Inspiratory muscle training and its effect on indices of physiological and perceived stress during incremental walking exercise in normobaric hypoxia

This study evaluated the effects of inspiratory muscle training (IMT) on inspiratory muscle fatigue (IMF) and physiological and perceptual responses during trekking-specific exercise. An 8-week IMT program was completed by 21 males (age 32.4 ± 9.61 years, VO2peak 58.8 ± 6.75 mL/kg/min) randomised within matched pairs to either the IMT group (n = 11) or the placebo group [(P), n = 9]. Twice daily, participants completed 30 (IMT) or 60 (P) inspiratory efforts using a Powerbreathe initially set at a resistance of 50% (IMT) or used at 15% (P) of maximal inspiratory pressure (MIP) throughout. A loaded (12.5 kg) 39-minute incremental walking protocol (3–5 km/hour and 1–15% gradient) was completed in normobaric hypoxia (PIO2 = 110 mmHg, 3000 m) before and after training. MIP increased from 164 to 188 cmH2O (18%) and from 161 to 171 cmH2O (6%) in the IMT and P groups (P = 0.02). The 95% CI for IMT showed a significant improvement in MIP (5.21±43.33 cmH2O), but not for P. IMF during exercise (MIP) was*5%, showing no training effect for either IMT or P (P = 0.23). Rating of perceived exertion (RPE) was consistently reduced (*1) throughout exercise following training for IMT, but not for P (P = 0.03). The mean blood lactate concentration during exercise was significantly reduced by 0.26 and 0.15 mmol/L in IMT and P (P = 0.00), with no differences between groups (P = 0.34). Rating of dyspnoea during exercise decreased (*0.4) following IMT but increased (*0.3) following P (P = 0.01). IMT may attenuate the increased physiological and perceived exercise stress experienced during normobaric hypoxia, which may benefit moderate altitude expedition

Impact of Hanging Motionless in Harness on Respiratory and Blood Pressure Reflex Modulation in Mountain Climbers

Harness hang syncope (HHS) is a risk that specifically affects safety of harness users in mountain climbing. Aims: To evaluate individual patterns of breathing resulting from deranged cardiovascular reflexes triggering a syncopal event when a mismatch between cerebral O2 demand and supply is present. Results: Forty healthy participants [aged 39.1 (8.2) years] were enrolled in a motionless suspension test while hanging in harness. Respiratory gas exchange values were analyzed to assess the pattern of breathing (EpInWel, respiratory elastic power) and cardiovascular parameters were monitored (BP, blood pressure). Four participants experienced HHS after 30.0 (7.6) minutes, with an early manifestation of loss of control of both a sustainable EpInWel and BP, starting after 10-12 minutes. Among the other participants, two different reactions were observed during suspension: (1) group G1 tolerated 32.7 (11.4) minutes of suspension by a favorable adaptation of the EpInWel and BP parameters and (2) group G2 showed significantly shorter time of suspension 24.0 (10.4) minutes with unfavorable increase in EpInWel and BP. Conclusions: Greater resistance to HHS occurs in people developing less marked fluctuations of both respiratory and cardiovascular reflex responses. Conversely, wider fluctuations both in control of EpInWel and BP were observed in the event of decreased suspension tolerance or in syncopal events

Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells

The final published version can be found here: http://dx.doi.org/10.1073/pnas.141316511

Long-term effect of neonatal inhibition of APP gamma-secretase on hippocampal development in the Ts65Dn mouse model of Down syndrome

Neurogenesis impairment is considered a major determinant of the intellectual disability that characterizes Down syndrome (DS), a genetic condition caused by triplication of chromosome 21. Previous evidence obtained in the Ts65Dn mouse model of DS showed that the triplicated gene APP (amyloid precursor protein) is critically involved in neurogenesis alterations. In particular, excessive levels of AICD (amyloid precursor protein intracellular domain) resulting from APP cleavage by gamma-secretase increase the transcription of Ptch1, a Sonic Hedgehog (Shh) receptor that keeps the mitogenic Shh pathway repressed. Previous evidence showed that neonatal treatment with ELND006, an inhibitor of gamma-secretase, reinstates the Shh pathway and fully restores neurogenesis in Ts65Dn pups. In the framework of potential therapies for DS, it is extremely important to establish whether the positive effects of early intervention are retained after treatment cessation. Therefore, the goal of the current study was to establish whether early treatment with ELND006 leaves an enduring trace in the brain of Ts65Dn mice. Ts65Dn and euploid pups were treated with ELND006 in the postnatal period P3-P15 and the outcome of treatment was examined at ~ one month after treatment cessation. We found that in treated Ts65Dn mice the pool of proliferating cells in the hippocampal dentate gyrus (DG) and total number of granule neurons were still restored as was the number of pre- and postsynaptic terminals in the stratum lucidum of CA3, the site of termination of the mossy fibers from the DG. Accordingly, patch-clamp recording from field CA3 showed functional normalization of the input to CA3. Unlike in field CA3, the number of pre- and postsynaptic terminals in the DG of treated Ts65Dn mice was no longer fully restored. The finding that many of the positive effects of neonatal treatment were retained after treatment cessation provides proof of principle demonstration of the efficacy of early inhibition of gamma-secretase for the improvement of brain development in DS

The physical meaning of the de Sitter invariants

We study the Lie algebras of the covariant representations transforming the matter fields under the de Sitter isometries. We point out that the Casimir operators of these representations can be written in closed forms and we deduce how their eigenvalues depend on the field's rest energy and spin. For the scalar, vector and Dirac fields, which have well-defined field equations, we express these eigenvalues in terms of mass and spin obtaining thus the principal invariants of the theory of free fields on the de Sitter spacetime. We show that in the flat limit we recover the corresponding invariants of the Wigner irreducible representations of the Poincare group.Comment: 22 pages no figure

Calcium-dependent dephosphorylation of the histone chaperone DAXX regulates H3.3 loading and transcription upon neuronal activation.

