Integrated stoichiometric, thermodynamic and kinetic modelling of steady state metabolism

The quantitative analysis of biochemical reactions and metabolites is at frontier of biological sciences. The recent availability of high-throughput technology data sets in biology has paved the way for new modelling approaches at various levels of complexity including the metabolome of a cell or an organism. Understanding the metabolism of a single cell and multi-cell organism will provide the knowledge for the rational design of growth conditions to produce commercially valuable reagents in biotechnology. Here, we demonstrate how equations representing steady state mass conservation, energy conservation, the second law of thermodynamics, and reversible enzyme kinetics can be formulated as a single system of linear equalities and inequalities, in addition to linear equalities on exponential variables. Even though the feasible set is non-convex, the reformulation is exact and amenable to large-scale numerical analysis, a prerequisite for computationally feasible genome scale modelling. Integrating flux, concentration and kinetic variables in a unified constraint-based formulation is aimed at increasing the quantitative predictive capacity of flux balance analysis. Incorporation of experimental and theoretical bounds on thermodynamic and kinetic variables ensures that the predicted steady state fluxes are both thermodynamically and biochemically feasible. The resulting in silico predictions are tested against fluxomic data for central metabolism in Escherichia coli and compare favourably with in silico prediction by flux balance analysis.     

A semi-Markov model based on generalized Weibull distribution with an illustration for HIV disease

Multi-state stochastic models are useful tools for studying complex dynamics such as chronic diseases. Semi-Markov models explicitly define distributions of waiting times, giving an extension of continuous time and homogeneous Markov models based implicitly on exponential distributions. This paper develops a parametric model adapted to complex medical processes. (i) We introduced a hazard function of waiting times with a U or inverse U shape. (ii) These distributions were specifically selected for each transition. (iii) The vector of covariates was also selected for each transition. We applied this method to the evolution of HIV infected patients. We used a sample of 1244 patients followed up at the hospital in Nice, France.     

A Class of Distributions in the First Emptiness of a Semi-Infinite Reservoir

This paper considers the probability distribution of the volume of a certain substance (e.g. river discharge, rainfall, deposites of clay, organism, etc.) that flows into a semi-infinite reservoir before its first emptiness for continuous and homogeneous input process when the substance is released at unit rate per unit of time. A few moments of the distribution have been computed. A generalized gamma, and a generalized exponential distributions as particular cases are also discussed. Some possible applications of the generalized negative exponential distribution have been mentioned. These distributions are in fact the continuous analogues of the discrete LAGRANGE distributions recently considered by JAIN and others.     

Time Trends and Inequalities of Under-Five Mortality in Nepal: A Secondary Data Analysis of Four Demographic and Health Surveys between 1996 and 2011

Background

Inequalities in progress towards achievement of Millennium Development Goal four (MDG-4) reflect unequal access to child health services.

Objective

To examine the time trends, socio-economic and regional inequalities of under-five mortality rate (U5MR) in Nepal.

Methods

We analyzed the data from complete birth histories of four Nepal Demographic and Health Surveys (NDHS) done in the years 1996, 2001, 2006 and 2011. For each livebirth, we computed survival period from birth until either fifth birthday or the survey date. Using direct methods i.e. by constructing life tables, we calculated yearly U5MRs from 1991 to 2010. Projections were made for the years 2011 to 2015. For each NDHS, U5MRs were calculated according to child''s sex, mother’s education, household wealth index, rural/urban residence, development regions and ecological zones. Inequalities were calculated as rate difference, rate ratio, population attributable risk and hazard ratio.

Results

Yearly U5MR (per 1000 live births) had decreased from 157.3 (95% CIs 178.0-138.9) in 1991 to 43.2 (95% CIs 59.1-31.5) in 2010 i.e. 114.1 reduction in absolute risk. Projected U5MR for the year 2015 was 54.33. U5MRs had decreased in absolute terms in all sub groups but relative inequalities had reduced for gender and rural/urban residence only. Wide inequalities existed by wealth and education and increased between 1996 and 2011. For lowest wealth quintile (as compared to highest quintile) hazard ratio (HR) increased from 1.37 (95% CIs 1.27, 1.49) to 2.54 ( 95% CIs 2.25, 2.86) and for mothers having no education (as compared to higher education) HR increased from 2.55 (95% CIs 1.95, 3.33) to 3.75 (95% CIs 3.17, 4.44). Changes in regional inequities were marginal and irregular.

Conclusions

Nepal is most likely to achieve MDG-4 but eductional and wealth inequalities may widen further. National health policies should address to reduce inequalities in U5MR through ‘inclusive policies''.     

