On the identifiability of linear compartmental systems: a revisited transfer function approach based on topological properties

This work deals with the problem of the a priori identifiability of compartmental systems from input-output experiments. A new approach is presented, in which, having associated a directed graph with the matrix to be identified, a set of “forms” is defined which are functions of the elements of matrix itself. It is shown how, by exploiting the topological properties of the graph and its subgraphs, the problem can be simplified into one of smaller dimensions. Examples are provided to illustrate this new approach.     

Discovering local patterns of co - evolution: computational aspects and biological examples

Background

Co-evolution is the process in which two (or more) sets of orthologs exhibit a similar or correlative pattern of evolution. Co-evolution is a powerful way to learn about the functional interdependencies between sets of genes and cellular functions and to predict physical interactions. More generally, it can be used for answering fundamental questions about the evolution of biological systems. Orthologs that exhibit a strong signal of co-evolution in a certain part of the evolutionary tree may show a mild signal of co-evolution in other branches of the tree. The major reasons for this phenomenon are noise in the biological input, genes that gain or lose functions, and the fact that some measures of co-evolution relate to rare events such as positive selection. Previous publications in the field dealt with the problem of finding sets of genes that co-evolved along an entire underlying phylogenetic tree, without considering the fact that often co-evolution is local.

Results

In this work, we describe a new set of biological problems that are related to finding patterns of local co-evolution. We discuss their computational complexity and design algorithms for solving them. These algorithms outperform other bi-clustering methods as they are designed specifically for solving the set of problems mentioned above. We use our approach to trace the co-evolution of fungal, eukaryotic, and mammalian genes at high resolution across the different parts of the corresponding phylogenetic trees. Specifically, we discover regions in the fungi tree that are enriched with positive evolution. We show that metabolic genes exhibit a remarkable level of co-evolution and different patterns of co-evolution in various biological datasets. In addition, we find that protein complexes that are related to gene expression exhibit non-homogenous levels of co-evolution across different parts of the fungi evolutionary line. In the case of mammalian evolution, signaling pathways that are related to neurotransmission exhibit a relatively higher level of co-evolution along the primate subtree.

Conclusions

We show that finding local patterns of co-evolution is a computationally challenging task and we offer novel algorithms that allow us to solve this problem, thus opening a new approach for analyzing the evolution of biological systems.     

Atomic Force Microscopy Analysis of the Acinetobacter baumannii Bacteriophage AP22 Lytic Cycle

Background

Acinetobacter baumannii is known for its ability to develop resistance to the major groups of antibiotics, form biofilms, and survive for long periods in hospital environments. The prevalence of infections caused by multidrug-resistant A. baumannii is a significant problem for the modern health care system, and application of lytic bacteriophages for controlling this pathogen may become a solution.

Methodology/Principal Findings

In this study, using atomic force microscopy (AFM) and microbiological assessment we have investigated A. baumannii bacteriophage AP22, which has been recently described. AFM has revealed the morphology of bacteriophage AP22, adsorbed on the surfaces of mica, graphite and host bacterial cells. Besides, morphological changes of bacteriophage AP22-infected A. baumannii cells were characterized at different stages of the lytic cycle, from phage adsorption to the cell lysis. The phage latent period, estimated from AFM was in good agreement with that obtained by microbiological methods (40 min). Bacteriophage AP22, whose head diameter is 62±1 nm and tail length is 88±9 nm, was shown to disperse A. baumannii aggregates and adsorb to the bacterial surface right from the first minute of their mutual incubation at 37°C.

Conclusions/Significance

High rate of bacteriophage AP22 specific adsorption and its ability to disperse bacterial aggregates make this phage very promising for biomedical antimicrobial applications. Complementing microbiological results with AFM data, we demonstrate an effective approach, which allows not only comparing independently obtained characteristics of the lytic cycle but also visualizing the infection process.     

