IKs Computational Modeling to Enforce the Investigation of D242N, a KV7.1 LQTS Mutation

A KCNQ1 mutation, D242N, was found in a pair of twins and characterized at the cellular level. To investigate whether and how the mutation causes the clinically observed lost adaptation to fast heart rate, we performed a computational study. Firstly, we identified a new I Ks model based on voltage clamp experimental data. Then we included this formulation in the human action potential model of O'Hara Rudy (ORd) and simulate d the effects of the mutation. We also included adrenergic stimulation to the action potential, since the basal adrenergic tone is likely to affect the influence of I Ks on QTc in vivo. Finally, we simulated the pseudo-ECG, taking into account the heterogeneity of the cardiac wall. At the basal rate (60bpm), the mutation had negligible effects for all cell types, whereas at the high rate (180bpm), with concomitant β-adrenergic stimulation (mimicking exercise conditions), the mutant AP failed to adapt its duration to the same extent as the wild-type AP (e.g. 281ms vs. 267ms in M cells), due to a smaller amount of I Ks current. Pseudo-ECG results show only a slight rate adaptation, and the simulated QTc was significantly prolonged from 387ms to 493ms, similar to experimental recordings

Carbon and nitrogen isotopic ratios of urine and faeces as novel nutritional biomarkers of meat and fish intake

Purpose Meat and fish consumption are associated with changes in the risk of chronic diseases. Intake is mainly assessed using self-reporting, as no true quantitative nutritional biomarker is available. The measurement of plasma fatty acids, often used as an alternative, is expensive and time-consuming. As meat and fish differ in their stable isotope ratios, δ13C and δ15N have been proposed as biomarkers. However, they have never been investigated in controlled human dietary intervention studies. Objective In a short-term feeding study, we investigated the suitability of δ13C and δ15N in blood, urine and faeces as biomarkers of meat and fish intake. Methods The dietary intervention study (n = 14) followed a randomised cross-over design with three eight-day dietary periods (meat, fish and half-meat–half-fish). In addition, 4 participants completed a vegetarian control period. At the end of each period, 24-h urine, fasting venous blood and faeces were collected and their δ13C and δ15N analysed. Results There was a significant difference between diets in isotope ratios in faeces and urine samples, but not in blood samples (Kruskal–Wallis test, p < 0.0001). In pairwise comparisons, δ13C and δ15N were significantly higher in urine and faecal samples following a fish diet when compared with all other diets, and significantly lower following a vegetarian diet. There was no significant difference in isotope ratio between meat and half-meat–half-fish diets for blood, urine or faecal samples. Conclusions The results of this study show that urinary and faecal δ13C and δ15N are suitable candidate biomarkers for short-term meat and fish intake

Midlife managerial experience is linked to late life hippocampal morphology and function

An active cognitive lifestyle has been suggested to have a protective role in the long-term maintenance of cognition. Amongst healthy older adults, more managerial or supervisory experiences in midlife are linked to a slower hippocampal atrophy rate in late life. Yet whether similar links exist in individuals with Mild Cognitive Impairment (MCI) is not known, nor whether these differences have any functional implications. 68 volunteers from the Sydney SMART Trial, diagnosed with non-amnestic MCI, were divided into high and low managerial experience (HME/LME) during their working life. All participants underwent neuropsychological testing, structural and resting-state functional MRI. Group comparisons were performed on hippocampal volume, morphology, hippocampal seed-based functional connectivity, memory and executive function and self-ratings of memory proficiency. HME was linked to better memory function (p = 0.024), mediated by larger hippocampal volume (p = 0.025). More specifically, deformation analysis found HME had relatively more volume in the CA1 sub-region of the hippocampus (p  <  0.05). Paradoxically, this group rated their memory proficiency worse (p = 0.004), a result correlated with diminished functional connectivity between the right hippocampus and right prefrontal cortex (p  <  0.001). Finally, hierarchical regression modelling substantiated this double dissociation

Non-typeable Haemophilus influenzae and Streptococcus pneumoniae as primary causes of acute otitis media in colombian children: a prospective study

