162 research outputs found
Phylogenetic quantification of intra-tumour heterogeneity.
Intra-tumour genetic heterogeneity is the result of ongoing evolutionary change within each cancer. The expansion of genetically distinct sub-clonal populations may explain the emergence of drug resistance, and if so, would have prognostic and predictive utility. However, methods for objectively quantifying tumour heterogeneity have been missing and are particularly difficult to establish in cancers where predominant copy number variation prevents accurate phylogenetic reconstruction owing to horizontal dependencies caused by long and cascading genomic rearrangements. To address these challenges, we present MEDICC, a method for phylogenetic reconstruction and heterogeneity quantification based on a Minimum Event Distance for Intra-tumour Copy-number Comparisons. Using a transducer-based pairwise comparison function, we determine optimal phasing of major and minor alleles, as well as evolutionary distances between samples, and are able to reconstruct ancestral genomes. Rigorous simulations and an extensive clinical study show the power of our method, which outperforms state-of-the-art competitors in reconstruction accuracy, and additionally allows unbiased numerical quantification of tumour heterogeneity. Accurate quantification and evolutionary inference are essential to understand the functional consequences of tumour heterogeneity. The MEDICC algorithms are independent of the experimental techniques used and are applicable to both next-generation sequencing and array CGH data.This is the final published version. It was originally published by PLoS in PLoS Computational Biology here: http://www.ploscompbiol.org/article/info%3Adoi%2F10.1371%2Fjournal.pcbi.1003535
Limits of economy and fidelity for programmable assembly of size-controlled triply-periodic polyhedra
We propose and investigate an extension of the Caspar-Klug symmetry
principles for viral capsid assembly to the programmable assembly of
size-controlled triply-periodic polyhedra, discrete variants of the Primitive,
Diamond, and Gyroid cubic minimal surfaces. Inspired by a recent class of
programmable DNA origami colloids, we demonstrate that the economy of design in
these crystalline assemblies -- in terms of the growth of the number of
distinct particle species required with the increased size-scale (e.g.
periodicity) -- is comparable to viral shells. We further test the role of
geometric specificity in these assemblies via dynamical assembly simulations,
which show that conditions for simultaneously efficient and high-fidelity
assembly require an intermediate degree of flexibility of local angles and
lengths in programmed assembly. Off-target misassembly occurs via incorporation
of a variant of disclination defects, generalized to the case of hyperbolic
crystals. The possibility of these topological defects is a direct consequence
of the very same symmetry principles that underlie the economical design,
exposing a basic tradeoff between design economy and fidelity of programmable,
size controlled assembly.Comment: 15 pages, 5 figures, 6 supporting movies (linked), Supporting
Appendi
Social Preferences and the Efficiency of Bilateral Exchange
Under what conditions do social preferences, such as altruism or a concern for fair outcomes, generate efficient trade? I analyze theoretically a simple bilateral exchange game: Each player sequentially takes an action that reduces his own material payoff but increases the other player’s. Each player’s preferences may depend on both his/her own material payoff and the other player’s. I identify necessary conditions and sufficient conditions on the players’ preferences for the outcome of their interaction to be Pareto efficient. The results have implications for interpreting the rotten kid theorem, gift exchange in the laboratory, and gift exchange in the field
Efficient low-order approximation of first-passage time distributions
We consider the problem of computing first-passage time distributions for
reaction processes modelled by master equations. We show that this generally
intractable class of problems is equivalent to a sequential Bayesian inference
problem for an auxiliary observation process. The solution can be approximated
efficiently by solving a closed set of coupled ordinary differential equations
(for the low-order moments of the process) whose size scales with the number of
species. We apply it to an epidemic model and a trimerisation process, and show
good agreement with stochastic simulations.Comment: 5 pages, 3 figure
Age-dependent parathormone levels and different CKD-MBD treatment practices of dialysis patients in Hungary - results from a nationwide clinical audit
BACKGROUND: Achieving target levels of laboratory parameters of
bone and mineral metabolism in chronic kidney disease (CKD)
patients is important but also difficult in those living with
end-stage kidney disease. This study aimed to determine if there
are age-related differences in chronic kidney disease-mineral
and bone disorder (CKD-MBD) characteristics, including treatment
practice in Hungarian dialysis patients. METHODS: Data were
collected retrospectively from a large cohort of dialysis
patients in Hungary. Patients on hemodialysis and peritoneal
dialysis were also included. The enrolled patients were
allocated into two groups based on their age (=65
years). Characteristics of the age groups and differences in