Activity-dependent modifications of chromatin are believed to contribute to dramatic changes in neuronal circuitry. The mechanisms underlying these modifications are not fully understood. The histone variant H3.3 is incorporated in a replication-independent manner into different regions of the genome, including gene regulatory elements. It is presently unknown whether H3.3 deposition is involved in neuronal activity-dependent events. Here, we analyze the role of the histone chaperone DAXX in the regulation of H3.3 incorporation at activity-dependent gene loci. DAXX is found to be associated with regulatory regions of selected activity-regulated genes, where it promotes H3.3 loading upon membrane depolarization. DAXX loss not only affects H3.3 deposition but also impairs transcriptional induction of these genes. Calcineurin-mediated dephosphorylation of DAXX is a key molecular switch controlling its function upon neuronal activation. Overall, these findings implicate the H3.3 chaperone DAXX in the regulation of activity-dependent events, thus revealing a new mechanism underlying epigenetic modifications in neurons

Obstructive sleep apneas naturally occur in mice during REM sleep and are highly prevalent in a mouse model of Down syndrome

Study objectives: The use of mouse models in sleep apnea study is limited by the belief that central (CSA) but not obstructive sleep apneas (OSA) occur in rodents. We aimed to develop a protocol to investigate the presence of OSAs in wild-type mice and, then, to apply it to a validated model of Down syndrome (Ts65Dn), a human pathology characterized by a high incidence of OSAs. Methods: In a pilot study, nine C57BL/6J wild-type mice were implanted with electrodes for electroencephalography (EEG), neck electromyography (nEMG), and diaphragmatic activity (DIA), and then placed in a whole-body-plethysmographic (WBP) chamber for 8 h during the rest (light) phase to simultaneously record sleep and breathing activity. CSA and OSA were discriminated on the basis of WBP and DIA signals recorded simultaneously. The same protocol was then applied to 12 Ts65Dn mice and 14 euploid controls. Results: OSAs represented about half of the apneic events recorded during rapid-eye-movement-sleep (REMS) in each experimental group, while the majority of CSAs were found during non-rapid eye movement sleep. Compared with euploid controls, Ts65Dn mice had a similar total occurrence rate of apneic events during sleep, but a significantly higher occurrence rate of OSAs during REMS, and a significantly lower occurrence rate of CSAs during NREMS. Conclusions: Mice physiologically exhibit both CSAs and OSAs. The latter appear almost exclusively during REMS, and are highly prevalent in Ts65Dn. Mice may, thus, represent a useful model to accelerate the understanding of the pathophysiology and genetics of sleep-disordered breathing and to help the development of new therapies

Molecular Architectures of Trimeric SIV and HIV-1 Envelope Glycoproteins on Intact Viruses: Strain-Dependent Variation in Quaternary Structure

The initial step in target cell infection by human, and the closely related simian immunodeficiency viruses (HIV and SIV, respectively) occurs with the binding of trimeric envelope glycoproteins (Env), composed of heterodimers of the viral transmembrane glycoprotein (gp41) and surface glycoprotein (gp120) to target T-cells. Knowledge of the molecular structure of trimeric Env on intact viruses is important both for understanding the molecular mechanisms underlying virus-cell interactions and for the design of effective immunogen-based vaccines to combat HIV/AIDS. Previous analyses of intact HIV-1 BaL virions have already resulted in structures of trimeric Env in unliganded and CD4-liganded states at ∼20 Å resolution. Here, we show that the molecular architectures of trimeric Env from SIVmneE11S, SIVmac239 and HIV-1 R3A strains are closely comparable to that previously determined for HIV-1 BaL, with the V1 and V2 variable loops located at the apex of the spike, close to the contact zone between virus and cell. The location of the V1/V2 loops in trimeric Env was definitively confirmed by structural analysis of HIV-1 R3A virions engineered to express Env with deletion of these loops. Strikingly, in SIV CP-MAC, a CD4-independent strain, trimeric Env is in a constitutively “open” conformation with gp120 trimers splayed out in a conformation similar to that seen for HIV-1 BaL Env when it is complexed with sCD4 and the CD4i antibody 17b. Our findings suggest a structural explanation for the molecular mechanism of CD4-independent viral entry and further establish that cryo-electron tomography can be used to discover distinct, functionally relevant quaternary structures of Env displayed on intact viruses

Cross-Conjugated n-Dopable Aromatic Polyketone

This paper describes the synthesis and characterization of a high molecular weight cross-conjugated polyketone synthesized via scalable Friedel Crafts chemistry. Cross-conjugated polyketones are precursors to conjugated polyions; they become orders of magnitude more conductive after a two-electron reduction and demonstrate reversible spinless doping upon protonation with acids. Cross-conjugated polyketones are a new polymer platform that possess the same optoelectronic tunability as conventional polymers but with excellent thermal and oxidative stability. We constructed a proof-of-concept organic light-emitting diode device and demonstrate that a cross-conjugated polyketone can be successfully used as an n-dopable semiconducting material