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1.
NAR Genom Bioinform ; 6(4): lqae136, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39363891

RESUMEN

We can now analyze 3D physical interactions of chromatin regions with chromatin conformation capture technologies, in addition to the 1D chromatin state annotations, but methods to integrate this information are lacking. We propose a method to integrate the chromatin state of interacting regions into a vector representation through the contact-weighted sum of chromatin states. Unsupervised clustering on integrated chromatin states and Micro-C contacts reveals common patterns of chromatin interaction signatures. This provides an integrated view of the complex dynamics of concurrent change occurring in chromatin state and in chromatin interaction, adding another layer of annotation beyond chromatin state or Hi-C contact separately.

2.
J Clin Pharmacol ; 64(10): 1193-1203, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-38831713

RESUMEN

Diabetic nephropathy (DN), a severe complication of type 2 diabetes mellitus (T2DM), is marked by heightened endoplasmic reticulum stress (ERS) and oxidative stress (OS) due to protein misfolding and free radical generation. We investigated the sodium-glucose co-transporter-2 inhibitor (SGLT2i), canagliflozin (Cana), in alleviating ERS and OS in DN patients and THP-1 cells under hyperglycemic condition. A total of 120 subjects were divided into four groups, with 30 subjects in each group: healthy controls, T2DM individuals, DN patients receiving standard treatment, and those treated with Cana. The control group had no history of diabetes, cardiovascular or renal diseases, or other comorbidities. Cana was administered at doses of either 100 or 300 mg per day based on the estimated glomerular filtration rate (eGFR) value of DN individuals, with a mean follow-up of 6 months. Additionally, THP-1 monocytes were exposed to HGM (33.3 mM glucose with a cytokine cocktail of TNF-α and IFN-γ at 50 ng/mL each) to evaluate the relative levels of ERS, OS markers, and nuclear factor erythroid 2-related factor 2 (Nrf2), the transcription factor regulating cellular redox, which is downregulated in diabetes. Our results revealed that ERS markers GRP78 and PERK, as well as OS markers TXNIP and p22phox, were elevated in both DN patients and HGM-treated THP-1 monocytes and were reduced by Cana intervention. Furthermore, Cana regulated the phosphorylation of Nrf2, Akt, and EIF2α in HGM-treated monocytes. In conclusion, our findings highlight the role of Cana in activating Nrf2, thereby attenuating ERS and OS to mitigate DN progression.


Asunto(s)
Canagliflozina , Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Chaperón BiP del Retículo Endoplásmico , Estrés del Retículo Endoplásmico , Factor 2 Relacionado con NF-E2 , Estrés Oxidativo , Transducción de Señal , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Factor 2 Relacionado con NF-E2/metabolismo , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/tratamiento farmacológico , Estrés del Retículo Endoplásmico/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Masculino , Persona de Mediana Edad , Femenino , Transducción de Señal/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Canagliflozina/farmacología , Canagliflozina/uso terapéutico , Anciano , Células THP-1 , Adulto
3.
J Arthroplasty ; 39(2): 332-335, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37572726

RESUMEN

BACKGROUND: Augmented reality (AR) is a powerful multipurpose tool. With a dedicated visor, AR allows the visualization of a series of information and/or images superimposed on the user's field of vision. For this reason, it was recently introduced as a surgical assistant tool. This single-center study aimed to evaluate the intraoperative outcomes of total knee arthroplasties performed with AR assistance in terms of time required and the difference between preplanned and achieved implant positioning (in terms of tibial cut varus and slope angles). METHODS: A total of 76 consecutive patients was selected. Preplanning was performed according to the AR protocol, and the target varus and slope angles were defined to instruct the device, which subsequently guided the tibial cuts intraoperatively. Surgeries were performed starting from the tibial cut, and the time required to perform the calibration, registration, and fixation of the resection block was recorded. The varus and slope angles achieved were recorded to compare with the preplanned ones to determine the means and SDs of the differences. RESULTS: The mean usage time of the AR tool was 5 ± 1 minutes. Results showed a mean difference of 0.59 ± 0.55° for varus angles and 0.70 ± 0.75° for the slope. For varus angles, the differences were <1° for 96% of the cases. Concerning the slope, 89% of the cases were <1°. CONCLUSION: The results showed excellent accuracy of the surgical cuts and a limited increase in surgery duration. Therefore, these outcomes highlighted the potential of this new technology as a valid option for surgical assistance.


