Approximate parameter inference in systems biology using gradient matching: a comparative evaluation

Background

A challenging problem in current systems biology is that of parameter inference in biological pathways expressed as coupled ordinary differential equations (ODEs). Conventional methods that repeatedly numerically solve the ODEs have large associated computational costs. Aimed at reducing this cost, new concepts using gradient matching have been proposed, which bypass the need for numerical integration. This paper presents a recently established adaptive gradient matching approach, using Gaussian processes (GPs), combined with a parallel tempering scheme, and conducts a comparative evaluation with current state-of-the-art methods used for parameter inference in ODEs. Among these contemporary methods is a technique based on reproducing kernel Hilbert spaces (RKHS). This has previously shown promising results for parameter estimation, but under lax experimental settings. We look at a range of scenarios to test the robustness of this method. We also change the approach of inferring the penalty parameter from AIC to cross validation to improve the stability of the method.

Methods

Methodology for the recently proposed adaptive gradient matching method using GPs, upon which we build our new method, is provided. Details of a competing method using RKHS are also described here.

Results

We conduct a comparative analysis for the methods described in this paper, using two benchmark ODE systems. The analyses are repeated under different experimental settings, to observe the sensitivity of the techniques.

Conclusions

Our study reveals that for known noise variance, our proposed method based on GPs and parallel tempering achieves overall the best performance. When the noise variance is unknown, the RKHS method proves to be more robust.

     

The use of antisense oligonucleotides as chemotherapeutic agents for parasites

Although several approaches to the control of human parasites are possible, the prevention and therapy of the corresponding diseases still remain a difficult task. The development of vaccines has been hampered by the poor immunological response to or the high variability of parasitic antigens. Problems also arise for chemotherapy where differences in the biochemistry of host and parasite must be exploited. The increasingly difficult search for new drugs is always challenged by the appearance of resistance.     

Bicyclic peptidomimetic tetrahydrofuro[3,2-b]pyrrol-3-one and hexahydrofuro[3,2-b]pyridine-3-one based scaffolds: synthesis and cysteinyl proteinase inhibition

A stereoselective synthesis of (3aS,6aR)-tetrahydrofuro[3,2-b]pyrrol-3-ones and (3aS,7aR)-hexahydrofuro[3,2-b]pyridine-3-ones has been developed through Fmoc protected scaffolds 12 and 13. A key design element within these novel bicyclic scaffolds, in particular the 5,5-fused system, was the inherent stability of the cis-fused geometry in comparison to that of the corresponding trans-fused. Since the bridgehead stereocentre situated beta to the ketone was of a fixed and stable configuration, the fact that cis ring fusion is both kinetically and thermodynamically stable with respect to trans ring fusion provides chiral stability to the bridgehead stereocentre that is situated alpha to the ketone. To exemplify this principle, building blocks 12 and 13 were designed, prepared and utilised in a solid phase combinatorial synthesis of peptidomimetic inhibitors 10, 45a-e, 11 and 46. Both series were chirally stable with 5,5-series 10 and 45a-e exhibiting potent in vitro activity against a range of CAC1 cysteinyl proteinases. Compound 10, a potent and selective inhibitor of cathepsin K, possessed good primary DMPK properties along with promising activity in an in vitro cell-based human osteoclast assay of bone resorption.     

Helminth community structure in an expanding white-winged dove (Zenaida asiatica asiatica) population

Helminth communities of 171 fledged white-winged doves (Zenaida asiatica asiatica) from the expanding eastern population in Texas (USA) were examined from hosts collected 11 June to 19 September 1997 within their historical range, new breeding periphery, and an intermediate area. Eleven helminth species, representing 435 individuals, were found. Helminths occurred in three microhabitats, of which the small intestine was the most commonly occupied. Nematodes dominated numerically (76% of total worms), followed by cestodes (17%), and trematodes (7%). Infracommunities were species-poor; the most complex infracommunity consisted of three helminth species, which occurred in three host individuals, followed by two species that occurred in 13 hosts. The remaining 155 doves had one (70) or no (85) species. The overall helminth component community was species-poor and was dominated by Ascaridia columbae which occurred in 26% of the white-winged doves and accounted for 65% of all helminth individuals. Prevalence and abundance of A. columbae varied by geographic region and host age, but not by host sex. Helminth component communities varied by geographic region, host age, and host sex. These differences were primarily attributable to unique occurrences of uncommon species within specific host subpopulations. Results suggest that the white-winged doves' multimodal regional abundance pattern, sympatry with other columbids, and granivorous diet may be more important in shaping helminth community structure than the influences often associated with geographic range expansion.     

