Optimal policies for Bayesian olfactory search in turbulent flows

In many practical scenarios, a flying insect must search for the source of an emitted cue which is advected by the atmospheric wind. On the macroscopic scales of interest, turbulence tends to mix the cue into patches of relatively high concentration over a background of very low concentration, so that the insect will only detect the cue intermittently and cannot rely on chemotactic strategies which simply climb the concentration gradient. In this work, we cast this search problem in the language of a partially observable Markov decision process (POMDP) and use the Perseus algorithm to compute strategies that are near-optimal with respect to the arrival time. We test the computed strategies on a large two-dimensional grid, present the resulting trajectories and arrival time statistics, and compare these to the corresponding results for several heuristic strategies, including (space-aware) infotaxis, Thompson sampling, and QMDP. We find that the near-optimal policy found by our implementation of Perseus outperforms all heuristics we test by several measures. We use the near-optimal policy to study how the search difficulty depends on the starting location. We discuss additionally the choice of initial belief and the robustness of the policies to changes in the environment. Finally, we present a detailed and pedagogical discussion about the implementation of the Perseus algorithm, including the benefits -- and pitfalls -- of employing a reward shaping function.Comment: 35 pages, 19 figure

The Fragmented Mitochondrial Ribosomal RNAs of Plasmodium falciparum

The mitochondrial genome in the human malaria parasite Plasmodium falciparum is most unusual. Over half the genome is composed of the genes for three classic mitochondrial proteins: cytochrome oxidase subunits I and III and apocytochrome b. The remainder encodes numerous small RNAs, ranging in size from 23 to 190 nt. Previous analysis revealed that some of these transcripts have significant sequence identity with highly conserved regions of large and small subunit rRNAs, and can form the expected secondary structures. However, these rRNA fragments are not encoded in linear order; instead, they are intermixed with one another and the protein coding genes, and are coded on both strands of the genome. This unorthodox arrangement hindered the identification of transcripts corresponding to other regions of rRNA that are highly conserved and/or are known to participate directly in protein synthesis.The identification of 14 additional small mitochondrial transcripts from P. falciparum and the assignment of 27 small RNAs (12 SSU RNAs totaling 804 nt, 15 LSU RNAs totaling 1233 nt) to specific regions of rRNA are supported by multiple lines of evidence. The regions now represented are highly similar to those of the small but contiguous mitochondrial rRNAs of Caenorhabditis elegans. The P. falciparum rRNA fragments cluster on the interfaces of the two ribosomal subunits in the three-dimensional structure of the ribosome.All of the rRNA fragments are now presumed to have been identified with experimental methods, and nearly all of these have been mapped onto the SSU and LSU rRNAs. Conversely, all regions of the rRNAs that are known to be directly associated with protein synthesis have been identified in the P. falciparum mitochondrial genome and RNA transcripts. The fragmentation of the rRNA in the P. falciparum mitochondrion is the most extreme example of any rRNA fragmentation discovered

Biosimilars: what clinicians should know.

Biosimilar medicinal products (biosimilars) have become a reality in the European Union and will soon be available in the United States. Despite an established legal pathway for biosimilars in the European Union since 2005 and increasing and detailed regulatory guidance on data requirements for their development and licensing, many clinicians, particularly oncologists, are reluctant to consider biosimilars as a treatment option for their patients. Major concerns voiced about biosimilars relate to their pharmaceutical quality, safety (especially immunogenicity), efficacy (particularly in extrapolated indications), and interchangeability with the originator product. In this article, the members and experts of the Working Party on Similar Biologic Medicinal Products of the European Medicines Agency (EMA) address these issues. A clear understanding of the scientific principles of the biosimilar concept and access to unbiased information on licensed biosimilars are important for physicians to make informed and appropriate treatment choices for their patients. This will become even more important with the advent of biosimilar monoclonal antibodies. The issues also highlight the need for improved communication between physicians, learned societies, and regulators

