Structural Determinants for Functional Coupling Between the β and α Subunits in the Ca2+-activated K+ (BK) Channel

High conductance, calcium- and voltage-activated potassium (BK, MaxiK) channels are widely expressed in mammals. In some tissues, the biophysical properties of BK channels are highly affected by coexpression of regulatory (β) subunits. The most remarkable effects of β1 and β2 subunits are an increase of the calcium sensitivity and the slow down of channel kinetics. However, the detailed characteristics of channels formed by α and β1 or β2 are dissimilar, the most remarkable difference being a reduction of the voltage sensitivity in the presence of β1 but not β2. Here we reveal the molecular regions in these β subunits that determine their differential functional coupling with the pore-forming α-subunit. We made chimeric constructs between β1 and β2 subunits, and BK channels formed by α and chimeric β subunits were expressed in Xenopus laevis oocytes. The electrophysiological characteristics of the resulting channels were determined using the patch clamp technique. Chimeric exchange of the different regions of the β1 and β2 subunits demonstrates that the NH3 and COOH termini are the most relevant regions in defining the behavior of either subunit. This strongly suggests that the intracellular domains are crucial for the fine tuning of the effects of these β subunits. Moreover, the intracellular domains of β1 are responsible for the reduction of the BK channel voltage dependence. This agrees with previous studies that suggested the intracellular regions of the α-subunit to be the target of the modulation by the β1-subunit

Estimation of Molecular Pairwise Relatedness in Autopolyploid Crops

A suitable pairwise relatedness estimation is key to genetic studies. Several methods are proposed to compute relatedness in autopolyploids based on molecular data. However, unlike diploids, autopolyploids still need further studies considering scenarios with many linked molecular markers with known dosage. In this study, we provide guidelines for plant geneticists and breeders to access trustworthy pairwise relatedness estimates. To this end, we simulated populations considering different ploidy levels, meiotic pairings patterns, number of loci and alleles, and inbreeding levels. Analysis were performed to access the accuracy of distinct methods and to demonstrate the usefulness of molecular marker in practical situations. Overall, our results suggest that at least 100 effective biallelic molecular markers are required to have good pairwise relatedness estimation if methods based on correlation is used. For this number of loci, current methods based on multiallelic markers show lower performance than biallelic ones. To estimate relatedness in cases of inbreeding or close relationships (as parent-offspring, full-sibs, or half-sibs) is more challenging. Methods to estimate pairwise relatedness based on molecular markers, for different ploidy levels or pedigrees were implemented in the AGHmatrix R package

A Case Report of Acute Severe Myelitis and Meningitis Secondary to Varicella Zoster Virus Reactivation in a Patient with Acquired Immunodeficiency Syndrome

Background: Myelitis post Herpes-Zoster is a rare condition that is typically associated with immunocompromised states. It usually starts as an acute loss of sensory and motor functions below the affected spinal cord level. The condition can range in severity from a mild to a fatal presentation. Other neurological complications include meningitis, atypical presentations should encourage the search for undiagnosed immunosuppression states. The Case: We describe the case of a 42-year-old man, with previously undiagnosed HIV, who developed acute myelitis and meningitis after the appearance of the classic zoster lesions. On lumbar puncture and subsequent CSF analysis, the patient was found to have Froin's Syndrome. The patient was initiated with ceftriaxone, vancomycin, and acyclovir regimen and prophylactic antiphymic treatment was also added. After 14 days in the hospital, the fever, headache, and neck stiffness subsided while the sphincter function and lower limb paraplegia did not improve. Conclusion: Varicella zoster virus reactivation suggests underlying immunosuppression. This case demonstrates the importance of being cognizant to the wide range of clinical manifestations that may suggest spinal cord involvement after clinical reactivation. Furthermore, physicians also need to be mindful that Acquired Immunodeficiency Syndrome (AIDS) and other immunodeficiency states could present with atypical clinical manifestations

A Comparative Study of Efficient Initialization Methods for the K-Means Clustering Algorithm

K-means is undoubtedly the most widely used partitional clustering algorithm. Unfortunately, due to its gradient descent nature, this algorithm is highly sensitive to the initial placement of the cluster centers. Numerous initialization methods have been proposed to address this problem. In this paper, we first present an overview of these methods with an emphasis on their computational efficiency. We then compare eight commonly used linear time complexity initialization methods on a large and diverse collection of data sets using various performance criteria. Finally, we analyze the experimental results using non-parametric statistical tests and provide recommendations for practitioners. We demonstrate that popular initialization methods often perform poorly and that there are in fact strong alternatives to these methods.Comment: 17 pages, 1 figure, 7 table

