Structural basis of INTAC-regulated transcription

For the majority of expressed eukaryotic genes, RNA polymerase II (Pol II) forms a paused elongation complex (PEC) and undergoes promoter-proximal pausing downstream of the transcription start site. The polymerase either proceeds into productive elongation or undergoes promoter-proximal premature transcription termination. It remains incompletely understood how transcription is regulated at this stage. Here, we determined the structure of PEC bound to INTAC, an Integrator-containing PP2A complex, at near-atomic resolution. The structure shows that INTAC partially wraps around PEC through multiple contacts, permitting the memetic nascent RNA to run into substrate-entry tunnel of the endonuclease subunit INTS11 of INTAC for cleavage. Pol II C-terminal domain (CTD) winds over INTAC backbone module through multiple anchors and is suspended above the phosphatase of INTAC for dephosphorylation. Biochemical analysis shows that INTAC-PEC association requires unphosphorylated CTD and could tolerate CTD phosphorylation, suggesting an INTAC-mediated persistent CTD dephosphorylation followed by reinforcement of the INTAC-PEC complex. Our study reveals how INTAC binds PEC and orchestrates RNA cleavage and CTD dephosphorylation, two critical events in generating premature transcription termination.

Climbing parrots achieve pitch stability using forces and free moments produced by axial-appendicular couples

During vertical climbing, the gravitational moment tends to pitch the animal's head away from the climbing surface and this may be countered by 1) applying a correcting torque at a discrete contact point, or 2) applying opposing horizontal forces at separate contact points to produce a free moment. We tested these potential strategies in small parrots with an experimental climbing apparatus imitating the fine branches and vines of their natural habitat. The birds climbed on a vertical ladder with four instrumented rungs that measured three-dimensional force and torque, representing the first measurements of multiple contacts from a climbing bird. The parrots ascend primarily by pulling themselves upward using the beak and feet. They resist the gravitational pitching moment with a free moment produced by horizontal force couples between the beak and feet during the first third of the stride and the tail and feet during the last third of the stride. The reaction torque from individual rungs did not counter, but exacerbated the gravitational pitching moment, which was countered entirely by the free moment. Possible climbing limitations were explored using two different rung radii, each with low and high friction surfaces. Rung torque was limited in the large-radius, low-friction condition, however, rung condition did not significantly influence free moments produced. These findings have implications for our understanding of avian locomotor modules (i.e., coordinated actions of the head-neck, hindlimbs, and tail), the use of force couples in vertical locomotion, and the evolution of associated structures.

INPP5K and Atlastin-1 maintain the nonuniform distribution of ER–plasma membrane contacts in neurons

In neurons, the ER extends throughout all cellular processes, forming multiple contacts with the plasma membrane (PM) to fine-tune neuronal physiology. However, the mechanisms that regulate the distribution of neuronal ER-PM contacts are not known. Here, we used the Caenorhabditis elegans DA9 motor neuron as our model system and found that neuronal ER-PM contacts are enriched in soma and dendrite and mostly absent in axons. Using forward genetic screen, we identified that the inositol 5-phosphatase, CIL-1 (human INPP5K), and the dynamin-like GTPase, ATLN-1 (human Atlastin-1), help to maintain the non-uniform, somatodendritic enrichment of neuronal ER-PM contacts. Mechanistically, CIL-1 acts upstream of ATLN-1 to maintain the balance between ER tubules and sheets. In mutants of CIL-1 or ATLN-1, ER sheets expand and invade into the axon. This is accompanied by the ectopic formation of axonal ER-PM contacts and defects in axon regeneration following laser-induced axotomy. As INPP5K and Atlastin-1 have been linked to neurological disorders, the unique distribution of neuronal ER-PM contacts maintained by these proteins may support neuronal resilience during the onset and progression of these diseases.

HBO1-MLL interaction promotes AF4/ENL/P-TEFb-mediated leukemogenesis

Leukemic oncoproteins cause uncontrolled self-renewal of hematopoietic progenitors by aberrant gene activation, eventually causing leukemia. However, the molecular mechanism underlying aberrant gene activation remains elusive. Here, we showed that leukemic MLL fusion proteins associate with the HBO1 histone acetyltransferase (HAT) complex through their trithorax homology domain 2 (THD2) in various human cell lines. MLL proteins associated with the HBO1 complex through multiple contacts mediated mainly by the ING4/5 and PHF16 subunits in a chromatin-bound context where histone H3 lysine 4 tri-methylation marks were present. Of the many MLL fusions, MLL-ELL particularly depended on the THD2-mediated association with the HBO1 complex for leukemic transformation. The C-terminal portion of ELL provided a binding platform for multiple factors including AF4, EAF1, and p53. MLL-ELL activated gene expression in murine hematopoietic progenitors by loading an AF4/ENL/P-TEFb (AEP) complex onto the target promoters wherein the HBO1 complex promoted the association with AEP complex over EAF1 and p53. Moreover, the NUP98-HBO1 fusion protein exerted its oncogenic properties via interaction with MLL but not its intrinsic HAT activity. Thus, the interaction between the HBO1 complex and MLL is an important nexus in leukemic transformation, which may serve as a therapeutic target for drug development.

