Kinesin and Myosin Motors Compete to Drive Rich Multi-Phase Dynamics in Programmable Cytoskeletal Composites

The cytoskeleton of biological cells relies on a diverse population of motors, filaments, and binding proteins acting in concert to enable non-equilibrium processes ranging from mitosis to chemotaxis. The cytoskeleton’s versatile reconfigurability, programmed by interactions between its constituents, make it a foundational active matter platform. However, current active matter endeavors are limited largely to single force-generating components acting on a single substrate – far from the composite cytoskeleton in live cells. Here, we engineer actin-microtubule composites, driven by kinesin and myosin motors and tuned by crosslinkers, that restructure into diverse morphologies from interpenetrating filamentous networks to de-mixed amorphous clusters. Our Fourier analyses reveal that kinesin and myosin compete to delay kinesin-driven restructuring and suppress de-mixing and flow, while crosslinking accelerates reorganization and promotes actin-microtubule correlations. The phase space of non-equilibrium dynamics falls into three broad classes– slow reconfiguration, fast advective flow, and multi-mode ballistic dynamics – with structure-dynamics relations described by the relative contributions of elastic and dissipative responses to motor-generated forces.

KLF4 Induces Mesenchymal–Epithelial Transition (MET) by Suppressing Multiple EMT-Inducing Transcription Factors

Epithelial–Mesenchymal Plasticity (EMP) refers to reversible dynamic processes where cells can transition from epithelial to mesenchymal (EMT) or from mesenchymal to epithelial (MET) phenotypes. Both these processes are modulated by multiple transcription factors acting in concert. While EMT-inducing transcription factors (TFs)—TWIST1/2, ZEB1/2, SNAIL1/2/3, GSC, and FOXC2—are well-characterized, the MET-inducing TFs are relatively poorly understood (OVOL1/2 and GRHL1/2). Here, using mechanism-based mathematical modeling, we show that transcription factor KLF4 can delay the onset of EMT by suppressing multiple EMT-TFs. Our simulations suggest that KLF4 overexpression can promote a phenotypic shift toward a more epithelial state, an observation suggested by the negative correlation of KLF4 with EMT-TFs and with transcriptomic-based EMT scoring metrics in cancer cell lines. We also show that the influence of KLF4 in modulating the EMT dynamics can be strengthened by its ability to inhibit cell-state transitions at the epigenetic level. Thus, KLF4 can inhibit EMT through multiple parallel paths and can act as a putative MET-TF. KLF4 associates with the patient survival metrics across multiple cancers in a context-specific manner, highlighting the complex association of EMP with patient survival.

KLF4 induces Mesenchymal-Epithelial Transition (MET) by suppressing multiple EMT-inducing transcription factors

Epithelial-Mesenchymal Plasticity (EMP) refers to reversible dynamic processes where cells can transition from epithelial to mesenchymal (EMT) or from mesenchymal to epithelial (MET) phenotypes. Both these processes are modulated by multiple transcription factors acting in concert. While EMT-inducing transcription factors (TFs) - TWIST1/2, ZEB1/2, SNAIL1/2/3, GSC, FOXC2 - are well-characterized, the MET-inducing TFs are relatively poorly understood (OVOL1/2, GRHL1/2). Here, using mechanism-based mathematical modeling, we show that the transcription factor KLF4 can delay the onset of EMT by suppressing multiple EMT-TFs. Our simulations suggest that KLF4 overexpression can promote phenotypic shift toward a more epithelial state, an observation suggested by negative correlation of KLF4 with EMT-TFs and with transcriptomic based EMT scoring metrics in cancer cell lines. We also show that the influence of KLF4 in modulating EMT dynamics can be strengthened by its ability to inhibit cell-state transitions at an epigenetic level. Thus, KLF4 can inhibit EMT through multiple parallel paths and can act as a putative MET-TF. KLF4 associates with patient survival metrics across multiple cancers in a context-specific manner, highlighting the complex association of EMP with patient survival.