Asunto(s)
Artroplastia de Reemplazo de Rodilla , Realidad Aumentada , Cirugía Asistida por Computador , Humanos , Artroplastia de Reemplazo de Rodilla/métodos , Cirugía Asistida por Computador/métodos , Tibia/cirugía , Articulación de la Rodilla/cirugía
4.
bioRxiv ; 2023 Nov 04.
Artículo en Inglés | MEDLINE | ID: mdl-37961132

RESUMEN

Merkel Cell Carcinoma (MCC) is a highly aggressive neuroendocrine cutaneous malignancy arising from either ultraviolet-induced mutagenesis or Merkel cell polyomavirus (MCPyV) integration. It is the only known neuroendocrine tumor (NET) with a virus etiology. Despite extensive research, our understanding of the molecular mechanisms driving the transition from normal cells to MCC remains limited. To address this knowledge gap, we assessed the impact of inducible MCPyV T antigens into normal human fibroblasts by performing RNA sequencing. Our findings suggested that the WNT signaling pathway plays a critical role in the development of MCC. To test this model, we bioinformatically evaluated various perturbagens for their ability to reverse the MCC gene expression signature and identified pyrvinium pamoate, an FDA-approved anthelminthic drug known for its anti-tumor potential in multiple cancers. Leveraging transcriptomic, network, and molecular analyses, we found that pyrvinium effectively targets multiple MCC vulnerabilities. Specifically, pyrvinium not only reverses the neuroendocrine features of MCC by modulating canonical and non-canonical WNT signaling pathways but also inhibits cancer cell growth by activating the p53-mediated apoptosis pathway, disrupting mitochondrial function, and inducing endoplasmic reticulum (ER) stress. Pyrvinium also effectively inhibits tumor growth in an MCC mouse xenograft model. These findings offer new avenues for the development of therapeutic strategies for neuroendocrine cancer and highlight the utility of pyrvinium as a potential treatment for MCC.

5.
Open Res Eur ; 3: 81, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38234865

RESUMEN

Easy-to-use libraries such as scikit-learn have accelerated the adoption and application of machine learning (ML) workflows and data-driven methods. While many of the algorithms implemented in these libraries originated in specific scientific fields, they have gained in popularity in part because of their generalisability across multiple domains. Over the past two decades, researchers in the chemical and materials science community have put forward general-purpose machine learning methods. The deployment of these methods into workflows of other domains, however, is often burdensome due to the entanglement with domainspecific functionalities. We present the python library scikit-matter that targets domain-agnostic implementations of methods developed in the computational chemical and materials science community, following the scikit-learn API and coding guidelines to promote usability and interoperability with existing workflows.

6.
Acad Radiol ; 28(9): 1296-1303, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-32807605

RESUMEN

RATIONALE AND OBJECTIVES: To evaluate the training of computed tomography (CT)-guided periradicular therapy in a realistic simulation environment and to derive recommendations for a training curriculum. MATERIALS AND METHODS: A novel simulation environment including the use of a 3D printed, patient-mimicking phantom was used to train medical students to perform CT-guided periradicular therapy of the lumbar spine. Seventeen participants underwent three training sessions (day 0, day 7, and after day 28) with six procedures per session. Procedure duration and the number of fluoroscopy image acquisitions were recorded. Participants' performance was assessed by an independent investigator using a six-point checklist scale (0 = lowest, 6 = highest). In addition, participants self-evaluated their skills and the simulation training in questionnaires. RESULTS: Procedure durations and image acquisitions decreased after one training session (p < 0.001) without further improvement thereafter (p > 0.6). They also decreased within training sessions and were lowest after five procedures in all sessions. Performance scores improved after the first session to nearly perfect scores in the second session (mean 5.7; 95%CI: 5.5-6.0; p < 0.001) and decreased again in the third session (mean 4.9; 95%CI: 4.6-5.3; p = 0.008). Participants were satisfied with their training progress and felt adequately prepared to perform CT-guided periradicular therapies on patients after the training. CONCLUSION: Simulation-based training of CT-guided periradicular therapy in a realistic environment is effective and should ideally be performed with one training session consisting of five procedures shortly before treating the first patient.