Life expectancy for a class of life distributions having the "setting the clock back to zero" property

It is demonstrated that the expression for the life expectancy of an individual in biomedical investigations can be greatly simplified if the class of life distributions possesses what has been called the "setting the clock back to zero" property, studied previously by Raja Rao and Talwalker. It is shown that the Gompertzian growth process, Krane's family of life distributions, and the linear hazard exponential distribution have this property. To illustrate the use of this property, an individual's life expectancy is tabulated for several choices of the parameter values when the individual's life distribution belongs to a Gompertzian growth process. In addition, it is shown that a new survival model considered by Chiang and Conforti for the estimation of time to tumor has the "setting the clock back to zero" property. Its life expectancy is evaluated at any given time chi 0 using this property.     

Surveys of new and rare microfungi in the Düsseltal (North Rhine-Westphalia)--Germany

In the years 2003 and 2004 we have observed an about 70 hectare large area in the Düsseltal, the eastern part of the Neandertal in North Rhine-Westphalia. There we collected on trees, bushes and herbs and found about 150 microfungi of which some are new for Germany or the entire world. E.g.: Pseudocercospora populigena N. ALE-AGHA, U. BRAUN & G.B. FEIGE on Populus berolinensis; Vialaea insculpta (FR.) SACC. on Ilex aquifolium L.; Passalora amelopsidis (PECK.) U. BRAUN on Parthenocissus quinquefolia (L.) PLANCH.: Pleiochaeta setosa (KIRCHN.) HUGHES on Genista angelica L.; Cercospora mercurialis PASS. on Mercurialis perennis L. (new for NRW); Pleurocytospora vestita PETRAK on Ribes aureum PURSH.; Gonatobotrys simplex CORDA on Lolium perenne L.; Phomatospora berckleyi SACC. on Dactylis glomerata L. and so on. All specimens are located in the Herbarium ESS, Mycotheca Parva collection G.B. Feige & N. Ale-Agha.     

An improved algorithm for stoichiometric network analysis: theory and applications

MOTIVATION: Genome scale analysis of the metabolic network of a microorganism is a major challenge in bioinformatics. The combinatorial explosion, which occurs during the construction of elementary fluxes (non-redundant pathways) requires sophisticated and efficient algorithms to tackle the problem. RESULTS: Mathematically, the calculation of elementary fluxes amounts to characterizing the space of solutions to a mixed system of linear equalities, given by the stoichiometry matrix, and linear inequalities, arising from the irreversibility of some or all of the reactions in the network. Previous approaches to this problem have iteratively solved for the equalities while satisfying the inequalities throughout the process. In an extension of previous work, here we consider the complementary approach and derive an algorithm which satisfies the inequalities one by one while staying in the space of solution of the equality constraints. Benchmarks on different subnetworks of the central carbon metabolism of Escherichia coli show that this new approach yields a significant reduction in the execution time of the calculation. This reduction arises since the odds that an intermediate elementary flux already fulfills an additional inequality are larger than when having to satisfy an additional equality constraint.     

Estimation of the incubation period of influenza A (H1N1-2009) among imported cases: addressing censoring using outbreak data at the origin of importation

Empirical estimates of the incubation period of influenza A (H1N1-2009) have been limited. We estimated the incubation period among confirmed imported cases who traveled to Japan from Hawaii during the early phase of the 2009 pandemic (n=72). We addressed censoring and employed an infection-age structured argument to explicitly model the daily frequency of illness onset after departure. We assumed uniform and exponential distributions for the frequency of exposure in Hawaii, and the hazard rate of infection for the latter assumption was retrieved, in Hawaii, from local outbreak data. The maximum likelihood estimates of the median incubation period range from 1.43 to 1.64 days according to different modeling assumptions, consistent with a published estimate based on a New York school outbreak. The likelihood values of the different modeling assumptions do not differ greatly from each other, although models with the exponential assumption yield slightly shorter incubation periods than those with the uniform exposure assumption. Differences between our proposed approach and a published method for doubly interval-censored analysis highlight the importance of accounting for the dependence of the frequency of exposure on the survival function of incubating individuals among imported cases. A truncation of the density function of the incubation period due to an absence of illness onset during the exposure period also needs to be considered. When the data generating process is similar to that among imported cases, and when the incubation period is close to or shorter than the length of exposure, accounting for these aspects is critical for long exposure times.     