Incongruences between nuclear and plastid phylogenies challenge the identification of correlates of diversification in Gentiana in the European Alpine System

Mountains are reservoirs for a tremendous biodiversity which was fostered by a suite of factors acting in concert throughout evolutionary times. These factors can be climatic, geological, or biotic, but the way they combine through time to generate diversity remains unknown. Here, we investigate these factors as correlates of diversification of three closely related sections of Gentiana in the European Alpine System. Based upon phylogenetic approaches coupled with divergence dating and ancestral state reconstructions, we attempted to identify the role of bedrock preferences, chromosome numbers coupled with relative genome sizes estimates, as well as morphological features through time. We also investigated extant climatic preferences using a heavily curated set of occurrence records individually selected for superior precision, and quantified rates of climatic niche evolution in each section. We found that a number of phylogenetic incongruences derail the identification of correlates of diversification, yet a number of patterns persist regardless of the topology considered. All the studied correlates are likely to have contributed to the diversification of Gentiana in Europe, however, their respective importance varied through time and across clades. Chromosomal variation and divergence of climatic preferences appear to correlate with diversification throughout the evolution of European Gentiana (Oligocene to present), whereas shifts in bedrock preferences appear to have been more defining during recent diversification (Pliocene). Overall, a complex interaction among climatic, geological and biotic attributes appear to have supported the diversification of Gentiana across the mountains of Europe, which based upon phylogenetic as well as other evidence, was probably also bolstered by hybridization.

Malware Variant Identification Using Incremental Clustering

Dynamic analysis and pattern matching techniques are widely used in industry, and they provide a straightforward method for the identification of malware samples. Yara is a pattern matching technique that can use sandbox memory dumps for the identification of malware families. However, pattern matching techniques fail silently due to minor code variations, leading to unidentified malware samples. This paper presents a two-layered Malware Variant Identification using Incremental Clustering (MVIIC) process and proposes clustering of unidentified malware samples to enable the identification of malware variants and new malware families. The novel incremental clustering algorithm is used in the identification of new malware variants from the unidentified malware samples. This research shows that clustering can provide a higher level of performance than Yara rules, and that clustering is resistant to small changes introduced by malware variants. This paper proposes a hybrid approach, using Yara scanning to eliminate known malware, followed by clustering, acting in concert, to allow the identification of new malware variants. F1 score and V-Measure clustering metrics are used to evaluate our results.

A globally fragmented and mobile lithosphere on Venus

Venus has been thought to possess a globally continuous lithosphere, in contrast to the mosaic of mobile tectonic plates that characterizes Earth. However, the Venus surface has been extensively deformed, and convection of the underlying mantle, possibly acting in concert with a low-strength lower crust, has been suggested as a source of some surface horizontal strains. The extent of surface mobility on Venus driven by mantle convection, however, and the style and scale of its tectonic expression have been unclear. We report a globally distributed set of crustal blocks in the Venus lowlands that show evidence for having rotated and/or moved laterally relative to one another, akin to jostling pack ice. At least some of this deformation on Venus postdates the emplacement of the locally youngest plains materials. Lithospheric stresses calculated from interior viscous flow models consistent with long-wavelength gravity and topography are sufficient to drive brittle failure in the upper Venus crust in all areas where these blocks are present, confirming that interior convective motion can provide a mechanism for driving deformation at the surface. The limited but widespread lithospheric mobility of Venus, in marked contrast to the tectonic styles indicative of a static lithosphere on Mercury, the Moon, and Mars, may offer parallels to interior–surface coupling on the early Earth, when global heat flux was substantially higher, and the lithosphere generally thinner, than today.

Emergency Politics After Globalization

Exceptional times call for exceptional measures—this formula is all too familiar in the domestic setting. Governments have often played loose with their state's constitution in the name of warding off an urgent threat. But after decades of increasing interconnectedness and emerging transnational governance, today one sees new forms of emergency politics that are cross-border in range. From the European Union to the World Health Organization, from supranational institutions to state governments acting in concert, the logic of emergency is embraced in international contexts, with Covid-19 the latest occasion. This Forum offers an entry-point into this emerging phenomenon. Taking as its point of departure two recent books, it examines the origins, forms, effects and normative stakes of emergency politics beyond the state. Among the matters discussed are the concept of emergency politics, the historical context of its contemporary forms, the patterns of decision-making associated with it, the implications for the legitimacy of transnational institutions, and the constitutional and political ways in which it might be contained. Transnational emergency politics seems likely to remain a central feature of the coming years, and our aim is to further its study in international relations.

