An O(2n) volume molecular algorithm for Hamiltonian path

We design volume-efficient molecular algorithms for all problems in #P, using only reasonable biological operations. In particular, we give a polynomial-time 0(2(n)n2log2n)-volume algorithm to compute the number of Hamiltonian paths in an n-node graph. This improves Adleman's celebrated n!-volume algorithm for finding a single Hamiltonian path.     

Physiological responses to interval training sessions at velocities associated with VO2max

Previous research has indicated that short-duration, high-intensity work intervals performed at velocities associated with maximal oxygen uptake (vVO2max) combined with active recovery intervals may be effective in eliciting improvements in endurance performance. This study was designed to characterize selected physiological responses to short-duration (< or = 60 seconds) interval work performed at velocities corresponding to 100% of vVO2max. Twelve men participated in 3 randomized trials consisting of treadmill running using work (W)/recovery (R) intervals of 15 seconds W/15 seconds R (15/15); 30 seconds W/15 seconds R (30/15); and 60 seconds W/15 seconds R (60/15). Work intervals were performed at 100% of vVO2max, whereas R intervals were performed at 50% of vVO2max. A fourth trial consisting of continuous work (C) at 100% of vVO2max was also performed. All subjects completed the 15/15 and 30/15 trials; however, only 5 of the 12 completed the 60/15 trial. The percentage of VO2max (mean +/- SD) during 15/15 (71.6 +/- 4.2%) was significantly lower (p < or = 0.05) than the percentages during 30/15 (84.6 +/- 4.0%), 60/15 (89.2 +/- 4.2%), or C (87.9 +/- 5.0%). Similar results were found for heart rate and perceived exertion. Blood lactate concentrations following exercise were significantly lower (p < or = 0.05) in 15/15 (7.3 +/- 2.4 mmol x L(-1)) than in the other trials. No significant differences (p > 0.05) existed among 30/15 (11.5 +/- 1.8 mmol x L(-1)), 60/15 (12.5 +/- 1.8 mmol x L(-1)) or C (12.1 +/- 1.8 mmol x L(-1)). High intensity, short-duration 2:1 W/R intervals appear to produce responses that may benefit both aerobic and anaerobic energy system development. A 4:1 W/R ratio may be an upper limit for individuals in the initial phases of interval training.     

Accuracy of popular automatic QT Interval algorithms assessed by a 'Gold Standard' and comparison with a Novel method: computer simulation study

Background

Accurate measurement of the QT interval is very important from a clinical and pharmaceutical drug safety screening perspective. Expert manual measurement is both imprecise and imperfectly reproducible, yet it is used as the reference standard to assess the accuracy of current automatic computer algorithms, which thus produce reproducible but incorrect measurements of the QT interval. There is a scientific imperative to evaluate the most commonly used algorithms with an accurate and objective 'gold standard' and investigate novel automatic algorithms if the commonly used algorithms are found to be deficient.

Methods

This study uses a validated computer simulation of 8 different noise contaminated ECG waveforms (with known QT intervals of 461 and 495 ms), generated from a cell array using Luo-Rudy membrane kinetics and the Crank-Nicholson method, as a reference standard to assess the accuracy of commonly used QT measurement algorithms. Each ECG contaminated with 39 mixtures of noise at 3 levels of intensity was first filtered then subjected to three threshold methods (T1, T2, T3), two T wave slope methods (S1, S2) and a Novel method. The reproducibility and accuracy of each algorithm was compared for each ECG.

Results

The coefficient of variation for methods T1, T2, T3, S1, S2 and Novel were 0.36, 0.23, 1.9, 0.93, 0.92 and 0.62 respectively. For ECGs of real QT interval 461 ms the methods T1, T2, T3, S1, S2 and Novel calculated the mean QT intervals(standard deviations) to be 379.4(1.29), 368.5(0.8), 401.3(8.4), 358.9(4.8), 381.5(4.6) and 464(4.9) ms respectively. For ECGs of real QT interval 495 ms the methods T1, T2, T3, S1, S2 and Novel calculated the mean QT intervals(standard deviations) to be 396.9(1.7), 387.2(0.97), 424.9(8.7), 386.7(2.2), 396.8(2.8) and 493(0.97) ms respectively. These results showed significant differences between means at >95% confidence level. Shifting ECG baselines caused large errors of QT interval with T1 and T2 but no error with Novel.

