Coarse-Grained Simulations of Release of Drugs Housed in Flexible Nanogels: New Insights into Kinetic Parameters

Funding: This research was funded by “Consejería de Economía, Conocimiento, Empresas y Universidad, Junta de Andalucía, Programa Operativo FEDER Andalucía 2014-2020”, grant number P20_00138 as well as “Ministerio de Ciencia e Innovación”, grant numbers PID2020-116615RA-I00 and PGC2018-098770-B-I00.The diffusion-controlled release of drugs housed in flexible nanogels has been simulated with the help of a coarse-grained model that explicitly considers polymer chains. In these in silico experiments, the effect of its flexibility is assessed by comparing it with data obtained for a rigid nanogel with the same volume fraction and topology. Our results show that the initial distribution of the drug can exert a great influence on the release kinetics. This work also reveals that certain surface phenomena driven by steric interactions can lead to apparently counterintuitive behaviors. Such phenomena are not usually included in many theoretical treatments used for the analysis of experimental release kinetics. Therefore, one should be very careful in drawing conclusions from these formalisms. In fact, our results suggest that the interpretation of drug release curves in terms of kinetic exponents (obtained from the Ritger–Peppas Equation) is a tricky question. However, such curves can provide a first estimate of the drug diffusion coefficient.Consejería de Economía, Conocimiento, Empresas y Universidad, Junta de Andalucía, Programa Operativo FEDER Andalucía 2014-2020, grant number P20_00138Ministerio de Ciencia e Innovación, grant numbers PID2020-116615RA-I00 and PGC2018-098770-B-I0

Interaction between charged lipid vesicles and point- or rod-like trivalent ions

This work examines the influence of the charge distribution of trivalent cations on their interaction with soft anionic particles, using a combination of experimental measurements and theoretical modelling. In particular, we perform electrophoresis measurements to determine the zeta-potential of anionic liposomes in the presence of spermidine and lanthanum cations. We work in a range of electrolyte concentration where a reversal in the electrophoretic mobility of the liposomes is expected; however, unlike the case of lanthanum cations, spermidine does not induce mobility reversal of liposomes. As a result, the charge distribution within the counterion appears to be a key factor. This conclusion is supported by a theory that accounts for intra-ionic correlations, which has previously been successfully used to describe the colloidal electric double layer. It allows us to model spermidine as rod-like ions and lanthanum cations as point-like ions in order to test the importance of the ionic geometry in the interactions with soft particles such as lipid vesicles

Emotions Detection based on a Single-electrode EEG Device

The study of emotions using multiple channels of EEG represents a widespread practice in the field of research related to brain computer interfaces (Brain Computer Interfaces). To date, few studies have been reported in the literature with a reduced number of channels, which when used in the detection of emotions present results that are less accurate than the rest. To detect emotions using an EEG channel and the data obtained is useful for classifying emotions with an accuracy comparable to studies in which there is a high number of channels, is of particular interest in this research framework. This article uses the Neurosky Maindwave device; which has a single electrode to acquire the EEG signal, Matlab software and IBM SPSS Modeler; which process and classify the signals respectively. The accuracy obtained in the detection of emotions in relation to the economic resources of the hardware dedicated to the acquisition of EEG signal is remarkable