Normal and Lateral Casimir Forces between Deformed Plates

The Casimir force between macroscopic bodies depends strongly on their shape and orientation. To study this geometry dependence in the case of two deformed metal plates, we use a path integral quantization of the electromagnetic field which properly treats the many-body nature of the interaction, going beyond the commonly used pairwise summation (PWS) of van der Waals forces. For arbitrary deformations we provide an analytical result for the deformation induced change in Casimir energy, which is exact to second order in the deformation amplitude. For the specific case of sinusoidally corrugated plates, we calculate both the normal and the lateral Casimir forces. The deformation induced change in the Casimir interaction of a flat and a corrugated plate shows an interesting crossover as a function of the ratio of the mean platedistance H to the corrugation length \lambda: For \lambda \ll H we find a slower decay \sim H^{-4}, compared to the H^{-5} behavior predicted by PWS which we show to be valid only for \lambda \gg H. The amplitude of the lateral force between two corrugated plates which are out of registry is shown to have a maximum at an optimal wavelength of \lambda \approx 2.5 H. With increasing H/\lambda \gtrsim 0.3 the PWS approach becomes a progressively worse description of the lateral force due to many-body effects. These results may be of relevance for the design and operation of novel microelectromechanical systems (MEMS) and other nanoscale devices.Comment: 20 pages, 5 figure

Development of peptide-based lineage-specific serology for chronic Chagas disease: geographical and clinical distribution of epitope recognition.

BACKGROUND: Chagas disease, caused by infection with the protozoan Trypanosoma cruzi, remains a serious public health issue in Latin America. Genetically diverse, the species is sub-divided into six lineages, known as TcI-TcVI, which have disparate geographical and ecological distributions. TcII, TcV, and TcVI are associated with severe human disease in the Southern Cone countries, whereas TcI is associated with cardiomyopathy north of the Amazon. T. cruzi persists as a chronic infection, with cardiac and/or gastrointestinal symptoms developing years or decades after initial infection. Identifying an individual's history of T. cruzi lineage infection directly by genotyping of the parasite is complicated by the low parasitaemia and sequestration in the host tissues. METHODOLOGY/PRINCIPAL FINDINGS: We have applied here serology against lineage-specific epitopes of the T. cruzi surface antigen TSSA, as an indirect approach to allow identification of infecting lineage. Chagasic sera from chronic patients from a range of endemic countries were tested by ELISA against synthetic peptides representing lineage-specific TSSA epitopes bound to avidin-coated ELISA plates via a biotin labelled polyethylene glycol-glycine spacer to increase rotation and ensure each amino acid side chain could freely interact with their antibodies. 79/113 (70%) of samples from Brazil, Bolivia, and Argentina recognised the TSSA epitope common to lineages TcII/TcV/TcVI. Comparison with clinical information showed that a higher proportion of Brazilian TSSApep-II/V/VI responders had ECG abnormalities than non-responders (38% vs 17%; p<0.0001). Among northern chagasic sera 4/20 (20%) from Ecuador reacted with this peptide; 1/12 Venezuelan and 1/34 Colombian samples reacted with TSSApep-IV. In addition, a proposed TcI-specific epitope, described elsewhere, was demonstrated here to be highly conserved across lineages and therefore not applicable to lineage-specific serology. CONCLUSIONS/SIGNIFICANCE: These results demonstrate the considerable potential for synthetic peptide serology to investigate the infection history of individuals, geographical and clinical associations of T. cruzi lineages

Análisis de la sensibilidad barorefleja arterial mediante la aplicación de fenilefrina y nitroprusiato sódico en pacientes con trastorno depresivo mayor

La depresión mayor se ha asociado fuertemente con un riesgo aumentado de desarrollar enfermedades cardiovasculares (ECV) y con una tasa de mortalidad de dos a cuatro veces mayor después de un infarto agudo del miocardio. A pesar de la gran evidencia epidemiológica que soporta la relación entre la depresión y las ECV, los mecanismos fisiopatológicos de esta conexión permanecen poco conocidos. Las alteraciones en la función del sistema nervioso autónomo se han postulado como una de las causas probables del riesgo cardiovascular aumentado en pacientes con depresión. Diversos autores han mostrado que los síntomas depresivos están asociados con aberraciones en la regulación autonómica cardíaca, caracterizadas por una actividad simpática aumentada y un tono parasimpático disminuido, que aumentan el riesgo de isquemia miocárdica, taquicardia ventricular, fibrilación ventricular y muerte cardíaca súbita. Los barorreceptores arteriales son mecanorreceptores localizados en el arco aórtico y en el seno carotídeo, que sirven para regular la presión arterial mediante cambios rápidos en la frecuencia y contracción cardíacas y en la capacitancia venosa. El barorreflejo cardíaco muestra un equilibrio entre la actividad simpática y vagal para el mantenimiento de una presión arterial adecuada. Las alteraciones en la sensibilidad barorefleja se han asociado a un mayor riesgo de presentar arritmias ventriculares y muerte cardíaca súbita en sujetos con ECV. Recientemente, diversos estudios han mostrado que la sensibilidad de los barorreceptores arteriales está disminuida en sujetos con trastorno depresivo mayor (TDM) y ECV asociadas. Sin embargo, existen dudas razonables acerca de que estas alteraciones están mas relacionadas con la presencia de las ECV o con efectos secundarios de medicamentos antidepresivos que con el TDM mismo. Por lo tanto, el objetivo del presente estudio fue analizar la sensibilidad barorefleja arterial mediante la aplicación de fenilefrina y nitroprusiato de sódio en pacientes con TDM de novo sin ECV asociada y antes de la instauración de tratamiento antidepresivo. Salud UIS 2008; 40: 160-16