Conclusion

The algorithms T2, T1 and Novel gave low coefficients of variation for QT measurement. The Novel technique gave the most accurate measurement of QT interval, T3 (a differential threshold method) was the next most accurate by a large margin. The objective and accurate 'gold standard' presented in this paper may be useful to assess new QT measurement algorithms. The Novel algorithm may prove to be more accurate and reliable method to measure the QT interval.     

Algorithms for extracting structured motifs using a suffix tree with an application to promoter and regulatory site consensus identification.

This paper introduces two exact algorithms for extracting conserved structured motifs from a set of DNA sequences. Structured motifs may be described as an ordered collection of p > or = 1 "boxes" (each box corresponding to one part of the structured motif), p substitution rates (one for each box) and p - 1 intervals of distance (one for each pair of successive boxes in the collection). The contents of the boxes--that is, the motifs themselves--are unknown at the start of the algorithm. This is precisely what the algorithms are meant to find. A suffix tree is used for finding such motifs. The algorithms are efficient enough to be able to infer site consensi, such as, for instance, promoter sequences or regulatory sites, from a set of unaligned sequences corresponding to the noncoding regions upstream from all genes of a genome. In particular, both algorithms time complexity scales linearly with N2n where n is the average length of the sequences and N their number. An application to the identification of promoter and regulatory consensus sequences in bacterial genomes is shown.     

Nonparametric confidence interval estimators for heritability and expected selection response

Statistical methods have not been described for comparing estimates of family-mean heritability (H) or expected selection response (R), nor have consistently valid methods been described for estimating R intervals. Nonparametric methods, e.g., delete-one jackknifing, may be used to estimate variances, intervals, and hypothesis test statistics in estimation problems where parametric methods are unsuitable, nonrobust, or undefinable. Our objective was to evaluate normal-approximation jackknife interval estimators for H and R using Monte Carlo simulation. Simulations were done using normally distributed within-family effects and normally, uniformly, and exponentially distributed between-family effects. Realized coverage probabilities for jackknife interval (2) and parametric interval (5) for H were not significantly different from stated probabilities when between-family effects were normally distributed. Coverages for jackknife intervals (3) and (4) for R were not significantly different from stated coverages when between-family effects were normally distributed. Coverages for interval (3) for R were occasionally significantly less than stated when between-family effects were uniformly or exponentially distributed. Coverages for interval (2) for H were occasionally significantly less than stated when between-family effects were exponentially distributed. Thus, intervals (3) and (4) for R and (2) for H were robust. Means of analysis of variance estimates of R were often significantly less than parametric values when the number of families evaluated was 60 or less. Means of analysis of variance estimates of H were consistently significantly less than parametric values. Means of jackknife estimates of H calculated from log transformed point estimates and R calculated from untransformed or log transformed point estimates were not significantly different from parametric values. Thus, jackknife estimators of H and R were unbiased. Delete-one jackknifing is a robust, versatile, and effective statistical method when applied to estimation problems involving variance functions. Jackknifing is especially valuable in hypothesis test estimation problems where the objective is comparing estimates from different populations.     

Optimal sum-of-pairs multiple sequence alignment using incremental Carrillo and Lipman bounds.

Alignment of sequences is an important routine in various areas of science, notably molecular biology. Multiple sequence alignment is a computationally hard optimization problem which involves the consideration of different possible alignments in order to find an optimal one, given a measure of goodness of alignments. Dynamic programming algorithms are generally well suited for the search of optimal alignments, but are constrained by unwieldy space requirements for large numbers of sequences. Carrillo and Lipman devised a method that helps to reduce the search space for an optimal alignment under a sum-of-pairs measure using bounds on the scores of its pairwise projections. In this paper, we generalize Carrillo and Lipman bounds and demonstrate a novel approach for finding optimal sum-of-pairs multiple alignments that allows incremental pruning of the optimal alignment search space. This approach can result in a drastic pruning of the final search space polytope (where we search for the optimal alignment) when compared to Carrillo and Lipman's approach and hence allows many runs that are not feasible with the original method.     