The SOS Error-Prone DNA Polymerase V Mutasome and β-Sliding Clamp Acting in Concert on Undamaged DNA and during Translesion Synthesis

In the mid 1970s, Miroslav Radman and Evelyn Witkin proposed that Escherichia coli must encode a specialized error-prone DNA polymerase (pol) to account for the 100-fold increase in mutations accompanying induction of the SOS regulon. By the late 1980s, genetic studies showed that SOS mutagenesis required the presence of two “UV mutagenesis” genes, umuC and umuD, along with recA. Guided by the genetics, decades of biochemical studies have defined the predicted error-prone DNA polymerase as an activated complex of these three gene products, assembled as a mutasome, pol V Mut = UmuD’2C-RecA-ATP. Here, we explore the role of the β-sliding processivity clamp on the efficiency of pol V Mut-catalyzed DNA synthesis on undamaged DNA and during translesion DNA synthesis (TLS). Primer elongation efficiencies and TLS were strongly enhanced in the presence of β. The results suggest that β may have two stabilizing roles: its canonical role in tethering the pol at a primer-3’-terminus, and a possible second role in inhibiting pol V Mut’s ATPase to reduce the rate of mutasome-DNA dissociation. The identification of umuC, umuD, and recA homologs in numerous strains of pathogenic bacteria and plasmids will ensure the long and productive continuation of the genetic and biochemical journey initiated by Radman and Witkin.

Taking Care of Business: Privileging Private Sector Hospitals During the COVID Crisis

In the early days of the COVID crisis, many commentators argued that it presented opportunities for progressive change, notably toward redress of structural inequalities in health. As with the financial slump of 2008, however, such notions have proved almost ridiculously optimistic as it has been capital, through its near symbiosis with the state, that has been best able to respond, with the English government—the devolved nations adopted a markedly different approach—taking every opportunity to ensure the pandemic has proved a bonanza for private-sector healthcare interests. However, this has not just been about individual contracts in, for example, test and trace, vaccination, or personal protective equipment; the crisis has been used to both rescue the private acute market following 2 years of contracted revenues and to provide enormous stimulus for its future growth. This has required the support of several organizations acting in concert, including the NHS Confederation and the Royal Colleges. While the pandemic has served to illuminate such relationships, the author also argues that the oft-recurring governmental praise of the NHS needs to be matched by genuine investment in public hospitals.

The Modular Circuitry of Apicomplexan Cell Division Plasticity

The close-knit group of apicomplexan parasites displays a wide variety of cell division modes, which differ between parasites as well as between different life stages within a single parasite species. The beginning and endpoint of the asexual replication cycles is a ‘zoite’ harboring the defining apical organelles required for host cell invasion. However, the number of zoites produced per division round varies dramatically and can unfold in several different ways. This plasticity of the cell division cycle originates from a combination of hard-wired developmental programs modulated by environmental triggers. Although the environmental triggers and sensors differ between species and developmental stages, widely conserved secondary messengers mediate the signal transduction pathways. These environmental and genetic input integrate in division-mode specific chromosome organization and chromatin modifications that set the stage for each division mode. Cell cycle progression is conveyed by a smorgasbord of positively and negatively acting transcription factors, often acting in concert with epigenetic reader complexes, that can vary dramatically between species as well as division modes. A unique set of cell cycle regulators with spatially distinct localization patterns insert discrete check points which permit individual control and can uncouple general cell cycle progression from nuclear amplification. Clusters of expressed genes are grouped into four functional modules seen in all division modes: 1. mother cytoskeleton disassembly; 2. DNA replication and segregation (D&S); 3. karyokinesis; 4. zoite assembly. A plug-and-play strategy results in the variety of extant division modes. The timing of mother cytoskeleton disassembly is hard-wired at the species level for asexual division modes: it is either the first step, or it is the last step. In the former scenario zoite assembly occurs at the plasma membrane (external budding), and in the latter scenario zoites are assembled in the cytoplasm (internal budding). The number of times each other module is repeated can vary regardless of this first decision, and defines the modes of cell division: schizogony, binary fission, endodyogeny, endopolygeny.