Fast k-NNG Construction with GPU-Based Quick Multi-Select

In this paper, we describe a new brute force algorithm for building the -Nearest Neighbor Graph (k-NNG). The k-NNG algorithm has many applications in areas such as machine learning, bio-informatics, and clustering analysis. While there are very efficient algorithms for data of low dimensions, for high dimensional data the brute force search is the best algorithm. There are two main parts to the algorithm: the first part is finding the distances between the input vectors, which may be formulated as a matrix multiplication problem; the second is the selection of the k-NNs for each of the query vectors. For the second part, we describe a novel graphics processing unit (GPU)-based multi-select algorithm based on quick sort. Our optimization makes clever use of warp voting functions available on the latest GPUs along with user-controlled cache. Benchmarks show significant improvement over state-of-the-art implementations of the k-NN search on GPUs.     

Mutations in AP22.65 accelerate flowering in Arabidopsis thaliana

Identification of the gene(s) responsible for flowering time in Arabidopsis has significant implications. We used the T-DNA insertion library of Arabidopsis thaliana to screen an early-flowering mutant that exhibits accelerated flowering under short-day conditions. AP22.65, a novel flowering-time gene in that species, was isolated and identified via genome-walking and bioinformatics analysis. The flowering time of AP22.65-complementing plants was similar to that of the Col-0 wild type (WT). Conversely, its overexpression delayed flowering. Consistent with this phenotype, expression of AP22.65 was decreased in the ap22.65-1 mutant, recovered in AP22.65-complementing plants, and increased in AP22.65-overexpressing plants. Compared with the WT, expression levels of critical genes in different flowering pathways, i.e., SPY, FLC, GI, CO, FT, and LFY, were down-regulated in loss-of-function mutants. Expression of AP22.65 was distributed in flowers, siliques, rosette leaves, and whole seedlings. Therefore, this gene may be a negative regulator of Arabidopsis flowering.     

Enhanced Regulatory Sequence Prediction Using Gapped k-mer Features

Oligomers of length k, or k-mers, are convenient and widely used features for modeling the properties and functions of DNA and protein sequences. However, k-mers suffer from the inherent limitation that if the parameter k is increased to resolve longer features, the probability of observing any specific k-mer becomes very small, and k-mer counts approach a binary variable, with most k-mers absent and a few present once. Thus, any statistical learning approach using k-mers as features becomes susceptible to noisy training set k-mer frequencies once k becomes large. To address this problem, we introduce alternative feature sets using gapped k-mers, a new classifier, gkm-SVM, and a general method for robust estimation of k-mer frequencies. To make the method applicable to large-scale genome wide applications, we develop an efficient tree data structure for computing the kernel matrix. We show that compared to our original kmer-SVM and alternative approaches, our gkm-SVM predicts functional genomic regulatory elements and tissue specific enhancers with significantly improved accuracy, increasing the precision by up to a factor of two. We then show that gkm-SVM consistently outperforms kmer-SVM on human ENCODE ChIP-seq datasets, and further demonstrate the general utility of our method using a Naïve-Bayes classifier. Although developed for regulatory sequence analysis, these methods can be applied to any sequence classification problem.     

Solving the coastal eutrophication problem by large scale seaweed cultivation

Eutrophication is becoming a serious problem in coastal waters in many parts of the world. It induces the phytoplankton blooms including `Red Tides', followed by heavy economic losses to extensive aquaculture area. Some cultivated seaweeds have very high productivity and could absorb large quantities of N, P, CO₂, produce large amount of O₂ and have excellent effect on decreasing eutrophication. The author believes that seaweed cultivation in large scale should be a good solution to the eutrophication problem in coastal waters. To put this idea into practice, four conditions should be fulfilled: (a) Large-scale cultivation could be conducted within the region experiencing eutrophication. (b) Fundamental scientific and technological problems for cultivation should have been solved. (c) Cultivation should not impose any harmful ecological effects. (d) Cultivation must be economically feasible and profitable. In northern China, large-scale cultivation of Laminaria japonica Aresch. has been encouraged for years to balance the negative effects from scallop cultivation. Preliminary research in recent years has shown that Gracilaria lemaneiformis (Bory) Daws. and Porphyra haitanensis Chang et Zheng are the two best candidates for this purpose along the Chinese southeast to southern coast from Fujian to Guangdong, Guangxi and Hong Kong. Gracilaria tenuistipitata var. liui Chang et Xia is promising for use in pond culture condition with shrimps and fish.     