Confidence intervals for the mean of diagnostic test charge data containing zeros

In this paper, we consider the problem of interval estimation for the mean of diagnostic test charges. Diagnostic test charge data may contain zero values, and the nonzero values can often be modeled by a log-normal distribution. Under such a model, we propose three different interval estimation procedures: a percentile-t bootstrap interval based on sufficient statistics and two likelihood-based confidence intervals. For theoretical properties, we show that the two likelihood-based one-sided confidence intervals are only first-order accurate and that the bootstrap-based one-sided confidence interval is second-order accurate. For two-sided confidence intervals, all three proposed methods are second-order accurate. A simulation study in finite-sample sizes suggests all three proposed intervals outperform a widely used minimum variance unbiased estimator (MVUE)-based interval except for the case of one-sided lower end-point intervals when the skewness is very small. Among the proposed one-sided intervals, the bootstrap interval has the best coverage accuracy. For the two-sided intervals, when the sample size is small, the bootstrap method still yields the best coverage accuracy unless the skewness is very small, in which case the bias-corrected ML method has the best accuracy. When the sample size is large, all three proposed intervals have similar coverage accuracy. Finally, we analyze with the proposed methods one real example assessing diagnostic test charges among older adults with depression.     

Fast optimal genome tiling with applications to microarray design and homology search.

In this paper, we consider several variations of the following basic tiling problem: given a sequence of real numbers with two size-bound parameters, we want to find a set of tiles of maximum total weight such that each tiles satisfies the size bounds. A solution to this problem is important to a number of computational biology applications such as selecting genomic DNA fragments for PCR-based amplicon microarrays and performing homology searches with long sequence queries. Our goal is to design efficient algorithms with linear or near-linear time and space in the normal range of parameter values for these problems. For this purpose, we first discuss the solution to a basic online interval maximum problem via a sliding-window approach and show how to use this solution in a nontrivial manner for many of the tiling problems introduced. We also discuss NP-hardness results and approximation algorithms for generalizing our basic tiling problem to higher dimensions. Finally, computational results from applying our tiling algorithms to genomic sequences of five model eukaryotes are reported.     

Critical evaluation of the diagnostic value of systolic time intervals in the diagnosis of functional thyroid diseases. Comparison of results in a highly selected and a non-selected group of patients in relation to the blood PBI and T4I levels.

The value of measuring systolic time intervals for the diagnosis of functional thyroid disorders was studied. We were able to confirm that the systolic time intervals, namely the preejection period (PEP) are significantly shortened in hyperthyroidism and protracted in hypothyroidism. We were able to prove the rectilinear correlation between the PEP interval and Ig PBI in both highly selected and unselected groups of untreated patients with thyroid disorders. We were able to show much lower diagnostic value of other systolic intervals (as Q-S2) and indices (Weissler's index) compared to PEP. We are able to enumerate some pathological cardiovascular states, where the PEP interval is considerably influenced. With due respect to above-mentioned problems, we are convinced that the PEP measurement is of real diagnostic value in the bed-side diagnosis of thyroid disorders, moreover we believe it might help to solve some theoretical problems.     

Removal of deslorelin (Ovuplant) implant 48 h after administration results in normal interovulatory intervals in mares

