Effective algorithm of analysis of integrability via the Ziglin's method

In this paper we continue the description of the possibilities to use numerical simulations for mathematically rigorous computer assisted analysis of integrability of dynamical systems. We sketch some of the algebraic methods of studying the integrability and present a constructive algorithm issued from the Ziglin's approach. We provide some examples of successful applications of the constructed algorithm to physical systems.Comment: a figure added, version accepted to JDC

Inhibition of protein N-myristoylation blocks Plasmodium falciparum intraerythrocytic development, egress and invasion

We have combined chemical biology and genetic modification approaches to investigate the importance of protein myristoylation in the human malaria parasite, Plasmodium falciparum. Parasite treatment during schizogony in the last 10 to 15 hours of the erythrocytic cycle with IMP-1002, an inhibitor of N-myristoyl transferase (NMT), led to a significant blockade in parasite egress from the infected erythrocyte. Two rhoptry proteins were mislocalized in the cell, suggesting that rhoptry function is disrupted. We identified 16 NMT substrates for which myristoylation was significantly reduced by NMT inhibitor (NMTi) treatment, and, of these, 6 proteins were substantially reduced in abundance. In a viability screen, we showed that for 4 of these proteins replacement of the N-terminal glycine with alanine to prevent myristoylation had a substantial effect on parasite fitness. In detailed studies of one NMT substrate, glideosome-associated protein 45 (GAP45), loss of myristoylation had no impact on protein location or glideosome assembly, in contrast to the disruption caused by GAP45 gene deletion, but GAP45 myristoylation was essential for erythrocyte invasion. Therefore, there are at least 3 mechanisms by which inhibition of NMT can disrupt parasite development and growth: early in parasite development, leading to the inhibition of schizogony and formation of "pseudoschizonts," which has been described previously; at the end of schizogony, with disruption of rhoptry formation, merozoite development and egress from the infected erythrocyte; and at invasion, when impairment of motor complex function prevents invasion of new erythrocytes. These results underline the importance of P. falciparum NMT as a drug target because of the pleiotropic effect of its inhibition

Should physical activity recommendations be ethnicity-specific? Evidence from a cross-sectional study of south Asian and European men

Background Expert bodies and health organisations recommend that adults undertake at least 150 min.week−1 of moderate-intensity physical activity (MPA). However, the underpinning data largely emanate from studies of populations of European descent. It is unclear whether this level of activity is appropriate for other ethnic groups, particularly South Asians, who have increased cardio-metabolic disease risk compared to Europeans. The aim of this study was to explore the level of MPA required in South Asians to confer a similar cardio-metabolic risk profile to that observed in Europeans undertaking the currently recommended MPA level of 150 min.week−1.<p></p> Methods Seventy-five South Asian and 83 European men, aged 40–70, without cardiovascular disease or diabetes had fasted blood taken, blood pressure measured, physical activity assessed objectively (using accelerometry), and anthropometric measures made. Factor analysis was used to summarise measured risk biomarkers into underlying latent ‘factors’ for glycaemia, insulin resistance, lipid metabolism, blood pressure, and overall cardio-metabolic risk. Age-adjusted regression models were used to determine the equivalent level of MPA (in bouts of ≥10 minutes) in South Asians needed to elicit the same value in each factor as Europeans undertaking 150 min.week−1 MPA.<p></p> Findings For all factors, except blood pressure, equivalent MPA values in South Asians were significantly higher than 150 min.week−1; the equivalent MPA value for the overall cardio-metabolic risk factor was 266 (95% CI 185-347) min.week−1.<p></p> Conclusions South Asian men may need to undertake greater levels of MPA than Europeans to exhibit a similar cardio-metabolic risk profile, suggesting that a conceptual case can be made for ethnicity-specific physical activity guidance. Further study is needed to extend these findings to women and to replicate them prospectively in a larger cohort.<p></p&gt

