A Mathematical Programming Formulation for the Budding Yeast Cell Cycle

The budding yeast cell cycle can be modeled by a set of ordinary differential equations with 143 rate constant parameters. The quality of the model (and an associated vector of parameter settings) is measured by comparing simulation results to the experimental data derived from observing the cell cycles of over 100 selected mutated forms. Unfortunately, determining whether the simulated phenotype matches experimental data is difficult since the experimental data tend to be qualitative in nature (i.e., whether the mutation is viable, or which development phase it died in). Because of this, previous methods for automatically comparing simulation results to experimental data used a discontinuous penalty function, which limits the range of techniques available for automated estimation of the differential equation parameters. This paper presents a system of smooth inequality constraints that will be satisfied if and only if the model matches the experimental data. Results are presented for evaluating the mutants with the two most frequent phenotypes. This nonlinear inequality formulation is the first step toward solving a large-scale feasibility problem to determine the ordinary differential equation model parameters

Deterministic Parallel Global Parameter Estimation for a Model of the Budding Yeast Cell Cycle

Two parallel deterministic direct search algorithms are used to find improved parameters for a system of differential equations designed to simulate the cell cycle of budding yeast. Comparing the model simulation results to experimental data is difficult because most of the experimental data is qualitative rather than quantitative. An algorithm to convert simulation results to mutant phenotypes is presented. Vectors of parameters defining the differential equation model are rated by a discontinuous objective function. Parallel results on a 2200 processor supercomputer are presented for a global optimization algorithm, DIRECT, a local optimization algorithm, MADS, and a hybrid of the two

Diagnosing Schistosomiasis by Detection of Cell-Free Parasite DNA in Human Plasma

Bilharzia (schistosomiasis) occurs in the tropics and subtropics and is one of the most important parasite diseases of humans. It is caused by flukes residing in the vessels of the gut or bladder, causing fever, pain, and bleeding. Bladder cancer or esophageal varices may follow. Diagnosis is difficult, requiring detection of parasite eggs in stool, urine, or gut/bladder biopsies. In this paper, we introduce a fundamentally new way of diagnosing bilharzia from the blood. It has been known for almost 20 years that patients with cancer have tumor-derived DNA circulating in their blood, which can be used for diagnostic purposes. During pregnancy, free DNA from the fetus can be detected in motherly blood, which can be used for diagnosing a range of fetal diseases and pregnancy-associated complications. We found that parasite DNA can be detected in the same way in the blood of patients with bilharzia. In patients with early disease, diagnosis was possible earlier than with any other test. DNA could be detected in all patients with active disease in our study. Patients after treatment had significantly lower parasite DNA concentrations and turned negative 1–2 years after treatment. Future studies should implement the method in large cohorts of patients and should define criteria for the confirmation of the success of treatment by comparing the concentration of fluke DNA before and after therapy

Epigenetic modifications in cardiovascular disease

Epigenetics represents a phenomenon of altered heritable phenotypic expression of genetic information occurring without changes in DNA sequence. Epigenetic modifications control embryonic development, differentiation and stem cell (re)programming. These modifications can be affected by exogenous stimuli (e.g., diabetic milieu, smoking) and oftentimes culminate in disease initiation. DNA methylation has been studied extensively and represents a well-understood epigenetic mechanism. During this process cytosine residues preceding a guanosine in the DNA sequence are methylated. CpG-islands are short-interspersed DNA sequences with clusters of CG sequences. The abnormal methylation of CpG islands in the promoter region of genes leads to a silencing of genetic information and finally to alteration of biological function. Emerging data suggest that these epigenetic modifications also impact on the development of cardiovascular disease. Histone modifications lead to the modulation of the expression of genetic information through modification of DNA accessibility. In addition, RNA-based mechanisms (e.g., microRNAs and long non-coding RNAs) influence the development of disease. We here outline the recent work pertaining to epigenetic changes in a cardiovascular disease setting

Three-dimensional super-resolution microscopy of the inactive X chromosome territory reveals a collapse of its active nuclear compartment harboring distinct Xist RNA foci

Background: A Xist RNA decorated Barr body is the structural hallmark of the compacted inactive X territory in female mammals. Using super resolution three-dimensional structured illumination microscopy (3D-SIM) and quantitative image analysis, we compared its ultrastructure with active chromosome territories (CTs) in human and mouse somatic cells, and explored the spatio-temporal process of Barr body formation at onset of inactivation in early differentiating mouse embryonic stem cells (ESCs). Results: We demonstrate that all CTs are composed of structurally linked chromatin domain clusters (CDCs). In active CTs the periphery of CDCs harbors low-density chromatin enriched with transcriptionally competent markers, called the perichromatin region (PR). The PR borders on a contiguous channel system, the interchromatin compartment (IC), which starts at nuclear pores and pervades CTs. We propose that the PR and macromolecular complexes in IC channels together form the transcriptionally permissive active nuclear compartment (ANC). The Barr body differs from active CTs by a partially collapsed ANC with CDCs coming significantly closer together, although a rudimentary IC channel system connected to nuclear pores is maintained. Distinct Xist RNA foci, closely adjacent to the nuclear matrix scaffold attachment factor-A (SAF-A) localize throughout Xi along the rudimentary ANC. In early differentiating ESCs initial Xist RNA spreading precedes Barr body formation, which occurs concurrent with the subsequent exclusion of RNA polymerase II (RNAP II). Induction of a transgenic autosomal Xist RNA in a male ESC triggers the formation of an `autosomal Barr body' with less compacted chromatin and incomplete RNAP II exclusion. Conclusions: 3D-SIM provides experimental evidence for profound differences between the functional architecture of transcriptionally active CTs and the Barr body. Basic structural features of CT organization such as CDCs and IC channels are however still recognized, arguing against a uniform compaction of the Barr body at the nucleosome level. The localization of distinct Xist RNA foci at boundaries of the rudimentary ANC may be considered as snap-shots of a dynamic interaction with silenced genes. Enrichment of SAF-A within Xi territories and its close spatial association with Xist RNA suggests their cooperative function for structural organization of Xi

Creative destruction in science

Drawing on the concept of a gale of creative destruction in a capitalistic economy, we argue that initiatives to assess the robustness of findings in the organizational literature should aim to simultaneously test competing ideas operating in the same theoretical space. In other words, replication efforts should seek not just to support or question the original findings, but also to replace them with revised, stronger theories with greater explanatory power. Achieving this will typically require adding new measures, conditions, and subject populations to research designs, in order to carry out conceptual tests of multiple theories in addition to directly replicating the original findings. To illustrate the value of the creative destruction approach for theory pruning in organizational scholarship, we describe recent replication initiatives re-examining culture and work morality, working parents\u2019 reasoning about day care options, and gender discrimination in hiring decisions. Significance statement It is becoming increasingly clear that many, if not most, published research findings across scientific fields are not readily replicable when the same method is repeated. Although extremely valuable, failed replications risk leaving a theoretical void\u2014 reducing confidence the original theoretical prediction is true, but not replacing it with positive evidence in favor of an alternative theory. We introduce the creative destruction approach to replication, which combines theory pruning methods from the field of management with emerging best practices from the open science movement, with the aim of making replications as generative as possible. In effect, we advocate for a Replication 2.0 movement in which the goal shifts from checking on the reliability of past findings to actively engaging in competitive theory testing and theory building. Scientific transparency statement The materials, code, and data for this article are posted publicly on the Open Science Framework, with links provided in the article