Análisis de la sensibilidad barorefleja arterial mediante la aplicación de fenilefrina y nitroprusiato sódico en pacientes con trastorno depresivo mayor

La depresión mayor se ha asociado fuertemente con un riesgo aumentado de desarrollar enfermedades cardiovasculares (ECV) y con una tasa de mortalidad de dos a cuatro veces mayor después de un infarto agudo del miocardio. A pesar de la gran evidencia epidemiológica que soporta la relación entre la depresión y las ECV, los mecanismos fisiopatológicos de esta conexión permanecen poco conocidos. Las alteraciones en la función del sistema nervioso autónomo se han postulado como una de las causas probables del riesgo cardiovascular aumentado en pacientes con depresión. Diversos autores han mostrado que los síntomas depresivos están asociados con aberraciones en la regulación autonómica cardíaca, caracterizadas por una actividad simpática aumentada y un tono parasimpático disminuido, que aumentan el riesgo de isquemia miocárdica, taquicardia ventricular, fibrilación ventricular y muerte cardíaca súbita. Los barorreceptores arteriales son mecanorreceptores localizados en el arco aórtico y en el seno carotídeo, que sirven para regular la presión arterial mediante cambios rápidos en la frecuencia y contracción cardíacas y en la capacitancia venosa. El barorreflejo cardíaco muestra un equilibrio entre la actividad simpática y vagal para el mantenimiento de una presión arterial adecuada. Las alteraciones en la sensibilidad barorefleja se han asociado a un mayor riesgo de presentar arritmias ventriculares y muerte cardíaca súbita en sujetos con ECV. Recientemente, diversos estudios han mostrado que la sensibilidad de los barorreceptores arteriales está disminuida en sujetos con trastorno depresivo mayor (TDM) y ECV asociadas. Sin embargo, existen dudas razonables acerca de que estas alteraciones están mas relacionadas con la presencia de las ECV o con efectos secundarios de medicamentos antidepresivos que con el TDM mismo. Por lo tanto, el objetivo del presente estudio fue analizar la sensibilidad barorefleja arterial mediante la aplicación de fenilefrina y nitroprusiato de sódio en pacientes con TDM de novo sin ECV asociada y antes de la instauración de tratamiento antidepresivo. Salud UIS 2008; 40: 160-16

Transiting Exoplanet Studies and Community Targets for JWST's Early Release Science Program

The James Webb Space Telescope will revolutionize transiting exoplanet atmospheric science due to its capability for continuous, long-duration observations and its larger collecting area, spectral coverage, and spectral resolution compared to existing space-based facilities. However, it is unclear precisely how well JWST will perform and which of its myriad instruments and observing modes will be best suited for transiting exoplanet studies. In this article, we describe a prefatory JWST Early Release Science (ERS) program that focuses on testing specific observing modes to quickly give the community the data and experience it needs to plan more efficient and successful future transiting exoplanet characterization programs. We propose a multi-pronged approach wherein one aspect of the program focuses on observing transits of a single target with all of the recommended observing modes to identify and understand potential systematics, compare transmission spectra at overlapping and neighboring wavelength regions, confirm throughputs, and determine overall performances. In our search for transiting exoplanets that are well suited to achieving these goals, we identify 12 objects (dubbed "community targets") that meet our defined criteria. Currently, the most favorable target is WASP-62b because of its large predicted signal size, relatively bright host star, and location in JWST's continuous viewing zone. Since most of the community targets do not have well-characterized atmospheres, we recommend initiating preparatory observing programs to determine the presence of obscuring clouds/hazes within their atmospheres. Measurable spectroscopic features are needed to establish the optimal resolution and wavelength regions for exoplanet characterization. Other initiatives from our proposed ERS program include testing the instrument brightness limits and performing phase-curve observations.(Abridged)Comment: This is a white paper that originated from an open discussion at the Enabling Transiting Exoplanet Science with JWST workshop held November 16 - 18, 2015 at STScI (http://www.stsci.edu/jwst/science/exoplanets). Accepted for publication in PAS