Asunto(s)
Curriculum , Entrenamiento Simulado , Competencia Clínica , Fluoroscopía , Humanos , Fantasmas de Imagen , Tomografía Computarizada por Rayos X
7.
Eur J Pharmacol ; 892: 173749, 2021 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-33245896

RESUMEN

Cellular stress and inflammation, establishing as disease pathology, have reached great heights in the last few decades. Stress conditions such as hyperglycemia, hyperlipidemia and lipoproteins are known to disturb proteostasis resulting in the accumulation of unfolded or misfolded proteins, alteration in calcium homeostasis culminating in unfolded protein response. Protein disulfide isomerase and endoplasmic reticulum oxidase-1 are the key players in protein folding. The protein folding process assisted by endoplasmic reticulum oxidase-1 results in the production of reactive oxygen species in the lumen of the endoplasmic reticulum. Production of reactive oxygen species beyond the quenching capacity of the antioxidant systems perturbs ER homeostasis. Endoplasmic reticulum stress also induces the production of cytokines leading to inflammatory responses. This has been proven to be the major causative factor for various pathophysiological states compared to other cellular triggers in diseases, which further manifests to increased oxidative stress, mitochondrial dysfunction, and altered inflammatory responses, deleterious to cellular physiology and homeostasis. Numerous studies have drawn correlations between the progression of several diseases in association with endoplasmic reticulum stress, redox protein folding, oxidative stress and inflammatory responses. This review aims to provide an insight into the role of protein disulfide isomerase and endoplasmic reticulum oxidase-1 in endoplasmic reticulum stress, unfolded protein response, mitochondrial dysfunction, and inflammatory responses, which exacerbate the progression of various diseases.


Asunto(s)
Estrés del Retículo Endoplásmico , Retículo Endoplásmico/enzimología , Inflamación/enzimología , Mitocondrias/enzimología , Estrés Oxidativo , Oxidorreductasas/metabolismo , Proteína Disulfuro Isomerasas/metabolismo , Animales , Antiinflamatorios/uso terapéutico , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/patología , Inhibidores Enzimáticos/uso terapéutico , Humanos , Inflamación/tratamiento farmacológico , Inflamación/patología , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Oxidorreductasas/antagonistas & inhibidores , Proteína Disulfuro Isomerasas/antagonistas & inhibidores , Pliegue de Proteína , Transducción de Señal , Respuesta de Proteína Desplegada
8.
Cell Stress Chaperones ; 26(2): 311-321, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33161510

RESUMEN

Increasing evidence in substantiating the roles of endoplasmic reticulum stress, oxidative stress, and inflammatory responses and their interplay is evident in various diseases. However, an in-depth mechanistic understanding of the crosstalk between the intracellular stress signaling pathways and inflammatory responses and their participation in disease progression has not yet been explored. Progress has been made in our understanding of the cross talk and integrated stress signaling network between endoplasmic reticulum stress and oxidative stress towards the pathogenesis of diabetic nephropathy. In this present study, we studied the crosstalk between the endoplasmic reticulum stress and oxidative stress by understanding the role of protein disulfide isomerase and endoplasmic reticulum oxidase 1α, a key player in redox protein folding in the endoplasmic reticulum. We had recruited a total of 90 subjects and divided into three groups (control (n = 30), type 2 diabetes mellitus (n = 30), and diabetic nephropathy (n = 30)). We found that endoplasmic reticulum stress markers, activating transcription factor 6, inositol-requiring enzyme 1α, protein kinase RNA-like endoplasmic reticulum kinase, C/EBP homologous protein, and glucose-regulated protein-78; oxidative stress markers, thioredoxin-interacting protein and cytochrome b-245 light chain; and the crosstalk markers, protein disulfide isomerase and endoplasmic reticulum oxidase-1α, were progressively elevated in type 2 diabetes mellitus and diabetic nephropathy subjects. The association between the crosstalk markers showed a positive correlation with endoplasmic reticulum stress and oxidative stress markers. Further, the interplay between endoplasmic reticulum stress and oxidative stress was investigated in vitro using a human leukemic monocytic cell line under a hyperglycemic environment and examined the expression of protein disulfide isomerase and endoplasmic reticulum oxidase-1α. DCFH-DA assay and flow cytometry were performed to detect the production of free radicals. Further, phosphorylation of eIF2α in high glucose-exposed cells was studied using western blot. In conclusion, our results shed light on the crosstalk between endoplasmic reticulum stress and oxidative stress and significantly contribute to the onset and progression of diabetic nephropathy and therefore represent the major therapeutic targets for alleviating micro- and macrovascular complications associated with this metabolic disturbance. Graphical abstract.


Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Nefropatías Diabéticas/metabolismo , Estrés del Retículo Endoplásmico , Glicoproteínas de Membrana/metabolismo , Estrés Oxidativo , Oxidorreductasas/metabolismo , Adulto , Biomarcadores/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteína Disulfuro Isomerasas/metabolismo , Células THP-1
9.
Eur J Pharmacol ; 886: 173395, 2020 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-32710954

RESUMEN

Wound repair and regeneration is a complex orchestrated process, comprising several phases interconnecting various cellular events and triggering multiple intracellular molecular pathways in damaged cells and tissues. In several metabolic disorders including diabetes mellitus, delay in wound healing due to elevated levels of cellular stress poses a key challenge. Several therapeutic wound dressing materials and strategies including hyperbaric oxygen therapy and negative pressure wound therapy have been developed to accelerate repair and restore cellular homeostasis at the wound site. Further, tremendous progress has been made in identification of transcriptional regulators involved in the process of wound healing. Nuclear factor erythroid 2-related factor 2 (Nrf2), a redox sensitive transcription factor, is the key regulator of intracellular redox homeostasis which induces the expression of cytoprotective genes and increases the production of antioxidants that scavenge free radicals. Activators of Nrf2 have been reported to combat oxidative stress and enhance the process of wound healing in several pathophysiological conditions, including diabetes and its complications such as diabetic foot ulcer, and chronic kidney disease, and diabetic nephropathy. Several bioactive compounds have been reported to reduce cellular stress, and thus accelerate cell proliferation, neovascularization results in repairing damaged tissues by the activation of the transcription factor, Nrf2. This review is focused on the strategies for diabetic wound healing and the highlights the role of bioactive compounds that activate the Nrf2 signaling and revitalize the cellular and molecular mechanism in the chronic wound niche, regulate and restore redox homeostasis thereby promoting wound repair and regeneration.


Asunto(s)
Factor 2 Relacionado con NF-E2/agonistas , Cicatrización de Heridas/efectos de los fármacos , Animales , Antioxidantes/metabolismo , Enfermedad Crónica , Homeostasis/efectos de los fármacos , Humanos , Transducción de Señal
10.
Neuroradiology ; 62(3): 341-346, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31838562

RESUMEN

PURPOSE: To develop and evaluate a technical approach for CT-guided periradicular infiltration using quantitative needle access and guidance parameters extracted from CT scout images. METHODS: Five 3D-printed phantoms of the abdomen mimicking different patients were used to develop a technical approach for scout-guided periradicular infiltration. The needle access point, puncture depth, and needle angulation were calculated using measurements extracted from anterior-posterior and lateral CT scout images. Fifty needle placements were performed with the technique thus developed. Dose exposure and number of image acquisitions were compared with ten procedures performed using a conventional free-hand technique. Data were analyzed with the Mann-Whitney U test. RESULTS: Parameters derived solely from scout images provided adequate guidance for successful and reliable needle placement. Needle guidance was performed with the same equipment as the standard periradicular infiltration. Two scout images and 3.5 ± 2.3 (mean ± SD) single-shot images for needle positioning were acquired. Mean DLP ± SD was 3.8 ± 2.5 mGy cm. The number of single-shot acquisitions was reduced by 68% and the overall dose was reduced by 84% in comparison with the conventional free-hand technique (p < 0.0001). CONCLUSION: Scout-guided needle placement for periradicular infiltration is feasible and reduces radiation exposure significantly.


Asunto(s)
Radiculopatía/tratamiento farmacológico , Radiografía Intervencional/métodos , Tomografía Computarizada por Rayos X/métodos , Abdomen , Humanos , Inyecciones Espinales , Agujas , Fantasmas de Imagen , Impresión Tridimensional , Punciones , Dosis de Radiación , Radiculopatía/diagnóstico por imagen
11.
Rom J Morphol Embryol ; 58(4): 1217-1228, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29556610

RESUMEN

Bone determinations are usually the first sign of disseminated cancers, whether is a hematological malignancy or other type of neoplasia. The aim of this paper is the possibility of differentiating the bone lesions from hematological malignancies by other malignancies that give bone metastases for the purpose to guide the clinician concerning causality of bone lesions. The research involved a retrospective study, which included 309 cases that were investigated by magnetic resonance imaging (MRI) at a segment of the spine, between 2010 and 2014, from which 137 were diagnosed with a form of hematological neoplasia, and the remaining had another form of cancer. Imaging aspect differs in these two study groups. Bone determinations due to malignant hemopathies (MH) were in general hypointense on T1-weighted sequences, iso- or hyperintense on T2-weighted sequences. On the other hand, bone metastases were hypo- or isointense on T1-weighted sequences, and had no specific signal intensity on T2-weighted sequences. In post-contrast images, all lesions showed contrast enhancement, with some differences. In terms of imagistic aspect, there are certain characteristics that can make a clear differentiation between bone determinations due to MH from the bone metastases, and some are found in the majority of the cases studied.


