A multi-modal coarse grained model of DNA flexibility mappable to the atomistic level.

We present a new coarse grained method for the simulation of duplex DNA. The algorithm uses a generalized multi-harmonic model that can represent any multi-normal distribution of helical parameters, thus avoiding caveats of current mesoscopic models for DNA simulation and representing a breakthrough in the field. The method has been parameterized from accurate parmbsc1 atomistic molecular dynamics simulations of all unique tetranucleotide sequences of DNA embedded in long duplexes and takes advantage of the correlation between helical states and backbone configurations to derive atomistic representations of DNA. The algorithm, which is implemented in a simple web interface and in a standalone package reproduces with high computational efficiency the structural landscape of long segments of DNA untreatable by atomistic molecular dynamics simulations.

Modulation of the helical properties of DNA: next-to-nearest neighbour effects and beyond.

We used extensive molecular dynamics simulations to study the structural and dynamic properties of the central d(TpA) step in the highly polymorphic d(CpTpApG) tetranucleotide. Contrary to the assumption of the dinucleotide-model and its nearest neighbours (tetranucleotide-model), the properties of the central d(TpA) step change quite significantly dependent on the next-to-nearest (hexanucleotide) sequence context and in a few cases are modulated by even remote neighbours (beyond next-to-nearest from the central TpA). Our results highlight the existence of previously undescribed dynamical mechanisms for the transmission of structural information into the DNA and demonstrate the existence of certain sequences with special physical properties that can impact on the global DNA structure and dynamics.

The static and dynamic structural heterogeneities of B-DNA: extending Calladine-Dickerson rules.

We present a multi-laboratory effort to describe the structural and dynamical properties of duplex B-DNA under physiological conditions. By processing a large amount of atomistic molecular dynamics simulations, we determine the sequence-dependent structural properties of DNA as expressed in the equilibrium distribution of its stochastic dynamics. Our analysis includes a study of first and second moments of the equilibrium distribution, which can be accurately captured by a harmonic model, but with nonlocal sequence-dependence. We characterize the sequence-dependent choreography of backbone and base movements modulating the non-Gaussian or anharmonic effects manifested in the higher moments of the dynamics of the duplex when sampling the equilibrium distribution. Contrary to prior assumptions, such anharmonic deformations are not rare in DNA and can play a significant role in determining DNA conformation within complexes. Polymorphisms in helical geometries are particularly prevalent for certain tetranucleotide sequence contexts and are always coupled to a complex network of coordinated changes in the backbone. The analysis of our simulations, which contain instances of all tetranucleotide sequences, allow us to extend Calladine-Dickerson rules used for decades to interpret the average geometry of DNA, leading to a set of rules with quantitative predictive power that encompass nonlocal sequence-dependence and anharmonic fluctuations.

The patient-level effect of the cost of Cancer care - financial burden in German Cancer patients.

BACKGROUND: Financial toxicity of cancer has so far been discussed primarily in the US health care system and is associated with higher morbidity and mortality. In European health care systems, the socio-economic impact of cancer is poorly understood. This study investigates the financial burden and patient-reported outcomes of neuroendocrine (NET) or colorectal (CRC) cancer patients at a German Comprehensive Cancer Center. METHODS: This prospective cross-sectional study surveyed 247 advanced stage patients (n = 122 NET/n = 125 CRC) at the National Center for Tumor Diseases, in Germany about cancer-related out-of-pocket costs, income loss, distress, and quality of life. Multiple linear regression analysis was performed to demonstrate the effects of economic deterioration on patients' quality of life and distress. RESULTS: 81% (n = 199) of the patients reported out-of-pocket costs, and 37% (n = 92) income loss as a consequence of their disease. While monthly out-of-pocket costs did not exceed 200€ in 77% of affected patients, 24% of those with income losses reported losing more than 1.200€ per month. High financial loss relative to income was significantly associated with patients' reporting a worse quality of life (p < .05) and more distress (p < .05). CONCLUSIONS: Financial toxicity in third-party payer health care systems like Germany is caused rather by income loss than by co-payments. Distress and reduced quality of life due to financial problems seem to amplify the burden that already results from a cancer diagnosis and treatment. If confirmed at a broader scale, there is a need for targeted support measures at the individual and system level.

Parmbsc1: a refined force field for DNA simulations.

We present parmbsc1, a force field for DNA atomistic simulation, which has been parameterized from high-level quantum mechanical data and tested for nearly 100 systems (representing a total simulation time of ∼ 140 µs) covering most of DNA structural space. Parmbsc1 provides high-quality results in diverse systems. Parameters and trajectories are available at http://mmb.irbbarcelona.org/ParmBSC1/.

Long-timescale dynamics of the Drew-Dickerson dodecamer.