The overall distribution of survival times for U.K. AIDS patients

Data on the survival times of 997 U.K. AIDS patients are analysed with the aim of deriving a simple form for the overall survival distribution. The exponential and Weibull distributions are modified to accommodate specific features of the data, in particular, the recording of survival times to the nearest month and the occurrence of a significant proportion of cases recorded as having zero time on study. The final model has a probability 0.08 of underlying survival time being zero and, given non-zero survival time, takes the form of an exponential distribution with mean of 14.95 months. The results are in close agreement with those of a study of New York City patients as well as the empirical data.     

Piecewise exponential survival curves with smooth transitions

Several models of a population survival curve composed of two piecewise exponential distributions are developed. In one formulation the hazard rate changes at a point that is an unobservable random variable that varies between individuals. The population hazard function may decrease with age even when all individuals' hazards are increasing. In a second formulation, the population hazard function is modeled directly. Several models are fit to the survival history of a cohort of 5751 highly inbred male Drosophila melanogaster and the British coal mining disaster data.     

Sensitized fluorescence in polynucleotide-dye complexes and the problem of energy transfer in polynucleotides

New results on sensitization of fluorescence of Profiuvine, Acridine Orange and Ethidium Bromide complexes wilh double stranded poly A-poly U upon ultraviolet irradiation are presented. Together with older results on dye DNA complex, they are interpreted to show that base to base transfer plays essentially no role compared to direct base to dye transfer. A lower limit of base to base transfer time (which is at the same time a higher limit for life time of fluorescence) in DNA (2. 10^?11 sec.) and poly A-poly U (2. 10^?13 sec.) is obtained which cast some doubt upon the validity of calculations of optical properties using the exciton (strong coupling) approximation.     

Investigating reasons for socioeconomic inequalities in breast cancer survival in New Zealand

Background: This study investigated the role that demographic and tumour factors play in explaining socioeconomic inequalities in breast cancer survival. Methods: Breast cancer cases notified to the New Zealand Cancer Registry (NZCR) from April 2005 to April 2007 were followed up to April 2009. The New Zealand area-based deprivation index (NZDep) was used as a measure of socioeconomic position. Relative survival rates were estimated using sex-, deprivation- and ethnic-specific life tables. Multiple imputation was used to impute missing data. Excess mortality modelling was used to estimate the contribution of demographic and tumour factors to inequalities in survival. Results: There were 2968 breast cancer cases included and 433 recorded deaths. Relative survival rates at 4 years varied across deprivation groups. Using NZDep deciles 1–4 (least deprived) as the reference group, the age- and ethnicity-adjusted hazard ratio (HR) for NZDep deciles 7–8 was 2.03 (CI 1.36–3.04) and for NZDep deciles 9–10 was 1.93 (CI 1.28–2.92). In the fully adjusted model there remained 50% excess mortality for the two most deprived groups compared to the most affluent. Variables which measured timely access to care (extent/size) accounted for more of the survival disparity than breast cancer subtype variables (ER/PR/HER2). Conclusion: Women from deprived areas in New Zealand who are diagnosed with breast cancer are less likely to survive as long as those from affluent areas. A substantial proportion of these socioeconomic disparities can be attributed to differential access to health care although other factors, currently unknown, are also likely to play an important role.     

Confidence Intervals for the Relative Risk Ratio Parameter from Survival Data Under a Random Censorship Model in Biomedical and Epidemiologic Studies (By Simulation)

The present paper reports the results of a Monte Carlo simulation study to examine the performance of several approximate confidence intervals for the Relative Risk Ratio (RRR) parameter in an epidemiologic study, involving two groups of individuals. The first group consists of n₁ individuals, called the experimental group, who are exposed to some carcinogen, say radiation, whose effect on the incidence of some form of cancer, say skin cancer, is being investigated. The second group consists of n₂ individuals (called the control group) who are not exposed to the carcinogen. Two cases are considered in which the life times (or time to cancer) in the two groups follow (i) the exponential and (ii) the Weibull distributions. The case when the life times follow a Rayleigh distribution follows as a particular case. A general random censorship model is considered in which the life times of the individuals are censored on the right by random censoring times following (i) the exponential and (ii) the Weibull distributions. The Relative Risk Ratio parameter in the study is defined as the ratio of the hazard rates in the two distributions of the times to cancer. Approximate confidence intervals are constructed for the RRR parameter using its maximum likelihood estimator (m.l.e) and several other methods, including a method due to FIELLER. SPROTT'S (1973) and Cox's (1953) suggestions, as well as the Box-Cox (1964) transformation, are also utilized to construct approximate confidence intervals. The performance of these confidence intervals in small samples is investigated by means of some Monte Carlo simulations based on 500 random samples. Our simulation study indicates that many of these confidence intervals perform quite well in samples of size 10 and 15, in terms of the coverage probability and expected length of the interval.     