<p>Abstract</p> <p>Background</p> <p>Acute otitis media (AOM) is one of the most frequently encountered bacterial infections in children aged < 5 years; <it>Streptococcus pneumoniae </it>(<it>S. pneumoniae</it>) and non-typeable <it>Haemophilus influenzae </it>(NTHi) are historically identified as primary AOM causes. Nevertheless, recent data on bacterial pathogens causing AOM in Latin America are limited. This prospective study aimed to identify and characterize bacterial etiology and serotypes of AOM cases including antimicrobial susceptibility in < 5 year old Colombian children.</p> <p>Methods</p> <p>From February 2008 to January 2009, children ≥3 months and < 5 years of age presenting with AOM and for whom a middle ear fluid (MEF) sample was available were enrolled in two medical centers in Cali, Colombia. MEF samples were collected either by tympanocentesis procedure or spontaneous otorrhea swab sampling. Bacteria were identified using standard laboratory methods, and antimicrobial resistance testing was performed based on the 2009 Clinical and Laboratory Standards Institute (CLSI) criteria. Most of the cases included in the study were sporadic in nature.</p> <p>Results</p> <p>Of the 106 enrolled children, 99 were included in the analysis. Bacteria were cultured from 62/99 (63%) of samples with <it>S. pneumoniae, H. influenzae, or S. pyogenes</it>. The most commonly isolated bacteria were <it>H. influenzae </it>in 31/99 (31%) and <it>S. pneumoniae </it>in 30/99 (30%) of samples. The majority of <it>H. influenzae </it>episodes were NTHi (27/31; 87%). 19F was the most frequently isolated pneumococcal serotype (10/30; 33%). Of the 30 <it>S. pneumoniae </it>positive samples, 8/30 (27%) were resistant to tetracycline, 5/30 (17%) to erythromycin and 8/30 (27%) had intermediate resistance to penicillin. All <it>H. influenzae </it>isolates tested were negative to beta-lactamase.</p> <p>Conclusions</p> <p>NTHi and <it>S. pneumoniae </it>are the leading causes of AOM in Colombian children. A pneumococcal conjugate vaccine that prevents both pathogens could be useful in maximizing protection against AOM.</p

Análisis de los servicios de test del VIH de cinco centros comunitarios españoles para la mejora de nuevas estrategias de promoción del diagnóstico precoz

Background: In recent years, the number of people tested for HIV has experienced a significant increase. The purpose of this study is to analyze data obtained in Spain in the HIV testing services of five Community Centres members of Agrupación Prueba de VIHda throughout 2014 and 2015,to determine its effectiveness and to characterize the subpopulation with a HIV reactive result. Study design and methods: agrupación Prueba de VIHda performed free, anonymous and confidential HIV tests according to the Consolidated guidelines on HIV testing services of WHO (2015). Data were collected using the questionnaire of the COBATEST network, developed by the COBATEST Project, and its significance was determined statistically. Results: 3061 HIV tests were performed during 2014 and 2015, with a prevalence of reactive results of 2.5%. Heterosexual and bisexual men got tested at older ages than homosexual men and women. Non-Spanish origin seems to be a risk factor for HIV infection within the sample. Bisexual men showed as high prevalence of reactive test as homosexual men, as well as they reported less previous HIV tests. Finally, index testing performed by HIV positive peer educators to the sexual partners of newly diagnosed patients showed higher prevalence than that of the classical Voluntary Counselling and Testing approach outreach most at risk populations. Conclusion:The analysis of the data shows higher prevalence of reactive results in people of non-Spanish origin compared to that of the Spanish subgroup, the former still facing barriers to access the public health system in Spain. It also demonstrates the need of new and adapted approaches for promoting early diagnosis specifically in bisexual men. Index testing by peer HIV positive educators is a highly effective method for testing people at high risk of acquiring HIV infection.Antecedentes: En los últimos años, el número de personas sometidas a pruebas frente al VIH ha experimentado un aumento significativo. El propósito de este estudio es analizar los datos de prevalencia de la infección por VIH obtenidos por cinco centros comunitarios en España pertenecientes a la Agrupación Prueba de VIHda entre 2014 y 2015, determinar su efectividad y caracterizar la subpoblación con un resultado preliminar reactivo. Diseño experimental y métodos: La Agrupación Prueba de VIHda realizó pruebas de VIH gratuitas, anónimas y confidenciales de acuerdo con las directrices consolidadas por la OMS (2015). Los datos fueron recogidos mediante el cuestionario desarrollado por el Proyecto COBATEST y su significación se determinó estadísticamente. Resultados: Durante 2014 y 2015 se realizaron un total de 3061 pruebas frente al VIH, obteniendo una prevalencia de resultados preliminares positivos del 2,5%. Los hombres heterosexuales y bisexuales se realizaron la prueba a edades más avanzadas que los hombres homosexuales y las mujeres. Las personas de origen no español parecieron mostrar un mayor riesgo de infección frente al VIH. Hombres bisexuales mostraron una prevalencia elevada similar a la de hombres homosexuales, así como declararon menos pruebas anteriores frente al VIH. Finalmente, las pruebas realizadas a través de indextesting por los educadores pares de VIH a parejas sexuales de pacientes recién diagnosticados mostraron una prevalencia superior a la obtenida por el modelo tradicional de counselling y testado voluntario ofrecido desde los centros comunitarios a poblaciones de mayor riesgo. Conclusión: El análisis de los datos muestra mayores prevalencias de resultados preliminares reactivos en personas de origen no español comparadas con aquellas del subgrupo de personas españolas, el primero de ellos todavía enfrentando barreras de acceso al sistema sanitario público en España, El análisis también demuestra la necesidad de nuevos enfoques adaptados para promover el diagnóstico precoz especialmente entre hombres bisexuales. Las pruebas realizadas a través de indextesting por educadores pares VIH positivos es un método muy eficaz para el testado de las personas con alto riesgo de contraer la infección por VIH

