How motifs condition critical thresholds for tipping cascades in complex networks: Linking Micro- to Macro-scales

In this study, we investigate how specific micro interaction structures (motifs) affect the occurrence of tipping cascades on networks of stylized tipping elements. We compare the properties of cascades in Erd\"os-R\'enyi networks and an exemplary moisture recycling network of the Amazon rainforest. Within these networks, decisive small-scale motifs are the feed forward loop, the secondary feed forward loop, the zero loop and the neighboring loop. Of all motifs, the feed forward loop motif stands out in tipping cascades since it decreases the critical coupling strength necessary to initiate a cascade more than the other motifs. We find that for this motif, the reduction of critical coupling strength is 11% less than the critical coupling of a pair of tipping elements. For highly connected networks, our analysis reveals that coupled feed forward loops coincide with a strong 90% decrease of the critical coupling strength. For the highly clustered moisture recycling network in the Amazon, we observe regions of very high motif occurrence for each of the four investigated motifs suggesting that these regions are more vulnerable. The occurrence of motifs is found to be one order of magnitude higher than in a random Erd\"os-R\'enyi network. This emphasizes the importance of local interaction structures for the emergence of global cascades and the stability of the network as a whole

Dynamics of Tipping Cascades on Complex Networks

Tipping points occur in diverse systems in various disciplines such as ecology, climate science, economy or engineering. Tipping points are critical thresholds in system parameters or state variables at which a tiny perturbation can lead to a qualitative change of the system. Many systems with tipping points can be modeled as networks of coupled multistable subsystems, e.g. coupled patches of vegetation, connected lakes, interacting climate tipping elements or multiscale infrastructure systems. In such networks, tipping events in one subsystem are able to induce tipping cascades via domino effects. Here, we investigate the effects of network topology on the occurrence of such cascades. Numerical cascade simulations with a conceptual dynamical model for tipping points are conducted on Erd\H{o}s-R\'enyi, Watts-Strogatz and Barab\'asi-Albert networks. Additionally, we generate more realistic networks using data from moisture-recycling simulations of the Amazon rainforest and compare the results to those obtained for the model networks. We furthermore use a directed configuration model and a stochastic block model which preserve certain topological properties of the Amazon network to understand which of these properties are responsible for its increased vulnerability. We find that clustering and spatial organization increase the vulnerability of networks and can lead to tipping of the whole network. These results could be useful to evaluate which systems are vulnerable or robust due to their network topology and might help to design or manage systems accordingly.Comment: 22 pages, 12 figure

Selection of Potent Non-Toxic Inhibitory Sequences from a Randomized HIV-1 Specific Lentiviral Short Hairpin RNA Library

RNA interference (RNAi) has been considered as an efficient therapeutic approach against the human immunodeficiency virus type 1 (HIV-1). However, to establish a durable inhibition of HIV-1, multiple effective short hairpin RNAs (shRNAs) need to be stably expressed to prevent the emergence of viral escape variants. In this study, we engineered a randomized lentiviral H1-promoter driven shRNA-library against the viral genome. Potent HIV-1 specific shRNAs were selected by ganciclovir treatment of cell lines stably expressing the cDNA of Herpes Simplex Virus thymidine kinase (HSV-TK) fused to HIV-1 nucleotide sequences. More than 50% of 200 selected shRNAs inhibited an HIV-1 based luciferase reporter assay by more than 70%. Stable expression of some of those shRNAs in an HIV-1 permissive HeLa cell line inhibited infection of wild-type HIV-1 by more than 90%. The combination of a randomized shRNA-library directed against HIV-1 with a live cell selection procedure yielded non-toxic and highly efficient HIV-1 specific inhibitory sequences that could serve as valuable candidates for gene therapy studies

Modelling nonlinear dynamics of interacting tipping elements on complex networks: the PyCascades package

Tipping elements occur in various systems such as in socio-economics, ecology and the climate system. In many cases, the individual tipping elements are not independent of each other, but they interact across scales in time and space. To model systems of interacting tipping elements, we here introduce the PyCascades open source software package for studying interacting tipping elements (https://doi.org/10.5281/zenodo.4153102). PyCascades is an object-oriented and easily extendable package written in the programming language Python. It allows for investigating under which conditions potentially dangerous cascades can emerge between interacting dynamical systems, with a focus on tipping elements. With PyCascades it is possible to use different types of tipping elements such as double-fold and Hopf types and interactions between them. PyCascades can be applied to arbitrary complex network structures and has recently been extended to stochastic dynamical systems. This paper provides an overview of the functionality of PyCascades by introducing the basic concepts and the methodology behind it. In the end, three examples are discussed, showing three different applications of the software package. First, the moisture recycling network of the Amazon rainforest is investigated. Second, a model of interacting Earth system tipping elements is discussed. And third, the PyCascades modelling framework is applied to a global trade network

