Researchers, policymakers and law enforcement agencies across the globe struggle to find effective strategies to control criminal networks. The effectiveness of disruption strategies is known to depend on both network topology and network resilience. However, as these criminal networks operate in secrecy, data-driven knowledge concerning the effectiveness of different criminal network disruption strategies is very limited. By combining computational modeling and social network analysis with unique criminal network intelligence data from the Dutch Police, we discovered, in contrast to common belief, that criminal networks might even become ‘stronger’, after targeted attacks. On the other hand increased efficiency within criminal networks decreases its internal security, thus offering opportunities for law enforcement agencies to target these networks more deliberately. Our results emphasize the importance of criminal network interventions at an early stage, before the network gets a chance to (re-)organize to maximum resilience. In the end disruption strategies force criminal networks to become more exposed, which causes successful network disruption to become a long-term effort.

The recently developed concept of cancer stem cells (CSC) sheds new light on various aspects of tumor growth and progression. Here, we present a mathematical model of malignancies to investigate how a hierarchical organized cancer cell population affects the fundamental properties of solid malignancies. We establish that tumors modeled in a CSC context more faithfully resemble human malignancies and show invasive behavior, whereas tumors without a CSC hierarchy do not. These findings are corroborated by in vitro studies. In addition, we provide evidence that the CSC model is accompanied by highly altered evolutionary dynamics compared with the ones predicted to exist in a stochastic, nonhierarchical tumor model. Our main findings indicate that the CSC model allows for significantly higher tumor heterogeneity, which may affect therapy resistance. Moreover, we show that therapy which fails to target the CSC population is not only unsuccessful in curing the patient, but also promotes malignant features in the recurring tumor. These include rapid expansion, increased invasion, and enhanced heterogeneity. Cancer Res; 70(1); 46–56

The ability of cells to accurately control gene expression levels in response to extracellular cues is limited by the inherently stochastic nature of transcriptional regulation. A change in transcription factor (TF) activity results in changes in the expression of its targets, but the way in which cell-to-cell variability in expression (noise) changes as a function of TF activity, and whether targets of the same TF behave similarly, is not known. Here, we measure expression and noise as a function of TF activity for 16 native targets of the transcription factor Zap1 that are regulated by it through diverse mechanisms. For most activated and repressed Zap1 targets, noise decreases as expression increases. Kinetic modeling suggests that this is due to two distinct Zap1-mediated mechanisms that both change the frequency of transcriptional bursts. Notably, we found that another mechanism of repression by Zap1, which is encoded in the promoter DNA, likely decreases the size of transcriptional bursts, producing a unique transcriptional state characterized by low expression and low noise. In addition, we find that further reduction in noise is achieved when a single TF both activates and represses a single target gene. Our results suggest a global principle whereby at low TF concentrations, the dominant source of differences in expression between promoters stems from differences in burst frequency, whereas at high TF concentrations differences in burst size dominate. Taken together, we show that the precise amount by which noise changes with expression is specific to the regulatory mechanism of transcription and translation that acts at each gene. In response to environmental changes, cells regulate the activity of transcription factors (TFs), which in turn change the expression of dozens of downstream target genes by binding to their promoters. The response of each target gene is determined by the interplay between TF concentration and the context in which TF binding sites occur in each target promoter. To examine the relationship between promoter sequence, mechanism of regulation, and response to TF activity, we measured expression of 16 target genes of a single TF in response to changes in TF concentration in single cells. We found that different native promoters that are all targets of the same TF exhibit diverse responses to changing TF levels in terms of both gene expression level and cell-to-cell variability (noise) in expression. Using computational modeling and mutations of specific promoter elements, we show that the molecular mechanisms of regulation can be inferred by measuring how noise changes with expression. These results show that a single TF can regulate transcription through multiple mechanisms, resulting in similar changes in mean expression but vastly different changes in cell-to-cell variability.

Globally, healthcare systems face major challenges with medicines management and medication adherence. Medication adherence determines medication effectiveness and can be the single most effective intervention for improving health outcomes. In anticipation of growth in eHealth interventions worldwide, we explore the role of eHealth in the patients’ medicines management journey in primary care, focusing on personalisation and intelligent monitoring for greater adherence. eHealth offers opportunities to transform every step of the patient’s medicines management journey. From booking appointments, consultation with a healthcare professional, decision-making, medication dispensing, carer support, information acquisition and monitoring, to learning about medicines and their management in daily life. It has the potential to support personalisation and monitoring and thus lead to better adherence. For some of these dimensions, such as supporting decision-making and providing reminders and prompts, evidence is stronger, but for many others more rigorous research is urgently needed. Given the potential benefits and barriers to eHealth in medicines management, a fine balance needs to be established between evidence-based integration of technologies and constructive experimentation that could lead to a game-changing breakthrough. A concerted, transdisciplinary approach adapted to different contexts, including low- and middle-income contries is required to realise the benefits of eHealth at scale.

Several articles have been written regarding the hydraulic permeability of ordered and disordered fibrous media. Here, we explore wall effects on hydraulic permeabilities for ordered and disordered media using the lattice Boltzmann (LB) simulation method. Simulation results are found to be in excellent agreement with the semi analytic result of Sangani and Acrivos, and simulation results for disordered media are in good agreement with the results of Jackson and James and Higdon and Ford’s fcc lattice. The macroscopic behavior, the hydraulic permeability, shows a distinct connection with the geometry of the system. This connection is explored and elucidated for ordered and disordered media. Finally, hydraulic permeabilities for bounded media at various wall separations are presented for both ordered and disordered media and results are compared with hydraulic permeabilities calculated for the unbounded media, and a phenomenological correlation is presented to facilitate rapid prediction of hydraulic permeabilities for both unbounded and bounded fibrous media.

Calcium ions are the most ubiquitous and versatile signaling molecules in eukaryotic cells. Calcium homeostasis and signaling systems are crucial for both the normal growth of the budding yeast Saccharomyces cerevisiae and the intricate working of the mammalian heart. In this paper, we make a detailed comparison between the calcium homeostasis/signaling networks in yeast cells and those in mammalian cardiac myocytes. This comparison covers not only the components, structure and function of the networks but also includes existing knowledge on the measured and simulated network dynamics using mathematical models. Surprisingly, most of the factors known in the yeast calcium homeostasis/signaling network are conserved and operate similarly in mammalian cells, including cardiac myocytes. Moreover, the budding yeast S. cerevisiae is a simple organism that affords powerful genetic and genomic tools. Thus, exploring and understanding the calcium homeostasis/signaling system in yeast can provide a shortcut to help understand calcium homeostasis/signaling systems in mammalian cardiac myocytes. In turn, this knowledge can be used to help treat relevant human diseases such as pathological cardiac hypertrophy and heart failure.