Tuning chitosan’s chemical structure for enhanced biological functions

Chitosan, an amino polysaccharide mostly derived from crustaceans, has been recently highlighted for its biological activities that depend on its molecular weight (MW), degree of deacetylation (DD), and acetylation pattern (AP). More importantly, for some advanced biomaterials, the homogeneity of the chitosan structure is an important factor in determining its biological activity. Here we review emerging enzymes and cell factories, respectively, for in vitro and in vivo preparation of chitosan oligosaccharides (COSs), focusing on advances in the analysis of the AP and structural modification of chitosan to tune its functions. By ‘mapping’ current knowledge on chitosan’s in vitro and in vivo activity with its MW and AP, this work could pave the way for future studies in the field.     

Type specification and spatial pattern formation of floral organs: A dynamic development model

A mathematical model simulating spatial pattern formation (positioning) of floral organs is proposed. Computer experiment with this model demonstrated the following sequence of spatial pattern formation in a typical cruciferous flower: medial sepals, carpels, lateral sepals, long stamens, petals, and short stamens. The positioning was acropetal for the perianth organs and basipetal for the stamens and carpels. Organ type specification and positioning proceed non-simultaneously in different floral parts and organ type specification goes ahead of organ spatial pattern formation. Computer simulation of flower development in several mutants demonstrated that the AG and AP2 genes determine both organ type specification and formation of the zones for future organ development. The function of the AG gene is to determine the basipetal patterning zones for the development of the reproductive organs, while the AP2 gene maintains proliferative activity of the meristem establishing the acropetal patterning zone for the development of the perianth organs.     

Quantitative Mapping of Triacylglycerol Chain Length and Saturation Using Broadband CARS Microscopy

Lipid droplets (LDs), present in many cell types, are highly dynamic organelles that store neutral lipids, primarily triacylglycerols (TAGs). With the discovery of new LD functions (e.g., in immune response, protein clearage, and occurrence with disease), new methods to study LD chemical composition in situ are necessary. We present an approach for in situ, quantitative TAG analysis using label-free, coherent Raman microscopy that allows deciphering LD TAG composition in different biochemically complex samples with submicrometer spatial resolution. Employing a set of standard TAGs, we generate a spectral training matrix capturing the variation caused in Raman-like spectra by TAG backbone, chain length, and number of double bonds per chain, as well as the presence of proteins or other diluting molecules. Comparing our fitting approach to gas chromatography measurements for mixtures of standard TAGs and food oils, we find the root mean-square error for the prediction of TAG chemistry to be 0.69 CH₂ and 0.15 #C=C. When progressing to more complex samples such as oil emulsions and LDs in various eukaryotic cells, we find good agreement with bulk gas chromatography measurements. For differentiated adipocytes, we find a significant increase in the number of double bonds in small LDs (below 2 μm in diameter) compared to large LDs (above 2 μm in diameter). Coupled with a relatively limited sample preparation requirement, this approach should enable rapid and accurate TAG LD analysis for a variety of cell biology and technological applications.     

Allocation in life cycle inventory: partial set of solutions to an ill-posed problem

Background, aim, and scope

The primary aim of this paper is to indicate that partitioning allocation methods yields only a small subset of solutions to an ill-posed problem that has potentially infinitely many exact solutions. It will be shown that each of the existing partitioning methods arrives at just one particular solution from among infinitely many solutions of an underdetermined system of linear equations.

Materials and methods

Some life cycle inventories fall into a class of functions called estimable functions in linear model framework, in which case they are invariant to allocation assumptions. This class of functions unites results described by Heijungs and Frischknecht (Int J Life Cycle Assess 3:321–332, 1998) and Heijungs and Suh (2002, Conjecture 1, p. 91). The inventories for non-estimable functions obtained through allocation are, in fact, derived under a set of additional implicit equality constraints called side conditions, often resulting in inventory results which differ greatly from one allocation to the next.

Results and discussions

This paper explicates (1) identification of all estimable functions from any given technology matrix and (2) recovery of side conditions imposed on non-estimable functions through partitioning. These methods are illustrated in a simple example, and their relation to least squares techniques for allocation explored by Marvuglia et al. (Int J Life Cycle Assess 15:1020–1040, 2010) ;(Int J Agr Environ Inf Syst 3:51–71, 2012) are discussed.