Asunto(s)
Neoplasias Óseas/diagnóstico por imagen , Neoplasias Óseas/secundario , Neoplasias Hematológicas/diagnóstico por imagen , Neoplasias Hematológicas/diagnóstico , Imagen por Resonancia Magnética/métodos , Diagnóstico Diferencial , Femenino , Neoplasias Hematológicas/patología , Humanos , Masculino , Metástasis de la Neoplasia , Estudios Retrospectivos
12.
Peptides ; 78: 77-86, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26923803

RESUMEN

The Ca(2+)-binding protein centrin binds to a hydrophobic motif (W(1)xxL(4)xxxL(8)) included in the sequence of several cellular targets: XPC (xeroderma pigmentosum group C protein), Sfi1 (suppressor of fermentation-induced loss of stress resistance protein1), and Sac3 [the central component of the transcription and mRNA export (TREX-2) complex]. However, centrin binding occurs in a reversed orientation (L(8)xxxL(4)xxW(1)) for Sfi1 and Sac3 compared with XPC. Because D-peptides have been investigated for future therapeutic use, we analyzed their centrin-binding properties. Their affinity for centrin was measured using isothermal titration calorimetry. The chirality change in the target-derived peptides affected their ability to bind centrin in a specific manner depending on the sequence orientation of the centrin-binding motif. In contrast to L-XPC-P10, D-XPC-P10 bound C-HsCen1 in a Ca(2+)-dependent manner and to a lesser extent. D-XPC-P10 exhibited a reduced affinity for C-HsCen1 (Ka=0.064 × 10(6) M(-1)) by a factor of 2000 compared with L-XPC-P10 (Ka=132 × 10(6) M(-1)). D-peptides have a lower affinity than L-peptides for centrin, and the strength of this affinity depends on the sequence orientation of the target-derived peptides. The residual affinity observed for D-XPC suggests that the use of d-peptides represents a promising strategy for inhibiting centrin binding to its targets.


Asunto(s)
Proteínas de Unión al Calcio/química , Proteínas de Ciclo Celular/química , Chlorophyta/química , Proteínas de Unión al ADN/química , Péptidos/química , Proteínas Algáceas/química , Proteínas Algáceas/genética , Proteínas Algáceas/metabolismo , Secuencia de Aminoácidos , Sitios de Unión , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Flavoproteínas/química , Flavoproteínas/genética , Flavoproteínas/metabolismo , Expresión Génica , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Cinética , Datos de Secuencia Molecular , Péptidos/síntesis química , Monoéster Fosfórico Hidrolasas/química , Monoéster Fosfórico Hidrolasas/genética , Monoéster Fosfórico Hidrolasas/metabolismo , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Estereoisomerismo , Termodinámica
13.
Bioorg Med Chem ; 23(21): 6785-93, 2015 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-26481659

RESUMEN

Among the natural histone deacetylase inhibitors (HDACi), the bicyclic depsipeptide macrolactone FK228 stands out for its unique chemical structure and mechanism of action. In order to expand the chemical diversity, exploiting the FK228 peculiar structure, we have synthesized a collection of 24 simplified novel analogs. A first series consists of bicyclic macrolactones, where the carboxy terminus of the natural compound was substituted by peptidomimetic aminomethylphenylacetic acid derivatives. These analogs, 7a-i, showed submicromolar cytotoxic activity, even though very low inhibitory activity against HDAC enzymes, suggesting that most probably they behave with a mechanism different from the natural compound. One of the most active members in the group, 7g, was evaluated in vivo and exhibited significant antitumor activity. This evidence supports that the activity is unrelated to HDAC inhibition and these compounds represent a novel series of promising active agents. Another analog series consists of monocyclic macrolactones, 9a-c and 10a-d which lack the disulfide bridge and bear the protected sulfur on the linear external chain; they showed similar cytotoxic activities compared to the natural compound, but proved to be very sensitive to the nature of the sulfur protection. In fact, when the sulfur was protected by an 1-octanoyl residue, like in 9b, the product displayed a one digit nanomolar activity. The results provide evidence that our approach may be followed to develop novel series of FK228 analogs.