disease-related (epidemiology, laboratory, and treatment
practice) parameters between the groups were analyzed. RESULTS:
A total of 5008 patients were included in the analysis and the
mean age was 63.4+/-14.2 years. A total of 47.2% of patients
were women, 32.8% had diabetes, and 11.4% were on peritoneal
dialysis. Diabetes (37.9% vs 27.3%), bone disease (42.9% vs
34.1%), and soft tissue calcification (56.3% vs 44.7%) were more
prevalent in the older group than the younger group (p<0.001 for
all). We found an inverse relationship between age and
parathyroid hormone (PTH) levels (p<0.001). Serum PTH levels
were lower in patients with diabetes compared with those without
diabetes below 80 years (p<0.001). Diabetes and age were
independently associated with serum PTH levels (interaction:
diabetes x age groups, p=0.138). Older patients were more likely
than younger patients to achieve laboratory target ranges for
each parameter (Ca: 66.9% vs 62.1%, p<0.001; PO4: 52.6% vs
49.2%, p<0.05; and PTH: 50.6% vs 46.6%, p<0.01), and for
combined parameters (19.8% vs 15.8%, p<0.001). Older patients
were less likely to receive related medication than younger
patients (66.9% vs 79.7%, p<0.001). CONCLUSIONS: The achievement
of laboratory target ranges for bone and mineral metabolism and
clinical practice in CKD depends on the age of the patients. A
greater proportion of older patients met target criteria and
received less medication compared with younger patients
Screening and diagnostic breast MRI:how do they impact surgical treatment? Insights from the MIPA study
Objectives: To report mastectomy and reoperation rates in women who had breast MRI for screening (S-MRI subgroup) or diagnostic (D-MRI subgroup) purposes, using multivariable analysis for investigating the role of MRI referral/nonreferral and other covariates in driving surgical outcomes. Methods: The MIPA observational study enrolled women aged 18-80 years with newly diagnosed breast cancer destined to have surgery as the primary treatment, in 27 centres worldwide. Mastectomy and reoperation rates were compared using non-parametric tests and multivariable analysis. Results: A total of 5828 patients entered analysis, 2763 (47.4%) did not undergo MRI (noMRI subgroup) and 3065 underwent MRI (52.6%); of the latter, 2441/3065 (79.7%) underwent MRI with preoperative intent (P-MRI subgroup), 510/3065 (16.6%) D-MRI, and 114/3065 S-MRI (3.7%). The reoperation rate was 10.5% for S-MRI, 8.2% for D-MRI, and 8.5% for P-MRI, while it was 11.7% for noMRI (p ≤ 0.023 for comparisons with D-MRI and P-MRI). The overall mastectomy rate (first-line mastectomy plus conversions from conserving surgery to mastectomy) was 39.5% for S-MRI, 36.2% for P-MRI, 24.1% for D-MRI, and 18.0% for noMRI. At multivariable analysis, using noMRI as reference, the odds ratios for overall mastectomy were 2.4 (p < 0.001) for S-MRI, 1.0 (p = 0.957) for D-MRI, and 1.9 (p < 0.001) for P-MRI. Conclusions: Patients from the D-MRI subgroup had the lowest overall mastectomy rate (24.1%) among MRI subgroups and the lowest reoperation rate (8.2%) together with P-MRI (8.5%). This analysis offers an insight into how the initial indication for MRI affects the subsequent surgical treatment of breast cancer. Key points: • Of 3065 breast MRI examinations, 79.7% were performed with preoperative intent (P-MRI), 16.6% were diagnostic (D-MRI), and 3.7% were screening (S-MRI) examinations. • The D-MRI subgroup had the lowest mastectomy rate (24.1%) among MRI subgroups and the lowest reoperation rate (8.2%) together with P-MRI (8.5%). • The S-MRI subgroup had the highest mastectomy rate (39.5%) which aligns with higher-than-average risk in this subgroup, with a reoperation rate (10.5%) not significantly different to that of all other subgroups
Spike-Timing Theory of Working Memory
Working memory (WM) is the part of the brain's memory system that provides temporary storage and manipulation of information necessary for cognition. Although WM has limited capacity at any given time, it has vast memory content in the sense that it acts on the brain's nearly infinite repertoire of lifetime long-term memories. Using simulations, we show that large memory content and WM functionality emerge spontaneously if we take the spike-timing nature of neuronal processing into account. Here, memories are represented by extensively overlapping groups of neurons that exhibit stereotypical time-locked spatiotemporal spike-timing patterns, called polychronous patterns; and synapses forming such polychronous neuronal groups (PNGs) are subject to associative synaptic plasticity in the form of both long-term and short-term spike-timing dependent plasticity. While long-term potentiation is essential in PNG formation, we show how short-term plasticity can temporarily strengthen the synapses of selected PNGs and lead to an increase in the spontaneous reactivation rate of these PNGs. This increased reactivation rate, consistent with in vivo recordings during WM tasks, results in high interspike interval variability and irregular, yet systematically changing, elevated firing rate profiles within the neurons of the selected PNGs. Additionally, our theory explains the relationship between such slowly changing firing rates and precisely timed spikes, and it reveals a novel relationship between WM and the perception of time on the order of seconds
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