Deslorelin implants, approved for use in inducing ovulation in mares, have been associated with prolonged interovulatory intervals in some mares. Administration of prostaglandins in the diestrous period, following a deslorelin-induced ovulation, has been reported to increase the incidence of delayed ovulations. The goals of the present study were: (1) to determine the percentage of mares given deslorelin that experience delayed ovulations with or without subsequent prostaglandin treatment, and (2) to determine if removal of the implant 48 h after administration would effect the interval to subsequent ovulation. We considered interovulatory intervals to be prolonged if they were greater than the mean +/- 2 standard deviation (S.D.) of the control group in study 1 and the hCG group in study 2. In study 1, we retrospectively reviewed reproduction records for 278 mares. We either allowed the mare to ovulate spontaneously or induced ovulation using deslorelin acetate implants or hCG. We administered prostaglandin intramuscularly, 5-9 days after ovulation in selected mares in each group. A higher percentage of mares which were induced to ovulate with deslorelin and given prostaglandins had a prolonged interovulatory interval (23.5%; n = 16), as compared to deslorelin-treated mares that did not receive prostaglandins (11.1%; n = 5). In study 2, we induced ovulation in mares with hCG (n = 47), a subcutaneous deslorelin implant via an implanting device provided by the manufacturer (n = 28), or a deslorelin implant via an incision in the neck (n = 43) and we removed the implant 48 h after administration. We administered prostaglandin to all mares 5-9 days after ovulation. In study 2, mares from which the implant was removed had a normal ovulation rate and none had a prolonged interval to ovulation. Administration of prostaglandin after deslorelin treatment was associated with a longer interval from luteolysis to ovulation than that found in mares not treated with deslorelin. Prostaglandin administration during diestrus may have exacerbated the increased interval to ovulation in deslorelin-treated mares. We hypothesize that prolonged secretion of deslorelin from the implant was responsible for the extended interovulatory intervals.     

Contact intervals, survival analysis of epidemic data, and estimation of R(0)

We argue that the time from the onset of infectiousness to infectious contact, which we call the "contact interval," is a better basis for inference in epidemic data than the generation or serial interval. Since contact intervals can be right censored, survival analysis is the natural approach to estimation. Estimates of the contact interval distribution can be used to estimate R(0) in both mass-action and network-based models. We apply these methods to 2 data sets from the 2009 influenza A(H1N1) pandemic.     

Accumulation of cyclin E is not a prerequisite for passage through the restriction point

The restriction point (R) is defined as the point in G(1) after which cells can complete a division cycle without growth factors and divides G(1) into two physiologically different intervals in cycling cells, G(1)-pm (a postmitotic interval with a constant length of 3 to 4 h) and G(1)-ps (a pre-DNA-synthetic interval with a variable length of 1 to 10 h). Cyclin E is a G(1) regulatory protein whose accumulation has been suggested to be critical for passage through R. We have studied cyclin E protein levels in individual cells of asynchronously growing cell populations, with respect to both passage through R and entry into S phase. We found that the postmitotic G(1) cells that had not yet reached R were negative for cyclin E accumulation. On the other hand, cells that had passed R were found to accumulate cyclin E at variable times (1 to 8 h) after passage through R and 2 to 5 h before entry into S. These kinetic data rule out the hypothesis that passage through R is dependent on the accumulation of cyclin E but suggest, instead, the converse, that passage through R is a prerequisite for cyclin E accumulation. Furthermore, we found that most of the cyclin E protein is downregulated within 1 to 2 h after entry into S.     

扬子毛茛和石龙芮的核型研究

报道了浙江省常见的２种毛茛属植物－扬子毛茛和石龙芮的染色体资料,扬子毛茛体细胞染色体数目２ｎ＝３２,核型组成;Ｋ（２ｎ）＝４ｘ＝３２＝１６ｍ＋８ｓｍ＋８ｓｔ。石龙芮体细胞染色体数目２ｎ＝３２,核型组成;Ｋ（２ｎ）＝４ｘ＝３２＝８ｍ＋２４ｓｍ。     

QTL mapping using a memetic algorithm with modifications of BIC as fitness function

The problem of locating quantitative trait loci (QTL) for experimental populations can be approached by multiple regression analysis. In this context variable selection using a modification of the Bayesian Information Criterion (mBIC) has been well established in the past. In this article a memetic algorithm (MA) is introduced to find the model which minimizes the selection criterion. Apart from mBIC also a second modification (mBIC2) is considered, which has the property of controlling the false discovery rate. Given the Bayesian nature of our selection criteria, we are not only interested in finding the best model, but also in computing marker posterior probabilities using all models visited by MA. In a simulation study MA (with mBIC and mBIC2) is compared with a parallel genetic algorithm (PGA) which has been previously suggested for QTL mapping. It turns out that MA in combination with mBIC2 performs best, where determining QTL positions based on marker posterior probabilities yields even better results than using the best model selected by MA. Finally we consider a real data set from the literature and show that MA can also be extended to multiple interval mapping, which potentially increases the precision with which the exact location of QTLs can be estimated.     