Asunto(s)
Depsipéptidos/química , Diseño de Fármacos , Inhibidores de Histona Desacetilasas/síntesis química , Supervivencia Celular/efectos de los fármacos , Depsipéptidos/síntesis química , Depsipéptidos/toxicidad , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/toxicidad , Humanos , Lactonas/síntesis química , Lactonas/química , Lactonas/toxicidad , Microondas , Técnicas de Síntesis en Fase Sólida
14.
J Mol Model ; 20(4): 2196, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24728650

RESUMEN

Given the increasing complexity of simulated molecular systems, and the fact that simulation times have now reached milliseconds to seconds, immense amounts of data (in the gigabyte to terabyte range) are produced in current molecular dynamics simulations. Manual analysis of these data is a very time-consuming task, and important events that lead from one intermediate structure to another can become occluded in the noise resulting from random thermal fluctuations. To overcome these problems and facilitate a semi-automated data analysis, we introduce in this work a measure based on C(α) torsion angles: torsion angles formed by four consecutive C(α) atoms. This measure describes changes in the backbones of large systems on a residual length scale (i.e., a small number of residues at a time). Cluster analysis of individual C(α) torsion angles and its fuzzification led to continuous time patches representing (meta)stable conformations and to the identification of events acting as transitions between these conformations. The importance of a change in torsion angle to structural integrity is assessed by comparing this change to the average fluctuations in the same torsion angle over the complete simulation. Using this novel measure in combination with other measures such as the root mean square deviation (RMSD) and time series of distance measures, we performed an in-depth analysis of a simulation of the open form of DNA polymerase I. The times at which major conformational changes occur and the most important parts of the molecule and their interrelations were pinpointed in this analysis. The simultaneous determination of the time points and localizations of major events is a significant advantage of the new bottom-up approach presented here, as compared to many other (top-down) approaches in which only the similarity of the complete structure is analyzed.


Asunto(s)
Simulación de Dinámica Molecular , Modelos Moleculares , Conformación Molecular , Unión Proteica , Estructura Terciaria de Proteína
15.
J Comput Aided Mol Des ; 26(2): 185-97, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22231069

RESUMEN

Due to the large number of different docking programs and scoring functions available, researchers are faced with the problem of selecting the most suitable one when starting a structure-based drug discovery project. To guide the decision process, several studies comparing different docking and scoring approaches have been published. In the context of comparing scoring function performance, it is common practice to use a predefined, computer-generated set of ligand poses (decoys) and to reevaluate their score using the set of scoring functions to be compared. But are predefined decoy sets able to unambiguously evaluate and rank different scoring functions with respect to pose prediction performance? This question arose when the pose prediction performance of our piecewise linear potential derived scoring functions (Korb et al. in J Chem Inf Model 49:84-96, 2009) was assessed on a standard decoy set (Cheng et al. in J Chem Inf Model 49:1079-1093, 2009). While they showed excellent pose identification performance when they were used for rescoring of the predefined decoy conformations, a pronounced degradation in performance could be observed when they were directly applied in docking calculations using the same test set. This implies that on a discrete set of ligand poses only the rescoring performance can be evaluated. For comparing the pose prediction performance in a more rigorous manner, the search space of each scoring function has to be sampled extensively as done in the docking calculations performed here. We were able to identify relative strengths and weaknesses of three scoring functions (ChemPLP, GoldScore, and Astex Statistical Potential) by analyzing the performance for subsets of the complexes grouped by different properties of the active site. However, reasons for the overall poor performance of all three functions on this test set compared to other test sets of similar size could not be identified.


Asunto(s)
Dominio Catalítico , Diseño de Fármacos , Unión Proteica , Proteínas/química , Simulación por Computador , Bases de Datos de Proteínas , Ligandos , Modelos Moleculares , Conformación Proteica
16.
Acta Chim Slov ; 57(2): 466-9, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24061745

RESUMEN

We describe a simple and highly efficient procedure for the single-step preparation of isatins from the commercially available anilines using H-ß zeolite as a truly heterogeneous catalyst. H-ß zeolite is readily separated from reaction mixture by simple filtration and reused several times without considerable loss of activity.

17.
Cir Cir ; 75(2): 93-7, 2007.
Artículo en Español | MEDLINE | ID: mdl-17511904

RESUMEN

BACKGROUND: We undertook this study to determine the surgical treatments results performed often to correct scoliosis in the Spinal Surgery Service in the INR/Orthopedics (National Institute of Rehabilitation/Orthopedics), Mexico City. METHODS: We conducted a longitudinal, prospective, descriptive, and clinical study with a deliberated intervention controlled from a historical cohort. One hundred twenty patients with scoliosis were reviewed in whom surgery was performed during 1990-1999. For quantitative variables, pre- vs. postoperative measures were compared using non-parametric means with chi(2) or in this case with ANOVA by Kruskall-Wallis test. Differences are considered significant if p <0.05. RESULTS: Age average of patients was 12 years. There were 75 females and 45 males. There were 59 idiopathic scoliosis cases and 54 congenital scoliosis cases. Anterior approach was accomplished in 61 cases with posterior fixation. Posterior approach was used in 54 cases. There were 76 cases of Luque segmental instrumentation. Pre-operatively, scoliosis was ranked (18 to 110 grades) and postoperatively (5 to 90 grades) (p = 0.00001). There were 21 complications, 9 due to injuries or infection. In 76 patients, different fixation techniques were used, obtaining a correction average of 14.47 grades. Forty four patients were structured with bars, four distal screws, two compression screws, proximal hooks with sublaminar wire, and the angle was reduced on average 23.11 grades. CONCLUSIONS. Average reduction of scoliosis was higher with the modified Luque III instrumentation (p <0.045). There was no difference between etiology and preoperative angle.


