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An algorithm for design of beam compensators.

Beam compensators are optimally designed to give a uniform dose to any plane or midsurface that intersects a single beam, or to give a uniform dose to the volume defined by the intersection of two or more beams. The primary and scatter components are taken into account separately, as well as the patient's shape and internal heterogeneities. The design of the beam compensators is formulated as a linear programming problem and solved with a variation of the Simplex Method. Beam weighting factors are also obtained as part of the solution.

Algorithms

Large scale optimization of beam weights under dose-volume restrictions.

The problem of choosing weights for beams in a multifield plan which maximizes tumor dose under conditions that recognize the volume dependence of organ tolerance to radiation is considered, and its solution described. Structures are modelled as collections of discrete points, and the weighting problem described as a combinatorial linear program (LP). The combinatorial LP is solved as a mixed 0/1 integer program with appropriate restrictions on normal tissue dose. The method is illustrated through the assignment of weights to a set of 10 beams incident on a pelvic target. Dose-volume restrictions are placed on surrounding bowel, bladder, and rectum, and a limit placed on tumor dose inhomogeneity. Different tolerance restrictions are examined, so that the sensitivity of the target dose to changes in the normal tissue constraints may be explored. It is shown that the distributions obtained satisfy the posed constraints. The technique permits formal solution of the optimization problem, in a time short enough to meet the needs of treatment planners.

Humans

Transport properties of polymer solutions. A comparative approach.

A variety of transport properties have been measured for solutions of the water soluble polymer poly(ethylene oxide)(PEO) with molecular weights ranging from 200 to 14,000, and volume fractions ranging from 0-80%. The transport properties are thermal conductivity, electrical conductivity at audio frequencies (in solutions containing dilute electrolyte), and water self-diffusion. These data, together with dielectric relaxation data previously reported, are amenable to analysis by the same mixture theory. The ionic conductivity and water self-diffusion coefficient, but not the thermal conductivity, are substantially smaller than predicted by the Maxwell and Hanai mixture relations, calculated using the known transport properties of pure liquid water. A 25% (by volume) solution of PEO exhibits an average dielectric relaxation frequency of the suspending water of one half that of pure water, with clear evidence of a distribution of relaxation times present. The limits of the cumulative distribution of dielectric relaxation times that are consistent with the data are obtained using a linear programming technique. The application of simple mixture theory, under appropriate limiting conditions, yields hydration values for the more dilute polymer solutions that are somewhat larger than values obtained from thermodynamic measurements.

Biological Transport

Study of leucine-enkephalin in rat brain by a new high-performance liquid chromatographic method.

A specific method is presented for the assay of leucine-enkephalin (Leu-Enk) and its metabolites by reversed-phase high-performance liquid chromatography on a muBondapak C18 column with a mobile phase of methanol-water and 0.005 M tetrabutylammonium phosphate. The four substances are resolved by a linear program from 8 to 70% methanol in 25 min. Detection is achieved by monitoring the absorbance at 280 nm. Time of analysis can be reduced by means of a new high-speed liquid chromatography package. This method allows the study of the effect of Phe-Ala on the cerebral metabolism of Leu-Enk. For this purpose, membrane preparations from rat striatum were incubated in the presence of [3H]Leu-Enk with different concentrations of Phe-Ala from 10(-7) to 10(-3) M during 1 h at 37 degrees C. Collected eluates were counted by liquid scintillation. The results suggest the presence of three membrane enzymes which generate the three metabolites, Tyr, Tyr-Gly-Gly and Tyr-Gly, in order of abundance. Maximum inhibition of [3H]Leu-Enk degradation is obtained at a concentration of 10(-3) M Phe-Ala.

Animals

Computer-aided optimization of choice and positioning of bone plates and screws used for internal fixation of mandibular fractures.

The present study describes a biomechanical integrated model of the mandibular system in which the maxilla and mandible, the masticatory muscles, and the temporomandibular joints are regarded as one system. In this model, strains in plate-osteosynthesis devices for internal fixation of mandibular fractures can be minimized by optimizing their positions. The model evaluates maximal bite force strategies on all possible dental elements; it uses a linear programming technique and a muscle architecture model, resulting in muscle recruitment patterns. The shape of a "standard" lower jaw is digitized by means of a three-dimensional (3-D) coordinate retrieval device and drawn on a computer screen after its dimensions have been changed according to the clinical case at hand. The 3-D location of the fracture as well as the anatomic restrictions for screw placement can be indicated on the screen. Osteosynthesis devices can be indicated in terms of dimensions, number, and material properties.