Actualización de cardiomiopatía de Takotsubo

Takotsubo syndrome is a cardiomyopathy induced by physical or emotional stress, characterized by being a ventricular apical dilation, which predominantly affects postmenopausal women, currently its precise pathophysiological mechanisms are still unknown. It was initially considered a benign condition; however, it is currently known to be associated with severe clinical complications, including death. This pathology can be indistinguishable from acute coronary syndrome due to the similarity in clinical manifestations, electrocardiographic and laboratory findings. Coronary angiography with ventriculography is considered the diagnostic method of choice. Currently there is no management guide, however, the treatment goal is based on support measures and addressing associated complications.El síndrome de Takotsubo es una cardiomiopatía inducida por estrés físico o emocional, caracterizado por ser una dilatación apical ventricular, que afecta predominantemente a mujeres posmenopáusicas, sus mecanismos fisiopatológicos precisos aún son desconocidos. Inicialmente fue considerada un cuadro benigno; sin embargo, actualmente se conoce que está asociada a severas complicaciones clínicas, entre ellas la muerte. Esta patología puede ser indistinguible del síndrome coronario agudo por la similitud en manifestaciones clínicas, hallazgos electrocardiográficos y de laboratorio. La angiografía coronaria con ventriculografía, es considerado el método diagnóstico de elección. Actualmente no se cuenta con una guía de manejo, no obstante, la meta de tratamiento, se basa en medidas de soporte y abordaje de las complicaciones asociadas

Historia de los anticoagulantes y su uso clínico en el presente

The classic oral anticoagulants were exclusively used for more than 65 years, the effectiveness they have to treat thromboembolic events and their complications is known, in addition to this they have other advantages, such as low economic cost and the availability of antidotes, However, they have a wide variety of limitations and side effects, due to this and the prevalence of thromboembolic diseases in the growing geriatric population, new oral anticoagulants (NACOs) are developed, created to reinforce the limitations and reduce the adverse effects of classic anticoagulants, these drugs reached their peak with the approval of antidotes such as idarucizumab a monoclonal antibody that inhibits dabigatran and andexanet alfa a drug with the potential to reverse the effects of direct and indirect factor Xa inhibitors.Los anticoagulantes orales clásicos fueron de uso exclusivo por más de 65 años, es conocida la eficacia con la que cuentan para tratar eventos tromboembólicos y sus complicaciones, sumado a esto cuentan con otras ventajas, como el bajo costo económico y la disponibilidad de antídotos, sin embargo, cuentan con una amplia variedad de limitaciones y efectos secundarios, debido a esto y la prevalencia de enfermedades tromboembólicas en la creciente población geriátrica se desarrollan los nuevos anticoagulantes orales (NACOs), creados para reforzar las limitaciones y disminuir los efectos adversos que presentaban los anticoagulantes clásicos, estos fármacos alcanzaron su mayor auge con la aprobación de  antídotos como el idarucizumab un anticuerpo monoclonal que inhibe el dabigatran y el andexanet alfa un fármaco con potencial de revertir los efectos de los inhibidores directos e indirectos del factor Xa

Síndrome de Mirizzi

Mirizzi syndrome, a rare complication in patients with cholelithiasis, has been linked to gallbladder cancer, due to chronic inflation and bile stasis that it triggers. Risk factors are known in specific populations, mainly in women, adults over 40 and obese. To understand its pathophysiology, it is necessary to know the genesis of the formation of stones, these stones are embedded in the Hartman's sac, causing obstruction of the common hepatic duct, and can evolve into internal fistulas or necrosis. There are different radiodiagnostic means for Mirizzi syndrome, with endoscopic retrograde cholangiopancreatography being the gold standard. The surgical approach and treatment of the syndrome is dictated by the classification given to it, from a laparoscopic cholecystectomy to a laparotomy choledochoplasty. Preoperative diagnosis involves a more appropriate approach and better postoperative results.El síndrome de Mirizzi,  es una complicación poco frecuente en pacientes portadores de colelitiasis, se ha relacionado con el cáncer de vesícula biliar, por la inflación crónica y estasis biliar que desencadena. Se conocen factores de riesgo en poblaciones específicas, principalmente en mujeres, adultos mayores de 40 años y obesos. Para comprender su fisiopatología es necesario conocer la génesis de la formación de litos, estos cálculos se enclavan en el saco de Hartman produciendo obstrucción del conducto hepático común, pudiendo evolucionar a fístulas internas o necrosis. Hay diferentes medios radiodiagnósticos para el síndrome de Mirizzi, siendo la colangiopancreatografía retrógrada endoscópica el gold-standard. El abordaje y tratamiento quirúrgico del síndrome está dictado por la clasificación que se le otorgue, desde una colecistectomía laparoscópica hasta una coledocoplastía por laparotomía. El diagnóstico preoperatorio conlleva un abordaje más adecuado y mejores resultados postoperatorios