Ear, nose and throat (ENT) involvement in zoonotic diseases: a systematic review

INTRODUCTION: Zoonoses are infections transmitted from animal to man, either directly (through direct contact or contact with animal products) or indirectly (through an intermediate vector, such as an arthropod). The causative agents include bacteria, parasites, viruses, and fungi. The purpose of this review is to make an accurate examination of all zoonotic diseases that can be responsible of ear, nose, and throat (ENT) involvement. METHODOLOGY: A PubMed search was performed combining the terms (otorhinolaryngology OR rhinology OR laryngology OR otology OR mastoiditis OR otitis OR sinusitis OR laryngitis OR rhinitis OR pharyngitis OR epiglottitis OR dysphonia OR ear OR larynx OR nose OR pharynx) with each one of the etiological agents of zoonoses for the period between January 1997 and August 2012 without language restrictions. RESULTS: A total of 164 articles were selected and examined. Larynx was the most commonly involved ENT organ, followed by oral cavity, pharynx, and neck. Bacteria were the most representative microorganisms involved. Nose and major salivary glands were affected most frequently by protozoa; paranasal sinus, oral cavity, ear, neck, nerves and upper airway by bacteria; and larynx by fungi. CONCLUSIONS: ENT symptoms and signs may be present in many zoonotic diseases, some of which are also present in industrialized countries. Most zoonotic diseases are not commonly encountered by ENT specialists. Appreciation of the possible occurrence of these diseases is important for a correct microbiological approach, which often requires special culture media and diagnostic techniques

Integral Membrane Protein 2A Is a Negative Regulator of Canonical and Non-Canonical Hedgehog Signalling

The Hedgehog (Hh) receptor PTCH1 and the integral membrane protein 2A (ITM2A) inhibit autophagy by reducing autolysosome formation. In this study, we demonstrate that ITM2A physically interacts with PTCH1; however, the two proteins inhibit autophagic flux independently, since silencing of ITM2A did not prevent the accumulation of LC3BII and p62 in PTCH1-overexpressing cells, suggesting that they provide alternative modes to limit autophagy. Knockdown of ITM2A potentiated PTCH1-induced autophagic flux blockade and increased PTCH1 expression, while ITM2A overexpression reduced PTCH1 protein levels, indicating that it is a negative regulator of PTCH1 non-canonical signalling. Our study also revealed that endogenous ITM2A is necessary for timely induction of myogenic differentiation markers in C2C12 cells since partial knockdown delays the timing of differentiation. We also found that basal autophagic flux decreases during myogenic differentiation at the same time that ITM2A expression increases. Given that canonical Hh signalling prevents myogenic differentiation, we investigated the effect of ITM2A on canonical Hh signalling using GLI-luciferase assays. Our findings demonstrate that ITM2A is a strong negative regulator of GLI transcriptional activity and of GLI1 stability. In summary, ITM2A negatively regulates canonical and non-canonical Hh signalling

Wall shear stress at the initiation site of cerebral aneurysms

Hemodynamics are believed to play an important role in the initiation of cerebral aneurysms. In particular, studies have focused on wall shear stress (WSS), which is a key regulator of vascular biology and pathology. In line with the observation that aneurysms predominantly occur at regions of high WSS, such as bifurcation apices or outer walls of vascular bends, correlations have been found between the aneurysm initiation site and high WSS. The aim of our study was to analyze the WSS field at an aneurysm initiation site that was neither a bifurcation apex nor the outer wall of a vascular bend. Ten cases with aneurysms on the A1 segment of the anterior cerebral artery were analyzed and compared with ten controls. Aneurysms were virtually removed from the vascular models of the cases to mimic the pre-aneurysm geometry. Computational fluid dynamics (CFD) simulations were created to assess the magnitude, gradient, multidirectionality, and pulsatility of the WSS. To aid the inter-subject comparison of hemodynamic variables, we mapped the branch surfaces onto a two-dimensional parametric space. This approach made it possible to view the whole branch at once for qualitative evaluation. It also allowed us to empirically define a patch for quantitative analysis, which was consistent among subjects and encapsulated the aneurysm initiation sites in our dataset. To test the sensitivity of our results, CFD simulations were repeated with a second independent observer virtually removing the aneurysms and with a 20 % higher flow rate at the inlet. We found that branches harboring aneurysms were characterized by high WSS and high WSS gradients. Among all assessed variables, the aneurysm initiation site most consistently coincided with peaks of temporal variation in the WSS magnitude