Biomechanical Phenomena

The use of spectral analysis to determine regional cerebral glucose utilization with positron emission tomography and [18F]fluorodeoxyglucose: theory, implementation, and optimization procedures.

A method for kinetic analysis of dynamic positron emission tomography (PET) data by linear programming that allows identification of the components of a measured PET signal without predefining a compartmental model has recently been proposed by Cunningham and co-workers. The method identifies a small subset of functions from a large input set of feasible functions that best fits the time course of total radioactivity measured by PET. To investigate in detail the properties of this technique, we applied it to PET studies with [18F]fluorodeoxyglucose, a tracer with well-characterized kinetic properties. We examined dynamically acquired data over various time intervals in many brain regions and found that the number of components identified by the method is stable and consistent with the presence of kinetic heterogeneity in every region. We optimized the method for determination of regional rates of glucose utilization; calculated rates were found to be somewhat dependent upon the treatment of noise in the measured tissue data and upon the time interval in which the data were collected. The application of a numerical filter to remove noise in the data resulted in values for regional cerebral glucose utilization that were stable with time and consistent with rates determined by the other established techniques. Based on the results of the current study, we expect that the spectral analysis technique will prove to be a highly flexible tool for kinetic analysis of other tracer compounds; it is capable of producing low-variance, time-stable estimates of physiological parameters when optimized for time interval of application, input spectrum of components, and processing of noise in the data.

Adult

Fat synthesis in adipose tissue. An examination of stoichiometric constraints.

The requirement for net balance of synthesis, degradation and transport for all intermediates in the pathways from glucose to fat imposes constraints on the balance of fluxes between different pathways. Linear programming has been used to examine the interactions between these constraints on metabolism in adipocytes and the requirement for efficiency in the conversion of glucose into fat. The circumstances under which excessive ATP synthesis would accompany this conversion have been investigated.

Adipose Tissue

Multisurface method of pattern separation for medical diagnosis applied to breast cytology.

Multisurface pattern separation is a mathematical method for distinguishing between elements of two pattern sets. Each element of the pattern sets is comprised of various scalar observations. In this paper, we use the diagnosis of breast cytology to demonstrate the applicability of this method to medical diagnosis and decision making. Each of 11 cytological characteristics of breast fine-needle aspirates reported to differ between benign and malignant samples was graded 1 to 10 at the time of sample collection. Nine characteristics were found to differ significantly between benign and malignant samples. Mathematically, these values for each sample were represented by a point in a nine-dimensional space of real variables. Benign points were separated from malignant ones by planes determined by linear programming. Correct separation was accomplished in 369 of 370 samples (201 benign and 169 malignant). In the one misclassified malignant case, the fine-needle aspirate cytology was so definitely benign and the cytology of the excised cancer so definitely malignant that we believe the tumor was missed on aspiration. Our mathematical method is applicable to other medical diagnostic and decision-making problems.

Biopsy, Needle

Protein, essential amino acids and glycine requirements of the growing gosling (Anser cireneus).

The dietary requirements for protein and amino acids of the growing gosling (0-7 weeks) were calculated according to body composition, maintenance needs and the absorption rate of amino acids from feeds. The diets were formulated by least-cost linear programming, using the calculated requirements for amino acids, with or without minimal glycine + serine requirements. The diets formulated without minimal requirements of glycine + serine were supplemented with various amounts of glycine, and fed to growing goslings. The calculated requirements for protein and essential amino acids were lower than those suggested for growing broilers and turkeys. The requirements (g/MJ metabolizable energy) at 0-2, 2-4 and 4-7 weeks of age respectively, were: lysine 0.88, 0.48, 0.43; methionine + cystine 0.48, 0.38, 0.29; protein 14.5, 9.3, 7.6. The goslings did not respond to glycine supplementation of the diet.

Amino Acids, Essential

Effective energy: a concept of energy utilization applied across species.

