae of the DC rather than its direct complication.


Asunto(s)
Craniectomía Descompresiva , Hidrocefalia , Craniectomía Descompresiva/efectos adversos , Humanos , Presión Intracraneal , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/cirugía , Estudios Retrospectivos , Resultado del Tratamiento
18.
Chronobiol Int ; 38(12): 1661-1672, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34128445

RESUMEN

Circadian clocks regulate multiple physiological domains from molecular to behavioral levels and adjust bodily physiology to seasonal changes in day length. Circadian regulation of cellular bioenergy and immunity in the cardiovascular and muscle systems may underpin the individual diurnal differences in performance capacity during exercise. Several studies have shown diurnal differences in cardiopulmonary parameters at maximal and submaximal workloads in morning and evening circadian human phenotypes. However, the effect of seasons on these changes was not elucidated. In this study, we recruited subjects with Morningness-Eveningness Questionnaire scores corresponding to morning and evening types. Subjects underwent morning (7:00-9:00) and evening (20:00-22:00) maximal workload spiroergometry in both winter and summer seasons. We analyzed their performance time, anaerobic threshold, heart rate, and respiratory parameters. Our results suggest that evening types manifest diurnal variations in physical performance, particularly in winter. They also have slower heart rate recovery than morning types, irrespective of the time of day or season. Compared to winter, the chronotype effect on the magnitude of morning-evening differences in performance time, maximal heart rate, and anaerobic threshold onset was more significant in summer. Our data are in concordance with previous observations and confirm the difference between morning and evening types in the timing of maximum performance capacity.


Asunto(s)
Relojes Circadianos , Ritmo Circadiano , Ejercicio Físico , Humanos , Estaciones del Año , Encuestas y Cuestionarios
19.
J Struct Biol ; 167(2): 145-52, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19401235

RESUMEN

Opportunistic pathogens of the genus Candida cause infections representing a major threat to long-term survival of immunocompromised patients. Virulence of the Candida pathogens is enhanced by production of extracellular proteolytic enzymes and secreted aspartic proteases (Saps) are therefore studied as potential virulence factors and possible targets for therapeutic drug design. Candida parapsilosis is less invasive than C. albicans, however, it is one of the leading causative agents of yeast infections. We report three-dimensional crystal structure of Sapp1p from C. parapsilosis in complex with pepstatin A, the classical inhibitor of aspartic proteases. The structure of Sapp1p was determined from protein isolated from its natural source and represents the first structure of Sap from C. parapsilosis. Overall fold and topology of Sapp1p is very similar to the archetypic fold of monomeric aspartic protease family and known structures of Sap isoenzymes from C. albicans and Sapt1p from C. tropicalis. Structural comparison revealed noticeable differences in the structure of loops surrounding the active site. This resulted in differential character, shape, and size of the substrate binding site explaining divergent substrate specificities and inhibitor affinities. Determination of structures of Sap isoenzymes from various species might contribute to the development of new Sap-specific inhibitors.


Asunto(s)
Ácido Aspártico Endopeptidasas/química , Candida/enzimología , Proteínas Fúngicas/química , Pepstatinas/química , Sitios de Unión , Candida/patogenicidad , Dominio Catalítico , Cristalografía por Rayos X , Unión Proteica , Conformación Proteica , Pliegue de Proteína
20.
J Neurol Surg A Cent Eur Neurosurg ; 80(4): 250-254, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-30887487

RESUMEN

BACKGROUND AND STUDY AIMS: Both general anesthesia (GA) and local anesthesia (LA) are used in our department for carotid endarterectomy. The decision of which anesthetic technique to use during surgery is made on an individual basis. The aim of our study was to analyze the reasons for using GA or LA. MATERIAL AND METHODS: The reasons that led to the selection of either GA or LA were analyzed retrospectively in a group of 409 patients. RESULTS: GA was used in 304 patients (74%) and LA in 105 patients (26%). The reasons for a preference for GA were clopidogrel use (88 patients), patient preference (80), increased risk of shunt insertion (43), unfavorable anatomical conditions (41), surgeon preference (21), simultaneous carotid endarterectomy and cardiac surgery (18), emergent carotid endarterectomy (12), and sleep apnea syndrome (1). The reasons for selecting LA were internal comorbidities (46 patients), patient preference (39), unavailability of intraoperative electrophysiologic monitoring (15), and pacemaker (5). CONCLUSION: GA is the dominant choice for carotid endarterectomy in our department because of its prevailing benefits and its preference among neurosurgeons and patients. However, in some subgroups of patients, LA is preferable. An optimal approach is therefore an individual indication for both anesthesia techniques.


Asunto(s)
Anestesia General , Anestesia Local , Estenosis Carotídea/cirugía , Endarterectomía Carotidea , Anciano , Estenosis Carotídea/complicaciones , Estenosis Carotídea/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Monitoreo Intraoperatorio , Selección de Paciente , Estudios Retrospectivos
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