Conclusions and outlook

Recommendations are made that may lead to more meaningful ways to obtain additional data or include additional information in life cycle inventories in the future.     

Responsiveness of dairy cows to human approach and novel stimuli

This study investigated intra-test and inter-test consistency of dairy cattle behavioural responses to a series of tests involving human approach and exposure to novelty. Thirty-six lactating Holstein–Friesian cows were each subjected to three human approach tests and three novel stimuli tests. Flight response score was assessed by an experimenter approaching cows when they were in the passageway of the home-pen (AP), lying down (AL) and at the feedface (FF). Each human approach test was repeated on each cow three times. The intra-animal repeatability estimates were 0.65, 0.40, 0.27 for AP, AL and FF tests, respectively. Repeatability evaluates an individual's consistency across tests by comparing it to the variation within the group. Cows showed moderate consistency in their flight response scores to the different approach tests (W₃₅ = 0.56, P < 0.01). Three novel stimuli (water spray, striped boards and flashing light) were individually presented once to each cow. Investigatory and reactivity behavioural responses were assessed. Cows showed the greatest reactivity response to the water spray compared to the striped boards (U₁ = 56, P < 0.001) and flashing light (U₁ = 66, P < 0.001). No statistically significant agreement existed between the novel stimuli reactivity and investigatory responses with the AP flight response scores. In conclusion, consistency over time was demonstrated over a relatively short period for the AP test and consistency between human approach situations was shown, however, consistency between human and novel situations was not found.     

Appendage patterning in the primitively wingless hexapods Thermobia domestica (Zygentoma: Lepismatidae) and Folsomia candida (Collembola: Isotomidae)

Arthropod appendages are among the most diverse animal organs and have been adapted to a variety of functions. Due to this diversity, it can be difficult to recognize homologous parts in different appendage types and different species. Gene expression patterns of appendage development genes have been used to overcome this problem and to identify homologous limb portions across different species and their appendages. However, regarding the largest arthropod group, the hexapods, most of these studies focused on members of the winged insects (Pterygota), but primitively wingless groups like the springtails (Collembola) or silverfish and allies (Zygentoma) are underrepresented. We have studied the expression of a set of appendage patterning genes in the firebrat Thermobia domestica and the white springtail Folsomia candida. The expressions of Distal-less (Dll) and dachshund (dac) are generally similar to the patterns reported for pterygote insects. Modifications of gene regulation, for example, the lack of Dll expression in the palp of F. candida mouthparts, however, point to changes in gene function that can make the use of single genes and specific expression domains problematic for homology inference. Such hypotheses should therefore not rely on a small number of genes and should ideally also include information about gene function. The expression patterns of homothorax (hth) and extradenticle (exd) in both species are similar to the patterns of crustaceans and pterygote insects, but differ from those in chelicerates and myriapods. The proximal specificity of hth thus appears to trace from a common hexapod ancestor and also provides a link to the regulation of this gene in crustaceans.     

An artificial immune system algorithm for the resource availability cost problem

In this paper, an artificial immune system (AIS) algorithm for the resource availability cost problem (RACP) is presented, in which the total cost of the (unlimited) renewable resources required to complete the project by a pre-specified project deadline should be minimized. The AIS algorithm makes use of mechanisms inspired by the vertebrate immune system and includes different algorithmic components, such as a new fitness function, a probability function for the composition of the capacity lists, and a K-means density function in order to avoid premature convergence. All components are explained in detail and computational results for the RACP are presented.     

The optimal configuration and workload allocation problem in flexible manufacturing systems

In this article we consider the problem of determining the minimum cost configuration (number of machines and pallets) for a flexible manufacturing system with the constraint of meeting a prespecified throughput, while simultaneously allocating the total workload among the machines (or groups of machines). Our procedure allows consideration of upper and lower bounds on the workload at each machine group. These bounds arise as a consequence of precedence constraints among the various operations and/or limitations on the number or combinations of operations that can be assigned to a machine because of constraints on tool slots or the space required to store assembly components. Earlier work on problems of this nature assumes that the workload allocation is given. For the single-machine-type problem we develop an efficient implicit enumeration procedure that uses fathoming rules to eliminate dominated configurations, and we present computational results. We discuss how this procedure can be used as a building block in solving the problem with multiple machine types.