Lower bounds on multiple sequence alignment using exact 3-way alignment

<p>Abstract</p> <p>Background</p> <p>Multiple sequence alignment is fundamental. Exponential growth in computation time appears to be inevitable when an optimal alignment is required for many sequences. Exact costs of optimum alignments are therefore rarely computed. Consequently much effort has been invested in algorithms for alignment that are heuristic, or explore a restricted class of solutions. These give an upper bound on the alignment cost, but it is equally important to determine the quality of the solution obtained. In the absence of an optimal alignment with which to compare, lower bounds may be calculated to assess the quality of the alignment. As more effort is invested in improving upper bounds (alignment algorithms), it is therefore important to improve lower bounds as well. Although numerous cost metrics can be used to determine the quality of an alignment, many are based on sum-of-pairs (SP) measures and their generalizations.</p> <p>Results</p> <p>Two standard and two new methods are considered for using exact 2-way and 3-way alignments to compute lower bounds on total SP alignment cost; one new method fares well with respect to accuracy, while the other reduces the computation time. The first employs exhaustive computation of exact 3-way alignments, while the second employs an efficient heuristic to compute a much smaller number of exact 3-way alignments. Calculating all 3-way alignments exactly and computing their average improves lower bounds on sum of SP cost in <it>v</it>-way alignments. However judicious selection of a subset of all 3-way alignments can yield a further improvement with minimal additional effort. On the other hand, a simple heuristic to select a random subset of 3-way alignments (a random packing) yields accuracy comparable to averaging all 3-way alignments with substantially less computational effort.</p> <p>Conclusion</p> <p>Calculation of lower bounds on SP cost (and thus the quality of an alignment) can be improved by employing a mixture of 3-way and 2-way alignments.</p

Oncogenic ERBB3 Mutations in Human Cancers

SummaryThe human epidermal growth factor receptor (HER) family of tyrosine kinases is deregulated in multiple cancers either through amplification, overexpression, or mutation. ERBB3/HER3, the only member with an impaired kinase domain, although amplified or overexpressed in some cancers, has not been reported to carry oncogenic mutations. Here, we report the identification of ERBB3 somatic mutations in ∼11% of colon and gastric cancers. We found that the ERBB3 mutants transformed colonic and breast epithelial cells in a ligand-independent manner. However, the mutant ERBB3 oncogenic activity was dependent on kinase-active ERBB2. Furthermore, we found that anti-ERBB antibodies and small molecule inhibitors effectively blocked mutant ERBB3-mediated oncogenic signaling and disease progression in vivo

The First Data Release of the Sloan Digital Sky Survey

The Sloan Digital Sky Survey has validated and made publicly available its First Data Release. This consists of 2099 square degrees of five-band (u, g, r, i, z) imaging data, 186,240 spectra of galaxies, quasars, stars and calibrating blank sky patches selected over 1360 square degrees of this area, and tables of measured parameters from these data. The imaging data go to a depth of r ~ 22.6 and are photometrically and astrometrically calibrated to 2% rms and 100 milli-arcsec rms per coordinate, respectively. The spectra cover the range 3800--9200 A, with a resolution of 1800--2100. Further characteristics of the data are described, as are the data products themselves.Comment: Submitted to The Astronomical Journal. 16 pages. For associated documentation, see http://www.sdss.org/dr

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

A note regarding extensions of fixed point theorems involving two metrics via an analysis of iterated functions