Circular RNAs of the nucleophosmin (NPM1) gene in acute myeloid leukemia

In acute myeloid leukemia, there is growing evidence for splicing pattern deregulation, including differential expression of linear splice isoforms of the commonly mutated gene nucleophosmin (NPM1). In this study, we detect circular RNAs of NPM1 and quantify circRNA hsa_circ_0075001 in a cohort of NPM1 wild-type and mutated acute myeloid leukemia (n=46). Hsa_circ_0075001 expression correlates positively with total NPM1 expression, but is independent of the NPM1 mutational status. High versus low hsa_circ_0075001 expression defines patient subgroups characterized by distinct gene expression patterns, such as lower expression of components of the Toll-like receptor signaling pathway in high hsa_circ_0075001 expression cases. Global evaluation of circRNA expression in sorted healthy hematopoietic controls (n=10) and acute myeloid leukemia (n=10) reveals circRNA transcripts for 47.9% of all highly expressed genes. While circRNA expression correlates globally with parental gene expression, we identify hematopoietic differentiation-associated as well as acute myeloid leukemia subgroup-specific circRNA signatures

Luria-Delbrück estimation of Turnip mosaic virus mutation rate in vivo

[EN] A potential drawback of recent antiviral therapies based on the transgenic expression of artificial microRNAs is the ease with which viruses may generate escape mutations. Using a variation of the classic Luria-Delbruck fluctuation assay, we estimated that the spontaneous mutation rate in the artificial microRNA (amiR) target of a plant virus was ca.6 x 10(-5) per replication event.This work was supported by grants BFU2009-06993 from the Spanish Ministerio de Ciencia e Innovación, RGP12/2008 from the Human Frontier Science Program Organization, and PROMETEO2010/019 from Generalitat Valenciana to S.F.E.; by CSIC grant 2010TW0015 to J.-A.D.; and by U.S. National Institutes of Health grants R01GM079843-01 and ARRA PDS#35063 and EC grant FP7231807 to P.J.G. F.M. was supported by a fellowship from Universidad Politénica de Valencia, J.H. was supported by a fellowship from the Spanish Ministerio de Ciencia e Innovación, and J.M.C. was contracted under the CSIC JAE-Doc program.De La Iglesia Jordán, F.; Martinez Garcia, F.; Hillung, J.; Cuevas Torrijos, JM.; Gerrish, PJ.; Daros Arnau, JA.; Elena Fito, SF. (2012). Luria-Delbrück estimation of Turnip mosaic virus mutation rate in vivo. Journal of Virology. 86(6):3386-3388. https://doi.org/10.1128/JVI.06909-11S3386338886

Comprehensive CRISPR-Cas9 screens identify genetic determinants of drug responsiveness in multiple myeloma

The introduction of new drugs in the past years has substantially improved outcome in multiple myeloma (MM). However, the majority of patients eventually relapse and become resistant to one or multiple drugs. While the genetic landscape of relapsed/ resistant multiple myeloma has been elucidated, the causal relationship between relapse-specific gene mutations and the sensitivity to a given drug in MM has not systematically been evaluated. To determine the functional impact of gene mutations, we performed combined whole-exome sequencing (WES) of longitudinal patient samples with CRISPR-Cas9 drug resistance screens for lenalidomide, bortezomib, dexamethasone, and melphalan. WES of longitudinal samples from 16 MM patients identified a large number of mutations in each patient that were newly acquired or evolved from a small subclone (median 9, range 1-55), including recurrent mutations in TP53, DNAH5, and WSCD2. Focused CRISPR-Cas9 resistance screens against 170 relapse-specific mutations functionally linked 15 of them to drug resistance. These included cereblon E3 ligase complex members for lenalidomide, structural genes PCDHA5 and ANKMY2 for dexamethasone, RB1 and CDK2NC for bortezomib, and TP53 for melphalan. In contrast, inactivation of genes involved in the DNA damage repair pathway, including ATM, FANCA, RAD54B, and BRCC3, enhanced susceptibility to cytotoxic chemotherapy. Resistance patterns were highly drug specific with low overlap and highly correlated with the treatment-dependent clonal evolution in patients. The functional association of specific genetic alterations with drug sensitivity will help to personalize treatment of MM in the future

The OTUD6B-LIN28B-MYC axis determines the proliferative state in multiple myeloma

Deubiquitylases (DUBs) are therapeutically amenable components of the ubiquitin machinery that stabilize substrate proteins. Their inhibition can destabilize oncoproteins that may otherwise be undruggable. Here, we screened for DUB vulnerabilities in multiple myeloma, an incurable malignancy with dependency on the ubiquitin proteasome system and identified OTUD6B as an oncogene that drives the G1/S-transition. LIN28B, a suppressor of microRNA biogenesis, is specified as a bona fide cell cycle-specific substrate of OTUD6B. Stabilization of LIN28B drives MYC expression at G1/S, which in turn allows for rapid S-phase entry. Silencing OTUD6B or LIN28B inhibits multiple myeloma outgrowth in vivo and high OTUD6B expression evolves in patients that progress to symptomatic multiple myeloma and results in an adverse outcome of the disease. Thus, we link proteolytic ubiquitylation with post-transcriptional regulation and nominate OTUD6B as a potential mediator of the MGUS-multiple myeloma transition, a central regulator of MYC, and an actionable vulnerability in multiple myeloma and other tumors with an activated OTUD6B-LIN28B axis