Electrofishing results corrected by selectivity functions in stock size estimates of brown trout (Salrno trutta L.) in brooks

To overcome the problems usually met as a consequence of small numbers of fish collected for trout stock size evaluation in small rivers, a selectivity function was developed and tested in two small rivers in western Switzerland. The function takes the form In E = bL ^−k where E is the fishing efficiency, L is the fish length in cm, k is a constant and b is the slope, estimated by regression analysis.
A good fit was obtained for k = 1 (R. Flon de Carrouge) and k = 2 (R. Cerjaule). Individual selectivity functions have to be computed for each survey, because they depend on the operators of the fishing gear and on the physical and biological conditions in the rivers.
The results are discussed in the light of the Petersen mark-recapture method and the De Lury removal method for stock evaluation. The mark-recapture method gives better results when time intervals between successive fish removals are short.     

Combining maxRatio analysis with real-time PCR and its potential application for the prediction of Meloidogyne incognita in field samples

Diagnosing and quantifying plant-parasitic nematodes is critical for efficient nematode management. Several studies have been performed intending to demonstrate nematode quantification via real-time quantitative PCR. However, most of the studies used dilution of DNA templates to make standard curves, while few studies used samples with different nematode numbers to make the standard curve, resulting in a high standard error. The objective of the present study was to develop a high quality standard curve using samples containing different numbers of the root-knot nematode Meloidogyne incognita and evaluate the results of real time qPCR with maxRatio analysis. The results showed that a high quality standard curve was obtained with different nematode numbers using specific primers and cycle threshold (Ct)-PCR (R(2)=0.9962, P<0.001, n=9). With the maxRatio analysis, the fractional cycle number (FCN)-PCR cycle curve and adjusted FCN (FCNadj)-PCR cycle curve had similar patterns as those of the Ct-PCR cycle curve. For quantification of nematodes in field soil samples, qPCR estimations with a FCNadj-PCR cycle standard curve was very close to microscope counting of second-stage juveniles (R(2)=0.9064, P<0.001, n=10), qPCR estimations with a FCN-PCR cycle standard curve was comparably good (R(2)=0.8509, P<0.001, n=10), and the biases with a Ct-PCR cycle standard curve were large (R(2)=0.7154, P<0.001, n=10). Moreover, we found that the concentration of Triton X-100 had less of an effect on FCN as compared to Ct, with delta FCN 0.52, and delta Ct 3.94 at 0.8% Triton. The present study suggests, that combined with maxRatio methods, real time qPCR could be a practical approach for quantifying M. incognita in field samples.     

Chromosome numbers of flowering plants from northern Norway and Svalbard

Chromosome numbers of 25 taxa of flowering plants from northern Norway and Svalbard are reported. Four species and one subspecies, Carex halophila F. Nyl. (2n = ca. 78), C. stenolepis Less. (2n = ca. 80), Salicorniapojarkovae N. Sem. (2n = 36), Alnus incano (L.) Moench ssp. kolaensis (Orlova) Love (2n = 28), and Saxifraga svalbardensis D. O. Øvstedal (2n = ca. 64), have not been studied karyologically before. Chromosome numbers of four additional species are reported for the first time from Norway; those of another six species for the first time from northern Norway. The hybrid Salix herbacea L. (2x) x 5. polaris Wahlenb. (6x) is proved tetraploid and may be fertile. A possible hybrid between Saxifraga hyperborea R. Br. and S. rivularis L. was revealed.     

Different expression of protein kinase A (PKA) regulatory subunits in cortisol-secreting adrenocortical tumors: relationship with cell proliferation

