Mutation accumulation in exponentially growing populations

Stochastic models of mutation accumulation in exponentially growing cellular populations are widely used to quantify cancer and bacterial evolution. Across manifold scenarios, recurrent research questions are: how many cells exist with a given set of alterations, and how long will it take for these cells to appear. These questions have been tackled in special cases, often within a branching processes framework. However, the general situation of cells sequentially acquiring an arbitrary number of mutations which may be selectively advantageous, neutral, or disadvantageous remains unaddressed. Here, we consider this setting in the biologically relevant limiting regimes of large times and small mutation rates. We provide analytic expressions for the number, and arrival time, of cells with $n$ mutations. Universal probability distributions for both quantities are presented, and the consequences of our results on cancer driver mutation accumulation and bacterial fluctuation assays are highlighted

Competing evolutionary paths in growing populations with applications to multidrug resistance

Investigating the emergence of a particular cell type is a recurring theme in models of growing cellular populations. The evolution of resistance to therapy is a classic example. Common questions are: when does the cell type first occur, and via which sequence of steps is it most likely to emerge? For growing populations, these questions can be formulated in a general framework of branching processes spreading through a graph from a root to a target vertex. Cells have a particular fitness value on each vertex and can transition along edges at specific rates. Vertices represents cell states, say \mic{genotypes }or physical locations, while possible transitions are acquiring a mutation or cell migration. We focus on the setting where cells at the root vertex have the highest fitness and transition rates are small. Simple formulas are derived for the time to reach the target vertex and for the probability that it is reached along a given path in the graph. We demonstrate our results on \mic{several scenarios relevant to the emergence of drug resistance}, including: the orderings of resistance-conferring mutations in bacteria and the impact of imperfect drug penetration in cancer.Comment: Minor corrections. Altered titl

Correlations, fluctuations and stability of a finite-size network of coupled oscillators

The incoherent state of the Kuramoto model of coupled oscillators exhibits marginal modes in mean field theory. We demonstrate that corrections due to finite size effects render these modes stable in the subcritical case, i.e. when the population is not synchronous. This demonstration is facilitated by the construction of a non-equilibrium statistical field theoretic formulation of a generic model of coupled oscillators. This theory is consistent with previous results. In the all-to-all case, the fluctuations in this theory are due completely to finite size corrections, which can be calculated in an expansion in 1/N, where N is the number of oscillators. The N -> infinity limit of this theory is what is traditionally called mean field theory for the Kuramoto model.Comment: 25 pages (2 column), 12 figures, modifications for resubmissio

Simple in-line stopped flow photolysis of copper complexes in natural waters using a flow injection system

The development of an in-line digestion system based on simple UV lamp is reported. The effect of photolysis on the preconcentration of copper was investigated using an in-line Chelex-l00 ion-exchange column linked to an atomic absorption spectrometer. Three model ligands, glycine, NTA and EDTA, have been used to demonstrate the effect of the digestion system. In a stopped-flow mode, over 90% of the complexed copper was recovered in the presence of any of the three ligands. When the UV lamp was turned off, this changed to 84, 45 and 2% recovery for the glycine, NTA and EDTA complexed copper, respectively. The ability to analyse samples with the UV lamp on or off means that the device may be used to study the speciation of the copper

The weather report from IRC+10216: Evolving irregular clouds envelop carbon star

High angular resolution images of IRC+10216 are presented in several near-infrared wavelengths spanning more than 8 years. These maps have been reconstructed from interferometric observations obtained at both Keck and the VLT, and also from stellar occultations by the rings of Saturn observed with the Cassini spacecraft. The dynamic inner regions of the circumstellar environment are monitored over eight epochs ranging between 2000 January and 2008 July. The system is shown to experience substantial evolution within this period including the fading of many previously reported persistent features, some of which had been identified as the stellar photosphere. These changes are discussed in the context of existing models for the nature of the underlying star and the circumstellar environment. With access to these new images, we are able to report that none of the previously identified bright spots in fact contains the star, which is buried in its own dust and not directly visible in the near-infrared

Neuroimmune disorders in COVID-19

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the aetiologic agent of the coronavirus disease 2019 (COVID-19), is now rapidly disseminating throughout the world with 147,443,848 cases reported so far. Around 30–80% of cases (depending on COVID-19 severity) are reported to have neurological manifestations including anosmia, stroke, and encephalopathy. In addition, some patients have recognised autoimmune neurological disorders, including both central (limbic and brainstem encephalitis, acute disseminated encephalomyelitis [ADEM], and myelitis) and peripheral diseases (Guillain–Barré and Miller Fisher syndrome). We systematically describe data from 133 reported series on the Neurology and Neuropsychiatry of COVID-19 blog (https://blogs.bmj.com/jnnp/2020/05/01/the-neurology-and-neuropsychiatry-of-covid-19/) providing a comprehensive overview concerning the diagnosis, and treatment of patients with neurological immune-mediated complications of SARS-CoV-2. In most cases the latency to neurological disorder was highly variable and the immunological or other mechanisms involved were unclear. Despite specific neuronal or ganglioside antibodies only being identified in 10, many had apparent responses to immunotherapies. Although the proportion of patients experiencing immune-mediated neurological disorders is small, the total number is likely to be underestimated. The early recognition and improvement seen with use of immunomodulatory treatment, even in those without identified autoantibodies, makes delayed or missed diagnoses risk the potential for long-term disability, including the emerging challenge of post-acute COVID-19 sequelae (PACS). Finally, potential issues regarding the use of immunotherapies in patients with pre-existent neuro-immunological disorders are also discussed

A comparison of collision cross section values obtained via travelling wave ion mobility-mass spectrometry and ultra high performance liquid chromatography-ion mobility-mass spectrometry : application to the characterisation of metabolites in rat urine

A comprehensive Collision Cross Section (CCS) library was obtained via Travelling Wave Ion Guide mobility measurements through direct infusion (DI). The library consists of CCS and Mass Spectral (MS) data in negative and positive ElectroSpray Ionisation (ESI) mode for 463 and 479 endogenous metabolites, respectively. For both ionisation modes combined, TWCCSN2 data were obtained for 542 non-redundant metabolites. These data were acquired on two different ion mobility enabled orthogonal acceleration QToF MS systems in two different laboratories, with the majority of the resulting TWCCSN2 values (from detected compounds) found to be within 1% of one another. Validation of these results against two independent, external TWCCSN2 data sources and predicted TWCCSN2 values indicated to be within 1-2% of these other values. The same metabolites were then analysed using a rapid reversed-phase ultra (high) performance liquid chromatographic (U(H)PLC) separation combined with IM and MS (IM-MS) thus providing retention time (tr), m/z and TWCCSN2 values (with the latter compared with the DI-IM-MS data). Analytes for which TWCCSN2 values were obtained by U(H)PLC-IM-MS showed good agreement with the results obtained from DI-IM-MS. The repeatability of the TWCCSN2 values obtained for these metabolites on the different ion mobility QToF systems, using either DI or LC, encouraged the further evaluation of the U(H)PLC-IM-MS approach via the analysis of samples of rat urine, from control and methotrexate-treated animals, in order to assess the potential of the approach for metabolite identification and profiling in metabolic phenotyping studies. Based on the database derived from the standards 63 metabolites were identified in rat urine, using positive ESI, based on the combination of tr, TWCCSN2 and MS data.</p