Nucleoporin Mediated Nuclear Positioning and Silencing of HMR

The organization of chromatin domains in the nucleus is an important factor in gene regulation. In eukaryotic nuclei, transcriptionally silenced chromatin clusters at the nuclear periphery while transcriptionally poised chromatin resides in the nuclear interior. Recent studies suggest that nuclear pore proteins (NUPs) recruit loci to nuclear pores to aid in insulation of genes from silencing and during gene activation. We investigated the role of NUPs at a native yeast insulator and show that while NUPs localize to the native tDNA insulator adjacent to the silenced HMR domain, loss of pore proteins does not compromise insulation. Surprisingly we find that NUPs contribute to silencing at HMR and are able to restore silencing to a silencing-defective HMR allele when tethered to the locus. We show that the perinuclear positioning of heterochromatin is important for the NUP-mediated silencing effect and find that loss of NUPs result in decreased localization of HMR to the nuclear periphery. We also show that loss of telomeric tethering pathways does not eliminate NUP localization to HMR, suggesting that NUPs may mediate an independent pathway for HMR association with the nuclear periphery. We propose that localization of NUPs to the tDNA insulator at HMR helps maintain the intranuclear position of the silent locus, which in turn contributes to the fidelity of silencing at HMR

Transplanckian axions !?

We discuss quantum gravitational effects in Einstein theory coupled to periodic axion scalars to analyze the viability of several proposals to achieve superplanckian axion periods (aka decay constants) and their possible application to large field inflation models. The effects we study correspond to the nucleation of euclidean gravitational instantons charged under the axion, and our results are essentially compatible with (but independent of) the Weak Gravity Conjecture, as follows: Single axion theories with superplanckian periods contain gravitational instantons inducing sizable higher harmonics in the axion potential, which spoil superplanckian inflaton field range. A similar result holds for multi-axion models with lattice alignment (like the Kim-Nilles-Peloso model). Finally, theories with $N$ axions can still achieve a moderately superplanckian periodicity (by a $\sqrt{N}$ factor) with no higher harmonics in the axion potential. The Weak Gravity Conjecture fails to hold in this case due to the absence of some instantons, which are forbidden by a discrete $\mathbf{Z}_N$ gauge symmetry. Finally we discuss the realization of these instantons as euclidean D-branes in string compactifications.Comment: 46 pages, 6 figures. Added references, clarifications, and missing factor of 1/2 to instanton action. Conclusions unchange

Amplitude Spectroscopy of a Solid-State Artificial Atom

The energy-level structure of a quantum system plays a fundamental role in determining its behavior and manifests itself in a discrete absorption and emission spectrum. Conventionally, spectra are probed via frequency spectroscopy whereby the frequency \nu of a harmonic driving field is varied to fulfill the conditions \Delta E = h \nu, where the driving field is resonant with the level separation \Delta E (h is Planck's constant). Although this technique has been successfully employed in a variety of physical systems, including natural and artificial atoms and molecules, its application is not universally straightforward, and becomes extremely challenging for frequencies in the range of 10's and 100's of gigahertz. Here we demonstrate an alternative approach, whereby a harmonic driving field sweeps the atom through its energy-level avoided crossings at a fixed frequency, surmounting many of the limitations of the conventional approach. Spectroscopic information is obtained from the amplitude dependence of the system response. The resulting ``spectroscopy diamonds'' contain interference patterns and population inversion that serve as a fingerprint of the atom's spectrum. By analyzing these features, we determine the energy spectrum of a manifold of states with energies from 0.01 to 120 GHz \times h in a superconducting artificial atom, using a driving frequency near 0.1 GHz. This approach provides a means to manipulate and characterize systems over a broad bandwidth, using only a single driving frequency that may be orders of magnitude smaller than the energy scales being probed.Comment: 12 pages, 13 figure

Challenges in the diagnosis and management of acromegaly : a focus on comorbidities

Q2Q1Introduction: Acromegaly is a rare, insidious disease resulting from the overproduction of growth hormone (GH) and insulin-like growth factor 1 (IGF-1), and is associated with a range of comorbidities. The extent of associated complications and mortality risk is related to length of exposure to the excess GH and IGF-1, thus early diagnosis and treatment is imperative. Unfortunately, acromegaly is often diagnosed late, when patients already have a wide range of comorbidities. The presence of comorbid conditions contributes significantly to patient morbidity/mortality and impaired quality of life. Methods: We conducted a retrospective literature review for information relating to the diagnosis of acromegaly, and its associated comorbidities using PubMed. The main aim of this review is to highlight the issues of comorbidities in acromegaly, and to reinforce the importance of early diagnosis and treatment. Findings and conclusions: Successful management of acromegaly goes beyond treating the disease itself, since many patients are diagnosed late in disease evolution, they present with a range of comorbid conditions, such as cardiovascular disease, diabetes, hypertension, and sleep apnea. It is important that patients are screened carefully at diagnosis (and thereafter), for common associated complications, and that biochemical control does not become the only treatment goal. Mortality and morbidities in acromegaly can be reduced successfully if patients are treated using a multimodal approach with comprehensive comorbidity management.https://orcid.org/0000-0002-8433-5435N/