We present a systematic study of the long-timescale dynamics of the Drew-Dickerson dodecamer (DDD: d(CGCGAATTGCGC)2) a prototypical B-DNA duplex. Using our newly parameterized PARMBSC1 force field, we describe the conformational landscape of DDD in a variety of ionic environments from minimal salt to 2 M Na(+)Cl(-) or K(+)Cl(-) The sensitivity of the simulations to the use of different solvent and ion models is analyzed in detail using multi-microsecond simulations. Finally, an extended (10 µs) simulation is used to characterize slow and infrequent conformational changes in DDD, leading to the identification of previously uncharacterized conformational states of this duplex which can explain biologically relevant conformational transitions. With a total of more than 43 µs of unrestrained molecular dynamics simulation, this study is the most extensive investigation of the dynamics of the most prototypical DNA duplex.

MiOS, an integrated imaging and computational strategy to model gene folding with nucleosome resolution.

The linear sequence of DNA provides invaluable information about genes and their regulatory elements along chromosomes. However, to fully understand gene function and regulation, we need to dissect how genes physically fold in the three-dimensional nuclear space. Here we describe immuno-OligoSTORM, an imaging strategy that reveals the distribution of nucleosomes within specific genes in super-resolution, through the simultaneous visualization of DNA and histones. We combine immuno-OligoSTORM with restraint-based and coarse-grained modeling approaches to integrate super-resolution imaging data with Hi-C contact frequencies and deconvoluted micrococcal nuclease-sequencing information. The resulting method, called Modeling immuno-OligoSTORM, allows quantitative modeling of genes with nucleosome resolution and provides information about chromatin accessibility for regulatory factors, such as RNA polymerase II. With Modeling immuno-OligoSTORM, we explore intercellular variability, transcriptional-dependent gene conformation, and folding of housekeeping and pluripotency-related genes in human pluripotent and differentiated cells, thereby obtaining the highest degree of data integration achieved so far to our knowledge.

[The problems of career (re)integration faced by cancer patients]. / Probleme der beruflichen (Re­)Integration von Krebserkrankten: Wie können wir unterstützen?

With the aim of better understanding the enabling and limiting factors regarding staying or returning to work for cancer patients and to test specific measures of support, advisory and survey projects took place at the Robert Bosch Hospital in Stuttgart (RBK), the National Centre for Tumor Diseases in Heidelberg (NCT) as well as partly on behalf of and in cooperation with the Working Group Social Work in Oncology (ASO) of the German Cancer Society e. V. All projects have shown that the problems of career (re)integration faced by cancer patients in treatment, therapy and aftercare need to be taken more into account, as they play an essential role in securing the livelihood of and managing the stress experienced by the patient. Experience with the implementation of specialised counselling (at the NCT) and low-threshold, relationship-oriented support (at the RBK) makes it clear in which direction psychosocial support services, in the context of the clinic, can be expanded to better support cancer patients in their efforts to "stay in life".

[Individual financial burden following a cancer diagnosis from the perspective of social services in Germany]. / Individuelle finanzielle Belastungen infolge einer Krebserkrankung aus der Perspektive von Sozialdiensten in Deutschland.

BACKGROUND: In addition to physical, psychological and social effects, economic effects and the associated financial burden of a cancer diagnosis may also gain in importance during prolonged disease progression. Counselling by social services is an important factor in coping with this burden. METHODS: People employed in social work in oncology were invited to participate in a survey. The survey comprises 16 items on the perception of financial burdens, changes in the relevance of the topic, risk factors and current counselling practice. RESULTS: 81% of the respondents reported that the financial burden arising from a cancer diagnosis is a relevant topic of consultation for at least half of the patients. For 55%, this topic has become more important in recent years, which is due to higher survival rates, an increased number of younger patients, and poorer social security and working conditions. DISCUSSION AND CONCLUSION: Despite comprehensive insurance coverage, the financial burden of cancer patients has also gained in importance in Germany and must be increasingly taken into account in everyday social service counselling. Due to numerous risk factors and complex reasons, further measures are required to enable the early identification of risk constellations and to improve the situation of those affected.

Multiscale simulation of DNA.

DNA is not only among the most important molecules in life, but a meeting point for biology, physics and chemistry, being studied by numerous techniques. Theoretical methods can help in gaining a detailed understanding of DNA structure and function, but their practical use is hampered by the multiscale nature of this molecule. In this regard, the study of DNA covers a broad range of different topics, from sub-Angstrom details of the electronic distributions of nucleobases, to the mechanical properties of millimeter-long chromatin fibers. Some of the biological processes involving DNA occur in femtoseconds, while others require years. In this review, we describe the most recent theoretical methods that have been considered to study DNA, from the electron to the chromosome, enriching our knowledge on this fascinating molecule.