Predictions from a stochastic polymer model for the MinDE dynamics in E.coli

The spatiotemporal oscillations of the Min proteins in the bacterium Escherichia coli play an important role in cell division. A number of different models have been proposed to explain the dynamics from the underlying biochemistry. Here, we extend a previously described discrete polymer model from a deterministic to a stochastic formulation. We express the stochastic evolution of the oscillatory system as a map from the probability distribution of maximum polymer length in one period of the oscillation to the probability distribution of maximum polymer length half a period later and solve for the fixed point of the map with a combined analytical and numerical technique. This solution gives a theoretical prediction of the distributions of both lengths of the polar MinD zones and periods of oscillations -- both of which are experimentally measurable. The model provides an interesting example of a stochastic hybrid system that is, in some limits, analytically tractable.Comment: 16 page

Highly Canalized MinD Transfer and MinE Sequestration Explain the Origin of Robust MinCDE-Protein Dynamics

Min-protein oscillations in Escherichia coli are characterized by the remarkable robustness with which spatial patterns dynamically adapt to variations of cell geometry. Moreover, adaption, and therefore proper cell division, is independent of temperature. These observations raise fundamental questions about the mechanisms establishing robust Min oscillations, and about the role of spatial cues, as they are at odds with present models. Here, we introduce a robust model based on experimental data, consistently explaining the mechanisms underlying pole-to-pole, striped, and circular patterns, as well as the observed temperature dependence of the oscillation period. Contrary to prior conjectures, the model predicts that MinD and cardiolipin domains are not colocalized. The transient sequestration of MinE and highly canalized transfer of MinD between polar zones are the key mechanisms underlying oscillations. MinD channeling enhances midcell localization and facilitates stripe formation, revealing the potential optimization process from which robust Min-oscillations originally arose

Functional DNA methylation signatures for autism spectrum disorder genomic risk loci: 16p11.2 deletions and CHD8 variants

Background: Autism spectrum disorder (ASD) is a common and etiologically heterogeneous neurodevelopmental disorder. Although many genetic causes have been identified (\u3e 200 ASD-risk genes), no single gene variant accounts for \u3e 1% of all ASD cases. A role for epigenetic mechanisms in ASD etiology is supported by the fact that many ASD-risk genes function as epigenetic regulators and evidence that epigenetic dysregulation can interrupt normal brain development. Gene-specific DNAm profiles have been shown to assist in the interpretation of variants of unknown significance. Therefore, we investigated the epigenome in patients with ASD or two of the most common genomic variants conferring increased risk for ASD. Genome-wide DNA methylation (DNAm) was assessed using the Illumina Infinium HumanMethylation450 and MethylationEPIC arrays in blood from individuals with ASD of heterogeneous, undefined etiology (n = 52), and individuals with 16p11.2 deletions (16p11.2del, n = 9) or pathogenic variants in the chromatin modifier CHD8 (CHD8 +/-, n = 7). Results: DNAm patterns did not clearly distinguish heterogeneous ASD cases from controls. However, the homogeneous genetically-defined 16p11.2del and CHD8 +/- subgroups each exhibited unique DNAm signatures that distinguished 16p11.2del or CHD8 +/- individuals from each other and from heterogeneous ASD and control groups with high sensitivity and specificity. These signatures also classified additional 16p11.2del (n = 9) and CHD8 (n = 13) variants as pathogenic or benign. Our findings that DNAm alterations in each signature target unique genes in relevant biological pathways including neural development support their functional relevance. Furthermore, genes identified in our CHD8 +/- DNAm signature in blood overlapped differentially expressed genes in CHD8 +/- human-induced pluripotent cell-derived neurons and cerebral organoids from independent studies. Conclusions: DNAm signatures can provide clinical utility complementary to next-generation sequencing in the interpretation of variants of unknown significance. Our study constitutes a novel approach for ASD risk-associated molecular classification that elucidates the vital cross-talk between genetics and epigenetics in the etiology of ASD

Deterministic mechanical model of T-killer cell polarization reproduces the wandering of aim between simultaneously engaged targets

T-killer cells of the immune system eliminate virus-infected and tumorous cells through direct cell-cell interactions. Reorientation of the killing apparatus inside the T cell to the T-cell interface with the target cell ensures specificity of the immune response. The killing apparatus can also oscillate next to the cell-cell interface. When two target cells are engaged by the T cell simultaneously, the killing apparatus can oscillate between the two interface areas. This oscillation is one of the most striking examples of cell movements that give the microscopist an unmechanistic impression of the cell's fidgety indecision. We have constructed a three-dimensional, numerical biomechanical model of the molecular-motor-driven microtubule cytoskeleton that positions the killing apparatus. The model demonstrates that the cortical pulling mechanism is indeed capable of orienting the killing apparatus into the functional position under a range of conditions. The model also predicts experimentally testable limitations of this commonly hypothesized mechanism of T-cell polarization. After the reorientation, the numerical solution exhibits complex, multidirectional, multiperiodic, and sustained oscillations in the absence of any external guidance or stochasticity. These computational results demonstrate that the strikingly animate wandering of aim in T-killer cells has a purely mechanical and deterministic explanation. © 2009 Kim, Maly

Acceptability, reliability, referential distributions and sensitivity to change in the Young Person's Clinical Outcomes in Routine Evaluation (YP-CORE) outcome measure: Replication and refinement

Background: Many outcome measures for young people exist, but the choices for services are limited when seeking measures that (a) are free to use in both paper and electronic format, and (b) have evidence of good psychometric properties. Method: Data on the Young Person's Clinical Outcomes in Routine Evaluation (YP-CORE), completed by young people aged 11-16, are reported for a clinical sample (N = 1269) drawn from seven services and a nonclinical sample (N = 380). Analyses report item omission, reliability, referential distributions and sensitivity to change. Results: The YP-CORE had a very low rate of missing items, with 95.6% of forms at preintervention fully completed. The overall alpha was .80, with the values for all four subsamples (11-13 and 14-16 by gender) exceeding .70. There were significant differences in mean YP-CORE scores by gender and age band, as well as distinct reliable change indices and clinically significant change cut-off points. Conclusions: These findings suggest that the YP-CORE satisfies standard psychometric requirements for use as a routine outcome measure for young people. Its status as a free to use measure and the availability of an increasing number of translations makes the YP-CORE a candidate outcome measure to be considered for routine services