Multiple common comorbidities produce left ventricular diastolic dysfunction associated with coronary microvascular dysfunction, oxidative stress, and myocardial stiffening

Aims More than 50% of patients with heart failure have preserved ejection fraction characterized by diastolic dysfunction. The prevalance of diastolic dysfunction is higher in females and associates with multiple comorbidities such as hypertension (HT), obesity, hypercholesterolemia (HC), and diabetes mellitus (DM). Although its pathophysiology remains incompletely understood, it has been proposed that these comorbidities induce systemic inflammation, coronary microvascular dysfunction, and oxidative stress, leading to myocardial fibrosis, myocyte stiffening and, ultimately, diastolic dysfunction. Here, we tested this hypothesis in a swine model chronically exposed to three common comorbidities. Methods and results DM (induced by streptozotocin), HC (produced by high fat diet), and HT (resulting from renal artery embolization), were produced in 10 female swine, which were followed for 6 months. Eight female healthy swine on normal pig-chow served as controls. The DM + HC + HT group showed hyperglycemia, HC, hypertriglyceridemia, renal dysfunction and HT, which were associated with systemic inflammation. Myocardial superoxide production was markedly increased, due to increased NOX activity and eNOS uncoupling, and associated with reduced NO production, and impaired coronary small artery endothelium-dependent vasodilation. These abnormalities were accompanied by increased myocardial collagen content, reduced capillary/fiber ratio, and elevated passive cardiomyocyte stiffness, resulting in an increased left ventricular end-diastolic stiffness (measured by pressure-volume catheter) and a trend towards a reduced E/A ratio (measured by cardiac MRI), while ejection fraction was maintained. Conclusions The combination of three common comorbidities leads to systemic inflammation, myocardial oxidative stress, and coronary microvascular dysfunction, which associate with myocardial stiffening and LV diastolic dysfunction with preserved ejection fraction

Targeted exercise against osteoporosis: A systematic review and meta-analysis for optimising bone strength throughout life

Background Exercise is widely recommended to reduce osteoporosis, falls and related fragility fractures, but its effect on whole bone strength has remained inconclusive. The primary purpose of this systematic review and meta-analysis was to evaluate the effects of long-term supervised exercise (≥6 months) on estimates of lower-extremity bone strength from childhood to older age. Methods We searched four databases (PubMed, Sport Discus, Physical Education Index, and Embase) up to October 2009 and included 10 randomised controlled trials (RCTs) that assessed the effects of exercise training on whole bone strength. We analysed the results by age groups (childhood, adolescence, and young and older adulthood) and compared the changes to habitually active or sedentary controls. To calculate standardized mean differences (SMD; effect size), we used the follow-up values of bone strength measures adjusted for baseline bone values. An inverse variance-weighted random-effects model was used to pool the results across studies. Results Our quality analysis revealed that exercise regimens were heterogeneous; some trials were short in duration and small in sample size, and the weekly training doses varied considerably between trials. We found a small and significant exercise effect among pre- and early pubertal boys [SMD, effect size, 0.17 (95% CI, 0.02-0.32)], but not among pubertal girls [-0.01 (-0.18 to 0.17)], adolescent boys [0.10 (-0.75 to 0.95)], adolescent girls [0.21 (-0.53 to 0.97)], premenopausal women [0.00 (-0.43 to 0.44)] or postmenopausal women [0.00 (-0.15 to 0.15)]. Evidence based on per-protocol analyses of individual trials in children and adolescents indicated that programmes incorporating regular weight-bearing exercise can result in 1% to8% improvements in bone strength at the loaded skeletal sites. In premenopausal women with high exercise compliance, improvements ranging from 0.5% to 2.5% have been reported. Conclusions The findings from our meta-analysis of RCTs indicate that exercise can significantly enhance bone strength at loaded sites in children but not in adults. Since few RCTs were conducted to investigate exercise effects on bone strength, there is still a need for further well-designed, long-term RCTs with adequate sample sizes to quantify the effects of exercise on whole bone strength and its structural determinants throughout life.BioMed Central Open acces