Síncope: generalidades

Syncope is a loss of the state of consciousness that is characterized by being transient and self-limited. It is produced by an acute fall in global cerebral perfusion, its duration does not usually exceed 20 seconds and its recovery is spontaneous and complete. It presents a peak of bimodal incidence between 10 and 30 years, the causes vary depending on the clinical context of each patient. It is classified according to its pathophysiological mechanisms in: neurally mediated syncope, cardiac and orthostatic hypotension. The initial evaluation is a key piece in the diagnosis of the patient, a detailed medical history, complete physical examination and electrocardiogram will define the risk stratification and thus the eventual management. The treatment of patients with syncope depends on the cause and its mechanism, it consists of 3 fundamental pillars, directed to reduce mortality, avoid traumatic injuries and prevents recurrences.El síncope es una pérdida del estado de conciencia que se caracteriza por ser transitoria y autolimitada. Es producida por una caída aguda de la perfusión global cerebral, su duración no suele sobrepasar los 20 segundos y su recuperación es espontánea y completa. Presenta un pico de incidencia bimodal entre los 10 y los 30 años, las causas varían dependiendo del contexto clínico de cada paciente. Se clasifica según sus mecanismos fisiopatológicos en: síncope neuralmente mediado, cardíaco y por hipotensión ortostática. La valoración inicial es una pieza clave en el diagnóstico del paciente, una historia clínica detallada, examen físico completo y electrocardiograma definirán la estratificación de riesgo y así el eventual manejo. El tratamiento de pacientes con síncope dependerá de la causa y mecanismo del mismo, este consiste en 3 pilares fundamentales, dirigidos a reducir la mortalidad, evitar lesiones traumáticas y recidivas

Infective endocarditis

La endocarditis infecciosa, es una patología poco usual que afecta principalmente válvulas nativas relacionadas a cuidados de la salud, se presenta con mayor frecuencia en adultos mayores de 60 años y en el sexo masculino. Sus factores predisponentes a lo largo del tiempo han ido modificándose, principalmente en países desarrollados, desplazando a la fiebre reumática. Son múltiples los microorganismos involucrados en la patología y su distribución a nivel global se ha mantenido estable, siendo las bacterias Cocos Gram-positivos las más frecuentes colonizadoras. Para que exista una infección debe haber bacteriemia en condiciones locales que permitan la proliferación e invasión de endocardio. Se debe sospechar en todo paciente con fiebre asociada a síntomas constitucionales y factores de riesgo para endocarditis, los métodos diagnósticos de elección son los hemocultivos y ecocardiografía respectivamente. El tratamiento se fundamenta en la erradicación del microorganismo, antibiótico terapia de amplio espectro y se reserva la cirugía para casos que desarrollen complicaciones que solo puedan ser tratadas en sala de operaciones. La profilaxis antibiótica solo está recomendada en pacientes de riesgo. Infective endocarditis, is a rare disease that mainly affects native valves related to health care, occurs more frequently in adults over 60 years of age and in the male sex. Its predisposing factors over time have been changing, mainly in developed countries, displacing rheumatic fever. There are many microorganisms involved in the pathology and its distribution at a global level has remained stable, with the Gram-positive Cocos bacteria being the most frequent colonizers. For an infection to exist, there must be bacteremia under local conditions that allow endocardial proliferation and invasion. It should be suspected in all patients with fever associated with constitutional symptoms and risk factors for endocarditis, the diagnostic methods of choice are blood cultures and echocardiography respectively. The treatment is based on the eradication of the microorganism, antibiotic broad-spectrum therapy and surgery is reserved for cases that develop complications that can only be treated in the operating room. Antibiotic prophylaxis is only recommended in patients at risk