Asunto(s)
Fijadores Internos , Escoliosis/cirugía , Fusión Vertebral/estadística & datos numéricos , Adolescente , Adulto , Niño , Preescolar , Falla de Equipo , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Estudios Prospectivos , Traumatismos de la Médula Espinal/epidemiología , Traumatismos de la Médula Espinal/etiología , Fusión Vertebral/métodos , Infección de la Herida Quirúrgica/epidemiología
18.
Cir. & cir ; Cir. & cir;74(5): 377-380, sept.-oct. 2006. ilus
Artículo en Español | LILACS | ID: lil-573409

RESUMEN

El quiste óseo aneurismático es un tumor de naturaleza neoplásica indefinida, de comportamiento benigno, crecimiento rápido y ocasionalmente de comportamiento agresivo, cuyo tratamiento de elección es la resección completa, aunque existe el riesgo de sangrado transquirúrgico excesivo. Se presenta el caso de una paciente con deformidad en columna torácica, con parestesias y debilidad muscular progresivas en extremidades inferiores, que evolucionó hasta la parálisis de dichas extremidades e incontinencia de ambos esfínteres. Mediante estudios de gabinete se localizaron lesiones líticas en cuerpos vetebrales T7 a T9 e invasión a conducto raquídeo. Los estudios electrofisiológicos identificaron bloqueo completo de la vía somatosensorial. Previa biopsia incisional, se realizó resección de la lesión y estabilización de la columna toracolumbar. La paciente evolucionó sin mejoría de la función medular. Los hallazgos morfológicos correspondieron a quiste óseo aneurismático en T8. Esta lesión se localiza principalmente en huesos largos y con mucho menor frecuencia en la columna vertebral, donde puede provocar inestabilidad y compresión de la médula espinal. Es posible confundirla con otras neoplasias, por lo que el diagnóstico definitivo mediante biopsia es imprescindible a fin de establecer el plan terapéutico adecuado, que elimine el riesgo de recurrencia o secuelas neurológicas asociadas, y lograr la estabilidad adecuada de los segmentos vertebrales afectados.


The aneurysmal bone cyst (ABC) is a fast-growing tumor of undefined neoplastic nature. It is occasionally an aggressive benign lesion whose treatment of choice is a complete resection, even though the risk of profuse transoperative bleeding exists. We present a female patient with thoracic spine deformity, with progressive paresthesias and muscle weakness of lower extremities that evolved to paralysis of both lower extremities and sphincter incontinence. Based on radiographic films, lytic lesions were identified at T7 to T9 vertebrae as well as medullary space invasion. In electrophysiologic tests, a complete somatosensorial pathway block was reported. Prior to resection of the neoplastic lesion and thoracolumbar stabilization, an incisional biopsy was performed. There was no postoperative medullary functional improvement. Morphological findings corresponded to an aneurysmal bone cyst at T8. This lesion is mainly located in the long bones and less frequently of the spine, where instability and medullary compression may occur. It is possible to confuse this neoplasia with other lesions. Hence, definite diagnosis with biopsy is necessary for determining an adequate therapeutic plan to eradicate recurrence risk or associated neurologic sequelae, as well as to gain proper stability at the involved vertebral segments.


Asunto(s)
Humanos , Femenino , Adolescente , Quistes Óseos Aneurismáticos/cirugía , Compresión de la Médula Espinal/etiología , Descompresión Quirúrgica/métodos , Enfermedades de la Columna Vertebral/cirugía , Fusión Vertebral/métodos , Vértebras Torácicas/cirugía , Progresión de la Enfermedad , Trasplante Óseo , Cifosis/etiología , Quistes Óseos Aneurismáticos/complicaciones , Quistes Óseos Aneurismáticos/patología , Diagnóstico Diferencial , Descompresión Quirúrgica/instrumentación , Enfermedades de la Columna Vertebral/complicaciones , Enfermedades de la Columna Vertebral/patología , Dolor de Espalda/etiología , Fijadores Internos , Incontinencia Fecal/etiología , Incontinencia Urinaria/etiología , Osteólisis/etiología , Paraplejía/etiología , Parestesia/etiología , Vértebras Torácicas/patología
19.
Cir Cir ; 74(1): 27-35, 2006.
Artículo en Español | MEDLINE | ID: mdl-17257485