The purpose of this work is to advance the current state of mathematical knowledge regarding fixed point theorems of functions. Such ideas have historically enjoyed many applications, for example, to the qualitative and quantitative understanding of differential, difference and integral equations. Herein, we extend an established result due to Rus [Studia Univ. Babes-Bolyai Math., 22, 1977, 40–42] that involves two metrics to ensure wider classes of functions admit a unique fixed point. In contrast to the literature, a key strategy herein involves placing assumptions on the iterations of the function under consideration, rather than on the function itself. In taking this approach we form new advances in fixed point theory under two metrics and establish interesting connections between previously distinct theorems, including those of Rus [Studia Univ. Babes-Bolyai Math., 22, 1977, 40–42], Caccioppoli [Rend. Acad. Naz. Linzei. 11, 1930, 31–49] and Bryant [Am. Math. Month. 75, 1968, 399–400]. Our results make progress towards a fuller theory of fixed points of functions under two metrics. Our work lays the foundations for others to potentially explore applications of our new results to form existence and uniqueness of solutions to boundary value problems, integral equations and initial value problems. References Almuthaybiri, S. S. and C. C. Tisdell. ``Global existence theory for fractional differential equations: New advances via continuation methods for contractive maps''. Analysis, 39(4):117–128, 2019. doi:10.1515/anly-2019-0027 Almuthaybiri, S. S. and C. C. Tisdell. ``Sharper existence and uniqueness results for solutions to third-order boundary value problems, mathematical modelling and analysis''. Math. Model. Anal. 25(3):409–420, 2020. doi:10.3846/mma.2020.11043 Banach, S. ``Sur les operations dans les ensembles abstraits et leur application aux equations integrales''. Fund. Math., 3:133–181 1922. doi:10.4064/fm-3-1-133-181 Brouwer, L. E. J. ``Ueber Abbildungen von Mannigfaltigkeiten''. Math. Ann. 71:598, 1912. doi:10.1007/BF01456812 Bryant, V. W. ``A remark on a fixed point theorem for iterated mappings'' Am. Math. Month. 75: 399–400, 1968. doi:10.2307/2313440 Caccioppoli, R. ``Un teorema generale sullesistenza de elemente uniti in una transformazione funzionale''. Rend. Acad. Naz. Linzei. 11:31–49, 1930. Goebel, K., and W. A. Kirk. Topics in metric fixed point theory. Cambridge University Press, 1990, doi:10.1017/CBO9780511526152 Leray, J., and J. Schauder. ``Topologie et equations fonctionnelles''. Ann. Sci. Ecole Norm. Sup. 51:45–78, 1934. doi:10.24033/asens.836 O'Regan, D. and R. Precup. Theorems of Leray–Schauder type and applications, Series in Mathematical Analysis and Applications, Vol. 3. CRC Press, London, 2002. doi:10.1201/9781420022209 Rus, I. A. ``On a fixed point theorem of Maia''. Studia Univ. Babes-Bolyai Math. 22:40–42, 1977. Schaefer, H. H. ``Ueber die Methode der a priori-Schranken''. Math. Ann. 129:415–416, 1955. doi:10.1007/bf01362380 Tisdell, C. C. ``When do fractional differential equations have solutions that are bounded by the Mittag-Leffler function?'' Fract. Calc. Appl. Anal. 18(3):642–650, 2015. doi:10.1515/fca-2015-0039 Tisdell, C. C. ``A note on improved contraction methods for discrete boundary value problems.'' J. Diff. Eq. Appl. 18(10):1773–1777, 2012. doi:10.1080/10236198.2012.681781 Tisdell, C. C. ``On the application of sequential and fixed-point methods to fractional differential equations of arbitrary order.'' J. Int. Eq. Appl. 24(2):283–319, 2012. doi:10.1216/JIE-2012-24-2-283 Ehrnstrom, M., Tisdell, C. C. and E. Wahlen. ``Asymptotic integration of second-order nonlinear difference equations.'' Glasg. Math. J. 53(2):223–243, 2011. doi:10.1017/S0017089510000650 Erbe, L., A. Peterson and C. C. Tisdell. ``Basic existence, uniqueness and approximation results for positive solutions to nonlinear dynamic equations on time scales.'' Nonlin. Anal. 69(7):2303–2317, 2008. doi:10.1016/j.na.2007.08.010 Tisdell, C. C. and A. Zaidi. ``Basic qualitative and quantitative results for solutions to nonlinear, dynamic equations on time scales with an application to economic modelling.'' Nonlin. Anal. 68(11):3504–3524, 2008. doi:10.1016/j.na.2007.03.043 Tisdell, C. C. ``Improved pedagogy for linear differential equations by reconsidering how we measure the size of solutions.'' Int.. J. Math. Ed. Sci. Tech. 48(7):1087–1095, 2017. doi:10.1080/0020739X.2017.1298856 Tisdell, C. C. ``On Picard's iteration method to solve differential equations and a pedagogical space for otherness.'' Int. J. Math. Ed. Sci. Tech. 50(5):788–799, 2019. doi:10.1080/0020739X.2018.1507051 Zeidler, E. Nonlinear functional analysis and its applications. Springer-Verlag, New York, 1986. doi:10.1007/978-1-4612-4838-

Steiner Triple Systems of Order 19 with Nontrivial Automorphism Group

There are 172,248 Steiner triple systems of order 19 having a nontrivial automorphism group. Computational methods suitable for generating these designs are developed