Next generation sequencing has enabled systematic discovery of mutational spectra in cancer samples. Here, we used whole genome sequencing to characterize somatic mutations and structural variation in a primary acral melanoma and its lymph node metastasis. Our data show that the somatic mutational rates in this acral melanoma sample pair were more comparable to the rates reported in cancer genomes not associated with mutagenic exposure than in the genome of a melanoma cell line or the transcriptome of melanoma short-term cultures. Despite the perception that acral skin is sun-protected, the dominant mutational signature in these samples is compatible with damage due to ultraviolet light exposure. A nonsense mutation in ERCC5 discovered in both the primary and metastatic tumors could also have contributed to the mutational signature through accumulation of unrepaired dipyrimidine lesions. However, evidence of transcription-coupled repair was suggested by the lower mutational rate in the transcribed regions and expressed genes. The primary and the metastasis are highly similar at the level of global gene copy number alterations, loss of heterozygosity and single nucleotide variation (SNV). Furthermore, the majority of the SNVs in the primary tumor were propagated in the metastasis and one nonsynonymous coding SNV and one splice site mutation appeared to arise de novo in the metastatic lesion.

This review provides a comprehensive description of the self-guided Langevin dynamics (SGLD) and the self-guided molecular dynamics (SGMD) methods and their applications. Example systems are included to provide guidance on optimal application of these methods in simulation studies. SGMD/SGLD has enhanced ability to overcome energy barriers and accelerate rare events to affordable time scales. It has been demonstrated that with moderate parameters, SGLD can routinely cross energy barriers of 20 kT at a rate that molecular dynamics (MD) or Langevin dynamics (LD) crosses 10 kT barriers. The core of these methods is the use of local averages of forces and momenta in a direct manner that can preserve the canonical ensemble. The use of such local averages results in methods where low frequency motion "borrows" energy from high frequency degrees of freedom when a barrier is approached and then returns that excess energy after a barrier is crossed. This self-guiding effect also results in an accelerated diffusion to enhance conformational sampling efficiency. The resulting ensemble with SGLD deviates in a small way from the canonical ensemble, and that deviation can be corrected with either an on-the-fly or a post processing reweighting procedure that provides an excellent canonical ensemble for systems with a limited number of accelerated degrees of freedom. Since reweighting procedures are generally not size extensive, a newer method, SGLDfp, uses local averages of both momenta and forces to preserve the ensemble without reweighting. The SGLDfp approach is size extensive and can be used to accelerate low frequency motion in large systems, or in systems with explicit solvent where solvent diffusion is also to be enhanced. Since these methods are direct and straightforward, they can be used in conjunction with many other sampling methods or free energy methods by simply replacing the integration of degrees of freedom that are normally sampled by MD or LD.

Abstract This paper offers a geometric framework for modeling port-Hamiltonian systems on discrete manifolds. The simplicial Dirac structure, capturing the topological laws of the system, is defined in terms of primal and dual cochains related by the coboundary operators. This finite-dimensional Dirac structure, as discrete analogue of the canonical Stokes-Dirac structure, allows for the formulation of finite-dimensional port-Hamiltonian systems that emulate the behaviour of the open distributed-parameter systems with Hamiltonian dynamics.

Background: In University Clinical Center, Department of Obstetrics and Gynaecology is using reference data from 1974 developed for the infants born in Belgrade (Serbia). It estimates the standards of term infants for neonatal weight, length and head circumference. Aim: This study was create to develop charts for birth weight, lenght and head circumference specific to gestational age, gender and parity for term singleton infants in Tuzla Canton. Methods: The study was conducted at University Clinical Center Tuzla, Department of Obstetrics and Gynecology, a primary obstetrical care facility for residents of Tuzla Canton over the one-year period. During the one year study period, 01.01.- 31.12.2009, there were 4106 infants born at 37th to 41th weeks of gestation (GW), 2168 (52.8 %) males and 1938 (47.2%) females. We analysed gestational age, birth weights, body length and head circumference. Results: Females infants of primiparae, born at 40th gestational week, had the lowest median birth weight, 3500 g, followed by female infants of multiparae, 3640 g, and male infants of primiparae, 3650 g. The greatest median birth weight, 3730 g, had male infants of multiparae. Median birth length value at the 40th gestational week for male infants of primiparae and multiparae, as well as female infants of multiparae is the same, 55 cm, while is lower in female infants of primiparae (54 cm). There is no difference in median head circumference at the 40th gestational week between female infants of primiparae and multiparae, and male infants of primiparae (35 cm). Mean birth weight and length of liveborn infants at 37. to 41. gestational week differed significantly between certain parities (F=8,723, Df=2, p<0,001; F=3,292, Df=2, p=0,037, respectively). No significant difference was found for head circumference (F=0,983, Df=2, p=0,374). Conclusion: The average birth weight of infants within Tuzla Canton is bigger in comparison with the centile that have been used so far.