An energy system is described in which, in both single-stomached and ruminant animals, the heat increment of feeding is considered to be linearly related to five measurable quantities. For both kinds of animals three of the quantities, with their heat increments in parentheses, are urinary N (wu; kJ/g), faecal organic matter (wd; kJ/g) and positive protein retention (wp; kJ/g). In ruminants the other two, with their heat increments in parentheses, are CH4 energy (wm; kJ/kJ) and positive lipid retention (w1; kJ/g); in single-stomached animals they are positive lipid retention from feed lipid (wII; kJ/g), and positive lipid retention not from feed lipid (wI; kJ/g). Data from suitable experiments on steers, pigs and chickens were used to test the system and to estimate wu 29.2, wd 3.80, wp 36.5, wm 0.616, wI 16.4 and wII 4.4. The values for wu, wd, wm and (wI - wII) allow an energy scale, called effective energy, to be defined for both single-stomached animals and ruminants. On this energy scale the values of wp and wI, together with the heats of combustion of protein and lipid of 23.8 and 39.6 kJ/g respectively, allow the energy requirement to be expressed as (MH + 50PR + 56LR) for both kinds of animal, where PR and LR are the rates of positive protein and lipid retention (g/d), and MH is the maintenance heat production (kJ/d) which can be estimated as 0.96 of the fasting heat production. The effective energy (EE) yielded to a ruminant animal by a feed ingredient can be estimated as EE (MJ/kg organic matter) = 1.15ME - 3.84 - 4.67DCP, where ME is the metabolizable energy value (MJ/kg organic matter) and DCP is the digested crude protein content (kg/kg organic matter) with both measured at maintenance. Alternatively, EE can be estimated as EE (MJ/kg) = GE (d - 0.228) - 4.67DCP, where GE is the gross energy (MJ/kg) and d is the energy digestibility (MJ/MJ) also measured at maintenance. The EE yielded to a single-stomached animal can be estimated as EE (kJ/g) = 1.17ME - 4.2CP - 2.44, where ME (kJ/g) is measured at, or corrected to, zero N-retention and CP (g/g) is the crude protein (N x 6.25) content of the feed ingredient. The system is simpler for ruminants, and more accurate for both kinds of animal, than those now in use. As effective energy values can be tabulated for ingredients, and are additive to the extent that ME values are additive, they can be used to formulate diets using linear programming.

Animal Nutritional Physiological Phenomena

The large-scale separation of peroxisomes, mitochondria, and lysosomes from the livers of rats injected with triton WR-1339. Improved isolation procedures, automated analysis, biochemical and morphological properties of fractions.

Improved, largely automated methods are described for the purification and analysis o peroxisomes, lysosomes, and mitochondria from the livers of rats injected with Triton WR-1339. With these new methods, it has become possible to obtain, in less than 6 hr and with reliable reproducibility, mitochondria practically free of contaminants, as well as the rarer cytoplasmic particles in amounts (about 100 mg of protein) and in a state of purity (95%) that make them suitable for detailed biochemical studies. The results obtained so far on these preparations have made more conclusive and precise previous estimates of the biochemical and morphological properties of the three groups of cytoplasmic particles. In addition, peroxisomes were found to contain essentially all the L-alpha-hydroxy acid oxidase of the liver, as well as a small, but significant fraction of its NADP-linked isocitrate dehydrogenase activity. Another small fraction of the latter enzyme is present in the mitochondria, the remainder being associated with the cell sap. The mitochondrial localization of the metabolically active cytoplasmic DNA could be verified. The relative content of the fractions in mitochondria, whole peroxisomes, peroxisome cores, lysosomes, and endoplasmic reticulum was estimated independently by direct measurements on electron micrographs, and by linear programming (based on the assumption that the particles are biochemically homogeneous) of the results of enzyme assays. The two types of estimates agreed very well, except for one fraction in which low cytochrome oxidase activity was associated with mitochondrial damage.

Acid Phosphatase

Uniform depth dose distribution for biological irradiation using negative pions.

A simple, flexible technique has been developed to generate uniform depth dose profiles for the biomedical pion beam at TRIUMF using dynamic momentum control and linear programming. Either the entrance dose or the irradiation time required for a certain dose over the uniform region can be minimised. The dynamic momentum control can operate automatically under computer control even with a highly unstable beam. Cell survival profiles have been obtained for this uniform dose distribution using the gelatin technique. The RBE increases with increasing depth through the uniform dose region.

Animals

A discrete model of bacterial metabolism.

This paper describes a computer model of the intermediary metabolism of bacteria during steady-state growth and during adaptations, e.g. to new carbon sources. Metabolic regulation is represented as a process of optimisation, in which the trend is towards improved metabolic performance. The model uses linear programming techniques for the optimisation. The implementation falls into four phases: (i) assembly of model parameters; (ii) calculations; (iii) storage of solutions and (iv) projection of solutions. The use of a commercial database and a commercial spreadsheet has proved to be of great assistance in the first and third phases. A metabolic map format, with the optional addition of conversion values, names of enzymes or co-factors has been used to project the results in a form convenient for inspection.