BUCHBESPRECHUNGEN

Book reviewed in this article:
reviews type of article–
M ason , J. L. (ed.): Evolution of domesticated animals . London, New York: Longman 1984.
G riffiths , G. C. D. (ed.): Flies of the Nearctic Region . Vol. VIII: Cyclorrhapha II (Schizophora: Calyptratae), Part 2 Anthomyiidae, Number 1 by G. C. D. G riffiths . Stuttgart: E. Schweitzerbart'sche Verlagsbuchhandlung 1982.
S impson , G. G.: Penguins . Past and Present, Here and There. New Haven and London: Yale University Press 1983.
G ans , E.; P ouch , F. H. (eds.): Biology of the Reptilia . Vol. 12. New York – London: Academic Press 1982. 564 S. DM 353,–. G ans , E. (ed.):
M atsuno , K.; D ose , K.; H arada , K.; R ohlfing , D. L. (eds.): Molecular Evolution and Protobiology . New York, London
F elsenstein , J. (ed.): Numerical Taxonomy . Nato AS1 Series. Series G Ecological Sciencesxs
S meets , W. J. A. J.; N ieuwenhuys , R.; R oberts , B. L.: The Central Nervous System of Cartilaginous Fishes . Structure and Functional Correlations. Berlin, Heidelberg, New York: Springer 1983
H echt , M. K.; W allace , B.; P range , G. T. (eds.): Evolutionary Biology . Vol. 18. New York and London     

New, rare and remarkable records of microfungi from the Slovakian Republic

During an excursion to the Slovakian Republic (lower and upper Tatra) of the Botanical Institute of the University of Essen in 2004 we were able to collect about 150 species of microfungi as parasites or saprophytes on cultivated crops and wild plants. Some of them are new for the entire world and a few of them are new for the Slovakian Republic, e.g: Ramularia liliicola N. Ale-Agha, U. Braun & G.B. Feige on Lilium martagon L.; Septoria aegopodii DESM. Ex Kickx. F. on Aegopodium podagaria L.; Puccinia asarina Kunze on Asarum europaeum L.; Puccinia polygoni ALB. & SCHW. and Puccinia polygoni-amphibii PERS. on Bilderdykia convolvulus (L.) Du Mont.; Ramularia chamaenerii Rostr. and Mycosphaerella chamaenerii Saville on Epilobium angustifolium L.; Plasmopara pusilla (de By.) Schroet on Geranium sylvaticum L.; Cercosporidium depressum (Berk. & Br.) Deighta on Angelica sylvestris L. All specimens are located in the Herbarium ESS, Mycotheca Parva collection G.B. Feige & N. Ale-Agha.     

THE LABORATORY CULTIVATION OF STEMONITIS

Alexopoulos , Constantine J. (State U. Iowa, Iowa City.) The laboratory cultivation of Stemonitis. Amer. Jour. Bot. 46(2): 140-142. Illus. 1959.—The cultivation of a species of Stemonitis, probably S. flavogenita, in laboratory culture is reported here for the first time. The organism completed its entire life cycle on artificial media from spore to spore, in the presence of contaminating bacteria, in 36 days. The plasmodium, characteristically different from those of the Physarales, is described and illustrated.     

BUCHBESPRECHUNGEN

S tebbins , L. (Hrsg.): Evolutionsprozesse. Bd. 2: Grundbegriffe der modernen Biologic Aus dem Amerikanischen von J utta Querner.
Systematische Zoologie. Stämme des Tierreichs. Begründet von A. R emane , V. S torch und U. W elsch .
K ämpfe , L. (Hrsg.): Evolution und Stammesgeschichte der Organismen. Bearb. von D. B ernhardt , F. F ukarek , E. G unther , L. K ämpfe .
L arwood , G. P.; A bbott , M. B. (Eds.): Advances in Bryozoology. Proceedings of the 4th International Conference of the International Bryozoology Association, Woods Hole, 1977.
Verhandlungen der Deutschen Zoologischen Gesellschaft. 72. Jahresversammlung vom 4.-9. Juni 1979 in Regensburg. Im Auftrag der Gesellschaft herausgegeben von Professor Dr. W. Rathmayer, Konstanz. Mit Beiträgen von zahlreichen Fachspezialisten.
R iedl , R., unter Mitarbeit von R. KASPAR: Biologie der Erkenntnis. Die stammesge-schichtlichen Grundlagen der Vemunft.
R emane , A.; S torch , V.; W elsch , U.: Kurzes Lehrbuch der Zoologie. 3., völlig neu bearbeitete Aufl.
K uhn , O.: Handbook of Paleoichthyology. Vol. 5: Acanthodii. By R. DENISON. Stuttgart und New York: Gustav Fischer 1979.
S tephan , H.; B aron , G.; S chwerdtfeger , W. K.: The brain of the Common Marmoset (Callithrix jacchus). A stereotaxic adas. Berlin, Heidelberg, New York:     