Characteristics of the haemoproteid community in an expanding white-winged dove population

The haemoproteid community of 171 eastern white-winged doves (Zenaida asiatica asiatica) from the expanding Texas population was examined using thin blood smears. During summer 1997, heart blood was taken from doves within their historical breeding range (Lower Rio Grande Valley of Texas), an intermediate region (San Antonio and surrounding area), and the new breeding periphery (north central to southeast Texas). Two species were found: Haemoproteus columbae and Haemoproteus sacharovi. Infracommunities rarely occurred in heart blood, as only 20 of 132 infected doves demonstrated gametocytes of both species. Overall prevalence of H. columbae and H. sacharovi was 77 and 15%, respectively. Prevalence of H. columbae was higher in the Lower Rio Grande Valley (LRGV) and intermediate regions than at the periphery, higher in adults than juveniles, and similar between males and females. Prevalence of H. sacharovi was lower in the LRGV than intermediate and peripheral regions, similar between juveniles and adults, and higher in females than males. Mean density of H. columbae and H. sacharovi was 15.9 +/- 2.7 and 0.3 +/- 0.1 (mean +/- SE per 3,000 erythrocytes), respectively. Overall mean abundance of H. columbae and H. sacharovi was 12.2 +/- 2.2 and 0.04 +/- 0.02, respectively. Mean abundance of H. columbae was higher in the LRGV and intermediate regions than at the periphery and was similar between host age and between host sex; H. sacharovi was similar among regions, host age, and host sex. This study emphasizes the importance of using prevalence, density, and abundance data to assess haemoproteid community structure and pattern.     

Mutation of the IIB myosin heavy chain gene results in muscle fiber loss and compensatory hypertrophy

The fast skeletal IIb gene is the source of most myosin heavy chain (MyHC) in adult mouse skeletal muscle. We have examined the effects of a null mutation in the IIb MyHC gene on the growth and morphology of mouse skeletal muscle. Loss in muscle mass of several head and hindlimb muscles correlated with amounts of IIb MyHC expressed in that muscle in wild types. Decreased mass was accompanied by decreases in mean fiber number, and immunological and ultrastructural studies revealed fiber pathology. However, mean cross-sectional area was increased in all fiber types, suggesting compensatory hypertrophy. Loss of muscle and body mass was not attributable to impaired chewing, and decreased food intake as a softer diet did not prevent the decrease in body mass. Thus loss of the major MyHC isoform produces fiber loss and fiber pathology reminiscent of muscle disease.     

The Brain Response to Peripheral Insulin Declines with Age: A Contribution of the Blood-Brain Barrier?

ObjectivesIt is a matter of debate whether impaired insulin action originates from a defect at the neural level or impaired transport of the hormone into the brain. In this study, we aimed to investigate the effect of aging on insulin concentrations in the periphery and the central nervous system as well as its impact on insulin-dependent brain activity.MethodsInsulin, glucose and albumin concentrations were determined in 160 paired human serum and cerebrospinal fluid (CSF) samples. Additionally, insulin was applied in young and aged mice by subcutaneous injection or intracerebroventricularly to circumvent the blood-brain barrier. Insulin action and cortical activity were assessed by Western blotting and electrocorticography radiotelemetric measurements.ResultsIn humans, CSF glucose and insulin concentrations were tightly correlated with the respective serum/plasma concentrations. The CSF/serum ratio for insulin was reduced in older subjects while the CSF/serum ratio for albumin increased with age like for most other proteins. Western blot analysis in murine whole brain lysates revealed impaired phosphorylation of AKT (P-AKT) in aged mice following peripheral insulin stimulation whereas P-AKT was comparable to levels in young mice after intracerebroventricular insulin application. As readout for insulin action in the brain, insulin-mediated cortical brain activity instantly increased in young mice subcutaneously injected with insulin but was significantly reduced and delayed in aged mice during the treatment period. When insulin was applied intracerebroventricularly into aged animals, brain activity was readily improved.ConclusionsThis study discloses age-dependent changes in insulin CSF/serum ratios in humans. In the elderly, cerebral insulin resistance might be partially attributed to an impaired transport of insulin into the central nervous system.     

Pyrrolizidine alkaloids in the antipodean genus Brachyglottis (Asteraceae)

The phylogeny of the genus Brachyglottis suggests that its constituent species should contain pyrrolizidine alkaloids. Consistent with this hypothesis, and the established occurrence of such alkaloids in Brachyglottis repanda, Brachyglottis kirkii, and Brachyglottis hectori, an investigation of Brachyglottis adamsii revealed the presence of senecionine and retrorsine; Brachyglottis huntii was found to contain senkirkine and retrorsine; 7-O-angelylheliotridine was the predominant alkaloid in Brachyglottis perdicioides, and the same alkaloid together with senecionine, senkirkine and intergerrimine was present in the Brachyglottis hectori × B. perdicioides “Alfred Atkinson” horticultural hybrid; Brachyglottis sciadophila contained clivorine and neopetasitenine (acetylfukinotoxin); the latter alkaloid was also present in B. kirkii together with the previously reported senkirkine and senkirkine 12-acetate.