A Cyanide-Induced 3-Cyanoalanine Nitrilase in the Cyanide-Assimilating Bacterium Pseudomonas pseudoalcaligenes Strain CECT 5344

Pseudomonas pseudoalcaligenes CECT 5344 es una bacteria capaz de asimilar el cianuro como única fuente de nitrógeno. Bajo esta condición de crecimiento, se indujo una actividad enzimática 3-cianoalanina nitrilasa. Esta actividad fue codificada por nit4, uno de los cuatro genes de nitrilasa detectados en el genoma de esta bacteria, y su expresión en Escherichia coli permitió a la cepa recombinante asimilar completamente la 3-cianoalanina. P. pseudoalcaligenes CECT 5344 mostró un nivel de crecimiento débil con 3-cianoalanina como fuente de N, a menos que también se agregara KCN. Además, un mutante knock-out de nit4 de P. pseudoalcaligenes CECT 5344 se deterioró gravemente en su capacidad para crecer con 3-cianoalanina y cianuro como fuentes de nitrógeno. La enzima nativa expresada en E. coli se purificó hasta homogeneidad electroforética y se caracterizó bioquímicamente. Nit4 parece ser específico para la 3-cianoalanina, y la cantidad de amonio derivada de la actividad enzimática se duplicó en presencia de actividad asparaginasa agregada exógenamente, lo que demostró que la enzima Nit4 tenía actividades tanto 3-cianoalanina nitrilasa como hidratasa. El gen nit4 está ubicado aguas abajo de la unidad transcripcional de resistencia al cianuro que contiene los genes cio1, cuyos niveles de expresión están bajo el control positivo del cianuro. Los experimentos de PCR en tiempo real revelaron que la expresión de nit4 también estaba regulada positivamente por el cianuro tanto en medios mínimos como en medios LB. Estos resultados sugieren que este grupo de genes, incluidos cio1 y nit4, podrían participar tanto en la resistencia al cianuro como en su asimilación por parte de P. pseudoalcaligenes CECT 5344.Pseudomonas pseudoalcaligenes CECT 5344 is a bacterium able to assimilate cyanide as a sole nitrogen source. Under this growth condition, a 3-cyanoalanine nitrilase enzymatic activity was induced. This activity was encoded by nit4, one of the four nitrilase genes detected in the genome of this bacterium, and its expression in Escherichia coli enabled the recombinant strain to fully assimilate 3-cyanoalanine. P. pseudoalcaligenes CECT 5344 showed a weak growth level with 3-cyanoalanine as the N source, unless KCN was also added. Moreover, a nit4 knockout mutant of P. pseudoalcaligenes CECT 5344 became severely impaired in its ability to grow with 3-cyanoalanine and cyanide as nitrogen sources. The native enzyme expressed in E. coli was purified up to electrophoretic homogeneity and biochemically characterized. Nit4 seems to be specific for 3-cyanoalanine, and the amount of ammonium derived from the enzymatic activity doubled in the presence of exogenously added asparaginase activity, which demonstrated that the Nit4 enzyme had both 3-cyanoalanine nitrilase and hydratase activities. The nit4 gene is located downstream of the cyanide resistance transcriptional unit containing cio1 genes, whose expression levels are under the positive control of cyanide. Real-time PCR experiments revealed that nit4 expression was also positively regulated by cyanide in both minimal and LB media. These results suggest that this gene cluster including cio1 and nit4 could be involved both in cyanide resistance and in its assimilation by P. pseudoalcaligenes CECT 5344.Trabajo financiado por: Ministerio de Ciencia, Innovación y Universidades. Beca BIO2011-30026-C02-01 Ministerio de Educación, Cultura y Deporte. Beca BIO2008-04542-C02-02 Ministerio de Economía y Competitividad. Beca AGL2016-74882-C3-2-R Junta de Extremadura. Becas PRI07A097, GR10165 y GR15083 Universidad de Extremadura y Fondos FEDER. Ayudas Becas FPI: BES-2006-11941 y BES-2009-027073peerReviewe