MicroRNA9 regulates neural stem cell differentiation by controlling Hes1 expression dynamics in the developing brain

Earlier studies show that Hes1 expression is oscillatory in neural stem cells but sustained and high in the roof plate and the floor plate, and that such different dynamics of Hes1 expression (oscillatory versus sustained) regulate different proliferation and differentiation characteristics of these cells (active in neural stem cells but rather dormant in roof/floor plate cells). The mechanism of how different dynamics of Hes1 expression is controlled remains to be determined. Here, we found that the seed sequence of microRNA‐9 (miR‐9) is complementary to the 3′‐UTR sequence of Hes1 mRNA. MiR‐9 is highly expressed in the ventricular zone of the developing brain, which contains neural stem cells, but it is not expressed in the roof plate or the floor plate. Over‐expression of miR‐9 negatively regulates the Hes1 protein expression by interacting with the 3′‐UTR of Hes1 mRNA, thereby inducing cell cycle exit and neuronal differentiation. Conversely, knockdown of miR‐9 inhibits neuronal differentiation. Furthermore, knockdown of miR‐9 inhibits the oscillatory expression of Hes1 mRNA in neural stem cells. These results indicate that miR‐9 regulates the proliferation and differentiation of neural stem cells by controlling the dynamics of Hes1 expression in the developing brain.     

Heart rate variability and pre-competitive anxiety in BMX discipline

Altered neural mechanisms implying autonomic functioning have been described related to anxiety. Pre-competitive stress may be considered as an anxiety-state associated with disorders (i.e. somatic and cognitive alterations, and self-confidence worsening) that severely impair sport performance, conditioning short-lasting strength-related disciplines like BMX. From the psychological perspective, coaches use questionnaires like CSAI-2R to identify these alterations. However, with the emergence of psycho-physiological and non-linear approaches, recent studies suggest that HRV analysis provides a non-invasive tool to assess them. Hence, our purpose was to analyze how BMX competition affects subjective perception of anxiety, and if this emotional alteration is reflected in HR dynamics, analyzed both linear and nonlinearly, exploring the evolution of this relationship in a 2-day competition. Eleven male athletes from the BMX Spanish National Team were assessed from baseline HRV the morning of a training session (rT) and on two successive days of competition (rC1 and rC2), repeating HRV recording with CSAI-2R 20 min prior to training (aT) and competition (pre-competitive: aC1 and aC2). Repeated measures MANOVA showed significant vagal slow-down responses in aC1 and aC2 comparing not only with aT, but also comparing with rT, rC1 and rC2, coinciding with significant greater scores for the somatic and cognitive anxiety (SA and CA) in aC1 and aC2 versus aT. Pearson analysis showed a large and positive correlation between α1 and SA in C1, and close to it between SampEn and CA in aC2; both were confirmed by Bland–Altman chart analysis. Our results confirm that HRV analysis provide a complementary tool to assess competitive pressure.     

Echocardiographic assessment of pulmonary arterial pressure in the follow-up of patients with pulmonary embolism

Background

Echocardiography remains a clinically useful screening test for chronic thromboembolic pulmonary hypertension (CTEPH) in patients with a history of pulmonary embolism (PE). To devise an effective screening strategy, the definition of a high-risk group is necessary.

Methods

We examined a total of 744 patients with acute symptomatic pulmonary embolism (PE) who were enrolled in a Spanish multicenter study. Patients were monitored every 6 months during the first two years, and then once a year thereafter. Transthoracic echocardiography was used to screen patients with a clinical suspicion of CTEPH during follow-up. Pulmonary arterial hypertension was defined as an estimated pulmonary artery systolic pressure (PAP) > 50 mm Hg. The index thromboembolic episode was considered severe if: (a) the patient was immobilized for medical reasons; or (b) systolic blood pressure was less than 90 mm Hg; or (c) troponin T values were above the reference range.

Results

The incidence of PAP > 50 mm Hg at 36 months was 8.3% (95% confidence interval = 4.6%-14.5%). Statistical analysis showed a highly significant association between a severe index thromboembolic episode and the subsequent detection of PAP > 50 mm Hg on echocardiography, with high positive likelihood ratio (2.40) and negative predictive value (> 0.97).

Conclusions

Patients with a severe index thromboembolic episode would constitute a high-risk group for the development of CTEPH. This group of patients should be subjected to a strict follow-up protocol.     

A New Master Donor Virus for the Development of Live-Attenuated Influenza B Virus Vaccines

Influenza B viruses (IBV) circulate annually, with young children, the elderly and immunocompromised individuals being at high risk. Yearly vaccinations are recommended to protect against seasonally influenza viruses, including IBV. Live attenuated influenza vaccines (LAIV) provide the unique opportunity for direct exposure to the antigenically variable surface glycoproteins as well as the more conserved internal components. Ideally, LAIV Master Donor Viruses (MDV) should accurately reflect seasonal influenza strains. Unfortunately, the continuous evolution of IBV have led to significant changes in conserved epitopes compared to the IBV MDV based on B/Ann Arbor/1/1966 strain. Here, we propose a recent influenza B/Brisbane/60/2008 as an efficacious MDV alternative, as its internal viral proteins more accurately reflect those of circulating IBV strains. We introduced the mutations responsible for the temperature sensitive (ts), cold adapted (ca) and attenuated (att) phenotype of B/Ann Arbor/1/1966 MDV LAIV into B/Brisbane/60/2008 to generate a new MDV LAIV. In vitro and in vivo analysis demonstrated that the mutations responsible of the ts, ca, and att phenotype of B/Ann Arbor/1/1966 MDV LAIV were able to infer the same phenotype to B/Brisbane/60/2008, demonstrating its potential as a new MDV for the development of LAIV to protect against contemporary IBV strains.     

Optimization and in vitro toxicity evaluation of G4 PAMAM dendrimer-risperidone complexes

Risperidone is an approved antipsychotic drug belonging to the chemical class of benzisoxazole. This drug has low solubility in aqueous medium and poor bioavailability due to extensive first-pass metabolism and high protein binding (>90%). As new strategies to improve treatments efficiency are needed, we have studied cationic G4 PAMAM dendrimers’ performance to act as efficient nanocarriers for this therapeutic drug. In this respect, we explored dendrimer-risperidone complexation dependence on solvent, temperature, pH and salt concentration, as well as in vitro cytotoxicity measured on L929 cell line and human red blood cells. The best dendrimer-risperidone incorporation was achieved when a mixture of 70:30 and 90:10 v/v chloroform:methanol was used, obtaining 17 and 32 risperidone molecules per dendrimer, respectively. No cytotoxicity on L929 cells was found when dendrimer concentration was below 3 × 10⁻² μM and risperidone concentration below 5.1 μM. Also, no significant hemolysis or morphological changes were observed on human red blood cells. Finally, attempting to obtain an efficient drug delivery system for risperidone, incorporation in G4 PAMAM dendrimers was optimized, improving drug solubility with low cytotoxicity.     

Tramadol effects on physical performance and sustained attention during a 20-min indoor cycling time-trial: A randomised controlled trial

Objectives

To investigate the effect of tramadol on performance during a 20-min cycling time-trial (Experiment 1), and to test whether sustained attention would be impaired during cycling after tramadol intake (Experiment 2).