The four regulatory subunits (R1A, R1B, R2A, R2B) of protein kinase A (PKA) are differentially expressed in several cancer cell lines and exert distinct roles in growth control. Mutations of the R1A gene have been found in patients with Carney complex and in a minority of sporadic primary pigmented nodular adrenocortical disease (PPNAD). The aim of this study was to evaluate the expression of PKA regulatory subunits in non-PPNAD adrenocortical tumors causing ACTH-independent Cushing's syndrome and to test the impact of differential expression of these subunits on cell growth. Immunohistochemistry demonstrated a defective expression of R2B in all cortisol-secreting adenomas (n=16) compared with the normal counterpart, while both R1A and R2A were expressed at high levels in the same tissues. Conversely, carcinomas (n=5) showed high levels of all subunits. Sequencing of R1A and R2B genes revealed a wild type sequence in all tissues. The effect of R1/R2 ratio on proliferation was assessed in mouse adrenocortical Y-1 cells. The R2-selective cAMP analogue 8-Cl-cAMP dose-dependently inhibited Y-1 cell proliferation and induced apoptosis, while the R1-selective cAMP analogue 8-HA-cAMP stimulated cell proliferation. Finally, R2B gene silencing induced up-regulation of R1A protein, associated with an increase in cell proliferation. In conclusion, we propose that a high R1/R2 ratio favors the proliferation of well differentiated and hormone producing adrenocortical cells, while unbalanced expression of these subunits is not required for malignant transformation.     

Prevalence of E/A Wave Fusion and A Wave Truncation in DDD Pacemaker Patients with Complete AV Block under Nominal AV Intervals

AimsOptimization of the AV-interval (AVI) in DDD pacemakers improves cardiac hemodynamics and reduces pacemaker syndromes. Manual optimization is typically not performed in clinical routine. In the present study we analyze the prevalence of E/A wave fusion and A wave truncation under resting conditions in 160 patients with complete AV block (AVB) under the pre-programmed AVI. We manually optimized sub-optimal AVI.MethodsWe analyzed 160 pacemaker patients with complete AVB, both in sinus rhythm (AV-sense; n = 129) and under atrial pacing (AV-pace; n = 31). Using Doppler analyses of the transmitral inflow we classified the nominal AVI as: a) normal, b) too long (E/A wave fusion) or c) too short (A wave truncation). In patients with a sub-optimal AVI, we performed manual optimization according to the recommendations of the American Society of Echocardiography.ResultsAll AVB patients with atrial pacing exhibited a normal transmitral inflow under the nominal AV-pace intervals (100%). In contrast, 25 AVB patients in sinus rhythm showed E/A wave fusion under the pre-programmed AV-sense intervals (19.4%; 95% confidence interval (CI): 12.6–26.2%). A wave truncations were not observed in any patient. All patients with a complete E/A wave fusion achieved a normal transmitral inflow after AV-sense interval reduction (mean optimized AVI: 79.4 ± 13.6 ms).ConclusionsGiven the rate of 19.4% (CI 12.6–26.2%) of patients with a too long nominal AV-sense interval, automatic algorithms may prove useful in improving cardiac hemodynamics, especially in the subgroup of atrially triggered pacemaker patients with AV node diseases.     

Comparison of two stocks of mice in spermatogonial response to different conditions of radiation exposure

In a previous report (Generoso et al., 1985) it was shown that the two hybrid stocks of mice, (C3H/R1 x 101/R1)F1 and (SEC/R1 x C57BL/6)F1, differed in their responses to induction of chromosomal aberrations following exposure of the stem-cell spermatogonia to 500 R x 4 (4-week intervals) acute X-rays. The levels of response in the two stocks were paralleled by the effects on the length of the sterile period, which presumably results from stem-cell killing and repopulation. The present study was conducted in order to determine whether the differences between the two stocks in these parameters hold true also for other conditions of radiation exposure. Thus, comparative experiments were conducted using the following acute exposure regimens: 500 R single dose, 500 R + 500 R (24-h interval), 100 R + 900 R (24-h interval), and 500 R x 4 (8-week intervals). The endpoints measured were chromosome rearrangements in diakinesis/metaphase-I meiocytes, embryonic lethality in conceptuses, length of sterile period and testis weight. Trend analysis indicated that higher frequencies of chromosome rearrangements and embryonic lethality were recovered from (C3H/R1 x 101/R1)F1 than from (SEC/R1 x C57BL/6)F1 males, that there were no significant differences between stocks in testis weight reductions, and that there was no consistency in the direction of the significant differences that occurred in the length of the sterile period. A definitive conclusion regarding the possible association between induction of chromosomal aberrations and induction of cell killing awaits direct histological analysis of the stem-cell population.