Massively parallel computing on an organic molecular layer

Current computers operate at enormous speeds of ~10^13 bits/s, but their principle of sequential logic operation has remained unchanged since the 1950s. Though our brain is much slower on a per-neuron base (~10^3 firings/s), it is capable of remarkable decision-making based on the collective operations of millions of neurons at a time in ever-evolving neural circuitry. Here we use molecular switches to build an assembly where each molecule communicates-like neurons-with many neighbors simultaneously. The assembly's ability to reconfigure itself spontaneously for a new problem allows us to realize conventional computing constructs like logic gates and Voronoi decompositions, as well as to reproduce two natural phenomena: heat diffusion and the mutation of normal cells to cancer cells. This is a shift from the current static computing paradigm of serial bit-processing to a regime in which a large number of bits are processed in parallel in dynamically changing hardware.Comment: 25 pages, 6 figure

Vertebrae reveal industrial-era increases in Atlantic bluefin tuna catch-at-size and juvenile growth

Climate change and size-selective overexploitation can alter fish size and growth, yet our understanding of how and to what extent is limited due to a lack of long-term biological data from wild populations. This precludes our ability to effectively forecast population dynamics and support sustainable fisheries management. Using modern, archived, and archaeological vertebrae dimensions and growth rings of one of the most intensely exploited populations, the eastern Atlantic and Mediterranean bluefin tuna (Thunnus thynnus, BFT), we estimated catch-at-size and early-life growth patterns from the 3 (rd) century bce to the 21 (st) century ce to understand responses to changes in its environment. We provide novel evidence that BFT juvenile growth increased between the 16 (th)-18 (th), 20 (th), and 21 (st) centuries, and is correlated with a warming climate and likely a decrease in stock biomass. We found it equally plausible that fisheries-induced evolution has acted to increase juvenile BFT growth, driving earlier maturation as a result of size-selective exploitation. Coincidently, we found limited evidence to suggest a long history of large ( >200 cm FL) BFT capture. Instead, we found that the catch-at-size of archaeological BFT was relatively small in comparison with more intensive, 20 (th) and 21 (st) century tuna trap fisheries which operated further from shore. This complex issue would benefit from studies using fine-scale biochronological analyses of otoliths and adaptation genomics, throughout the last century especially, to determine evolutionary responses to exploitation, and further disentangle the influence of temperature and biomass on fish growth

The selectivity, voltage-dependence and acid sensitivity of the tandem pore potassium channel TASK-1 : contributions of the pore domains

We have investigated the contribution to ionic selectivity of residues in the selectivity filter and pore helices of the P1 and P2 domains in the acid sensitive potassium channel TASK-1. We used site directed mutagenesis and electrophysiological studies, assisted by structural models built through computational methods. We have measured selectivity in channels expressed in Xenopus oocytes, using voltage clamp to measure shifts in reversal potential and current amplitudes when Rb+ or Na+ replaced extracellular K+. Both P1 and P2 contribute to selectivity, and most mutations, including mutation of residues in the triplets GYG and GFG in P1 and P2, made channels nonselective. We interpret the effects of these—and of other mutations—in terms of the way the pore is likely to be stabilised structurally. We show also that residues in the outer pore mouth contribute to selectivity in TASK-1. Mutations resulting in loss of selectivity (e.g. I94S, G95A) were associated with slowing of the response of channels to depolarisation. More important physiologically, pH sensitivity is also lost or altered by such mutations. Mutations that retained selectivity (e.g. I94L, I94V) also retained their response to acidification. It is likely that responses both to voltage and pH changes involve gating at the selectivity filter