RESUMEN

BACKGROUND: This study was undertaken to evaluate vertebral stability after two different types of fusion fixation (rigid and semirigid) in spondylolisthesis. MATERIAL AND METHODS: Ambispective study of a dynamic cohort constituted by 42 patients that underwent surgery between 1990 and 2000 for a spondilolistesis treatment. According to the fixing type, they were divided into two follow-up groups: to group 1, plate INO (semirigid system) was placed + posterolateral fusion (PLF), 20 cases; to group 2, plate INO was installed + intersomatic screw + PLF, 22 cases. RESULTS: Both groups achieved better listhesis, reduced pain according to Oswestry and SF36 Index (p <0.05), and less intervertebral height was lost. Group 1 lost the least amount (-0.61 mm) of invertebral height if grades of presurgical listhesis were 1-2, and higher (-2.0 mm) if grades of presurgical listhesis were 3-4. Inversely, group 2 lost the least (0.50 mm) if grade of listhesis was 3 or 4, and higher (-1.25 mm) if grades of listhesis were 1-2. From 4 to 7 years, in group 2 there was altered bending of 5.8 degrees to 8.3 degrees (p = 0.05), a significant difference from group 1. Group 2 showed higher flexion grades (p = 0.01) at 4-7 years postoperatively and a significant reduction in EVA (p = 0.04) at more than 7 years. The remaining patients showed no significant differences between groups. But loss of intervertebral height was higher in group 2 (-1.18 mm) than group 1 (-0.75 mm). Plate INO + PLF favored flexibility and reduced loss of intervertebral height in grades 1-2 of presurgical listhesis, INO + screw + PLF showed reduced listhesis and decrease of height lost in grades 3-4 of presurgical listhesis. CONCLUSIONS: We recommended the use of INO + PLF in grades 1-2 of presurgical listhesis and INO + screw + PLF in grades 3-4 of listhesis presurgically.


Asunto(s)
Fusión Vertebral/métodos , Espondilolistesis/cirugía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad
20.
Cir Cir ; 74(5): 377-80, 2006.
Artículo en Español | MEDLINE | ID: mdl-17224110

RESUMEN

The aneurysmal bone cyst (ABC) is a fast-growing tumor of undefined neoplastic nature. It is occasionally an aggressive benign lesion whose treatment of choice is a complete resection, even though the risk of profuse transoperative bleeding exists. We present a female patient with thoracic spine deformity, with progressive paresthesias and muscle weakness of lower extremities that evolved to paralysis of both lower extremities and sphincter incontinence. Based on radiographic films, lytic lesions were identified at T7 to T9 vertebrae as well as medullary space invasion. In electrophysiologic tests, a complete somatosensorial pathway block was reported. Prior to resection of the neoplastic lesion and thoracolumbar stabilization, an incisional biopsy was performed. There was no postoperative medullary functional improvement. Morphological findings corresponded to an aneurysmal bone cyst at T8. This lesion is mainly located in the long bones and less frequently of the spine, where instability and medullary compression may occur. It is possible to confuse this neoplasia with other lesions. Hence, definite diagnosis with biopsy is necessary for determining an adequate therapeutic plan to eradicate recurrence risk or associated neurologic sequelae, as well as to gain proper stability at the involved vertebral segments.


Asunto(s)
Quistes Óseos Aneurismáticos/cirugía , Descompresión Quirúrgica/métodos , Compresión de la Médula Espinal/etiología , Enfermedades de la Columna Vertebral/cirugía , Fusión Vertebral/métodos , Vértebras Torácicas/cirugía , Adolescente , Dolor de Espalda/etiología , Quistes Óseos Aneurismáticos/complicaciones , Quistes Óseos Aneurismáticos/patología , Trasplante Óseo , Descompresión Quirúrgica/instrumentación , Diagnóstico Diferencial , Progresión de la Enfermedad , Incontinencia Fecal/etiología , Femenino , Humanos , Fijadores Internos , Cifosis/etiología , Osteólisis/etiología , Paraplejía/etiología , Parestesia/etiología , Enfermedades de la Columna Vertebral/complicaciones , Enfermedades de la Columna Vertebral/patología , Vértebras Torácicas/patología , Incontinencia Urinaria/etiología
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