New and remarkable microfungi in North Rhine Westphalia, Germany

During our investigation on microfungi in North Rhine Westphalia in the years 2002 and 2003 we were able to collect and identify some new and rare species of microfungi as parasites and saprophytes on wild and ornamental plants. Some of these like Erysiphe elevata (BURILL.) U. BRAUN & S. TAKAMATSU COMB. NOV. [=Microsphaera elevata BURILL.] on Catalpa bignonioides WALT., Erysiphe syringae-japonicae (U. BRAUN) U. BRAUN & S. TAKAMATSU [= Microsphaera syringae-japonicae U. BRAUN, M. aceris BUNKINA. KOMAROVSKIE CHTENIYA, Erysiphe acerina U. BRAUN & S. TAKAMATSU] on Acer campestre L. and Acer barinerve L., Mycosphaerella iridis (DESM.) SCHROET., Ectostroma iridis FR. and Volutella melaloma BERK. & BR on Iris pseudacorus L., Puccinia doronicella P. SYD. & SYD. on Doronicum columnae TEN., Ascochyta lamiorum SACC. S.L. I=A. phlomidis BUB. & WROB.) on Phlomis tuberosa L., Colletotrichum gloeosporides (PENZ.) SACC. on Passiflora coerulea L., Oidium hortensiae JOERST on Hydrangea macrophylla (THUNB.) SER., Puccinia horiana P. HENN. on Chrysanthemum vulgare (L.) BERNH., Lophodermium pinastri (SCHRAD.) CHEV., Leptostroma pinorum SACC., Sclerophoma pythiophila (CDA) HOHN., Lichenoconium boreale (KARST.) PETRAK. & SYD., Anthostomella formosa KIRSCHST. and Sphaeropsis sapinae (FR.) DYKO & SUTTON on Pinus nigra L. are new for Germany. All samples are located in the Herbarium ESS Mycotheca Parva, Collection G.B. Feige/N. Ale-Agha.     

Potential of selective insecticides for managing Uraba lugens (Lepidoptera: Nolidae) on Eucalypts

The leaf skeletonizer Uraba lugens Walker (Lepidoptera: Nolidae), an Australian species, locally known as "gumleaf skeletonizer", is well established in New Zealand. This insect has the potential to become a serious pest of forestry and amenity eucalypts (Eucalyptus spp.) and is the focus of a long-term management program. The use of synthetic chemical or biological insecticides is one possible control method within an integrated control program. A series of dose-response trials were conducted using laboratory bioassays to test the efficacy of several insecticides against U. lugens: pyrethroids, spinosad, Bacillus thuringiensis kurstaki Berliner (Btk) and an insect growth regulator, Mimic. Pyrethroids and spinosad proved highly effective against U. lugens larvae, achieving 100% mortality after 3-6-d exposure. The performance of Btk was lower against gregarious skeletonizing larvae compared with solitary chewing larvae. When good coverage of the target foliage is achieved, >90% mortality is possible with Btk. Mimic performed poorly against U. lugens compared with other insecticides tested (<60% mortality). The Eucalyptus species on which larvae were feeding significantly altered insecticide efficacy. Treatments applied to Eucalyptus nitens (Deane & Maiden) Maiden had reduced efficacy compared with E. cinerea F. Muell. ex Benth. or E. fastigata Deane & Maiden. Cooler temperatures also reduced insecticide efficacy, presumably by decreasing movement and food consumption by U. lugens. Recommendations on spray applications to control U. lugens in New Zealand are given.     

BUCHBESPRECHUNGEN

Book reviewed in this article:
NOLF, D.: Otolithi piscium. Handbook of Paleoichthyology. Vol. 10. Edited by H.-P. SCHULTZE. Stuttgart
DELSON, ERICH (Ed.): Ancestors: The Hard Evidence. New York: Alan R. Liss, Inc.
REMANE, A.; STORCH, V.; WELSCH, U.: Systematische Zoologie. Fortgefiihrt von V. STORCH und U. WELSCH.
WILSON, R. R.: The Camel. London and New York: Longman
WHIITINGTON, H. B.: The Burgess Shale. London: Yale University Press