Algorithms

Using fragment lengths from incomplete digestion by multiply cleaving enzymes to map antibody binding sites on a protein.

The problem of mapping the positions of the unique binding sites of several monoclonal antibodies on a linear protein structure is considered. Data giving the incidence of binding of individual antibodies to fragments of the protein obtained from it by the incomplete chemical or enzymatic digestion are used to formulate a series of linear programming problems. The solution to these problems shows which orderings of binding sites are possible, and gives upper and lower bounds for the relative positions of the sites.

Algorithms

Detecting and reconstructing breakage-fusion-bridge cycles from long-read sequencing using BFBArchitect.

MOTIVATION: Focal oncogene amplification is a key driver of tumor progression. Remarkably, the increased pathology depends on the context-whether the amplification is extrachromosomal (ecDNA) or intrachromosomal. EcDNA amplifications promote heterogeneity, therapy resistance, and poor prognosis. Focal intrachromosomal amplifications often arise through breakage-fusion-bridge (BFB) cycles, which produce highly rearranged but stable chromosomes. Distinguishing BFB from ecDNA remains challenging due to overlapping genomic signatures. To address this, we present BFBArchitect, a computational method leveraging long-read Oxford Nanopore data to identify BFB sequences consistent with both copy number and structural variations. RESULTS: We provide a novel combinatorial characterization of BFB, which naturally leads to an integer linear programming (ILP) optimization. The ILP optimization generates a BFB sequence that best explains experimentally observed copy numbers and foldback structural variants. We implement this idea in a tool called BFBArchitect, which achieves near-perfect accuracy in distinguishing BFB from non-BFB structures in extensive simulations as well as on 18 validated tumor samples. Moreover, it generates sequence-level BFB reconstructions that provide mechanistic insights into BFB formation, including repair mechanisms with template switching and other structural variants, and recapture of telomere for stabilization. AVAILABILITY AND IMPLEMENTATION: BFBArchitect is available at https://github.com/AmpliconSuite/BFBArchitect.

Sequence Analysis, DNA

Limits to the relationship among recombination, disequilibrium and epistasis in two-locus models.

I determine limits to the equilibrium relationship among epistasis, recombination and disequilibrium in two-locus, two-allele models using linear programming techniques. I show that when allele frequencies are one-half at each locus, the symmetric model is the fitness pattern that generates the most disequilibrium for the smallest level of epistasis. When allele frequencies deviate from one-half much larger levels of epistasis are required to generate similar levels of disequilibrium. I determine the level of epistasis required to generate observed significant levels of disequilibrium in natural populations. The overall implication is that disequilibrium will be large at equilibrium only between strongly interacting, closely linked loci.

Alleles

Disequilibrium, selection, and recombination: limits in two-locus, two-allele models.

All possible combinations of equilibria and fitnesses in two-locus, two-allele, deterministic, discrete-generation selection models are enumerated. This knowledge is used to obtain limits (which can be calculated to arbitrary precision) to the relationships among disequilibrium, selection and recombination for fixed values of allele frequencies. In all cases, the inequality magnitude of rD less than s/10 holds, where r is recombination and D is disequilibrium, and all selection coefficients lie between 1 - s and 1 + s times that of the double heterozygote. Linear programming techniques are used to observed nonzero values of D reported in the literature. One conclusion is that the failure to observe nonzero values of D is not surprising.

Alleles

Amino acid requirements of growing mice: arginine, lysine, tryptophan and phenylalanine.

Linear programmed diets designed to maximize the use of proteins and to minimize the use of free (1-) amino acids, and containing five dietary levels of each amino acid under test, were fed to weanling crossbred Carworth Farms No. 1 x Swiss mice in 14-day growth trials. Arginine dietary levels were 0.1, 0.2, 0.3, 0.4 and 0.7%; lysine: 0.2, 0.3, 0.4, 0.5 and 1.0%; tryptophan: 0.03, 0.07, 0.10, 0.13 and 0.17%; and phenylalanine: 0.10, 0.25, 0.40, 0.55 and 0.89%. Growth, feed consumption and regression-adjusted growth rates indicated the following minimum requirements: arginine less than 0.1% and probably zero, lysine 0.4%, tryptophan 0.1% and phenylalanine 0.4%. The AIN '76 reference diet was included in each amino acid test and resulted in superior growth and feed utilization. It was postulated that the greater content of free amino acids in our diets may have affected the efficiency of feed utilization adversely.

Amino Acids, Essential