Mechanics of magnetic robots akin to soft beams supported at unanchored contacts

This article presents a novel algorithm to predict the shape and the support configurations of a magnetic robot acting like a supple beam which deforms due to an imposed magnetic field. The soft magnet loosely rests on a flat horizontal surface which provides the pivoting supports to the robot to attain its deformed shape. The key difficulty in analysis of the mechanics is the lack of any prior knowledge about the location of the contacts where the distorted beam finds support from the ground. This paper outlines an algorithm in which different possibilities referred to as modes are checked systematically to locate the placement and the nature of such supports. Consequently, the 2D shape of the soft beam can be determined without any heuristic assumption about where the magnetic robot is touching the solid surface. This work focuses on single contact sections although the algorithm idea is valid for multiple contacts as well. The mathematical theory and the numerical scheme are validated by comparing the simulated results with existing experimentally obtained configurations. Also, the parametric space of system-defining non-dimensional parameters is explored to determine when a transition happens from one mode to another, and which magnetization methods are desirable for higher stability. Through theoretical simulation the results show that a thin rectangular cross-section provides higher deformation when compared to the other two tested shapes (circular and equilateral triangle cross-section).

Multiple Outbreaks Resulting from Asymptomatic Infection in Spreading of COVID-19

In this paper, we establish a compartmental model for the transmission of COVID-19 with both symptomatic and asymptomatic infections. The difference is that in our model, we consider the infection caused by multiple contacts with asymptomatic infected population. Through the dynamic analysis of the model, we found that when there is only one contact with an asymptomatic infected people, the system has a unique threshold to control the disease. When there is two contact with asymptomatic infected population, the system will undergo forward bifurcation, backward bifurcation, saddle-node bifurcation, supercritical Hopf bifurcation, subcritical Hopf bifurcation, and Bogdanov-Takens bifurcation with codimension 2. Finally, we give The complete bifurcation diagram and global phase diagram of the system, and the biological significance of our results are also given.

TemporalRI: subgraph isomorphism in temporal networks with multiple contacts

Temporal networks are graphs where each edge is associated with a timestamp denoting when two nodes interact. Temporal Subgraph Isomorphism (TSI) aims at retrieving all the subgraphs of a temporal network (called target) matching a smaller temporal network (called query), such that matched target edges appear in the same chronological order of corresponding query edges. Few algorithms have been proposed to solve the TSI problem (or variants of it) and most of them are applicable only to small or specific queries. In this paper we present TemporalRI, a new subgraph isomorphism algorithm for temporal networks with multiple contacts between nodes, which is inspired by RI algorithm. TemporalRI introduces the notion of temporal flows and uses them to filter the search space of candidate nodes for the matching. Our algorithm can handle queries of any size and any topology. Experiments on real networks of different sizes show that TemporalRI is very efficient compared to the state-of-the-art, especially for large queries and targets.

A mode I crack with multiple islands of ideal contact between the crack faces: An asymptotic model

The problem of a mode I crack having multiple contacts between the crack faces is considered. In the case of small contact islands of arbitrary shapes, which are arbitrarily located inside the crack, the first-order asymptotic model for the crack opening displacement is constructed using the method of matched asymptotic expansions. The case of a penny-shaped crack has been studied in detail. A scaling hypothesis for the compliance reduction factor is formulated.

Buckling between soft walls: sequential stabilization through contact

Motivated by applications of soft-contact problems such as guidewires used in medical and engineering applications, we consider a compressed rod deforming between two parallel elastic walls. Free elastica buckling modes other than the first are known to be unstable. We find the soft constraining walls to have the effect of sequentially stabilizing higher modes in multiple contacts by a series of bifurcations, in each of which the degree of instability (the index) is decreased by one. Further symmetry-breaking bifurcations in the stabilization process generate solutions with different contact patterns that allow for a classification in terms of binary symbol sequences. In the hard-contact limit, all these bifurcations collapse into highly degenerate ‘contact bifurcations’. For any given wall separation at most a finite number of modes can be stabilized and eventually, under large enough compression, the rod jumps into the inverted straight state. We chart the sequence of events, under increasing compression, leading from the initial straight state in compression to the final straight state in tension, in effect the process of pushing a rod through a cavity. Our results also give new insight into universal features of symmetry-breaking in higher mode elastic deformations. We present this study also as a showcase for a practical approach to stability analysis based on numerical bifurcation theory and without the intimidating mathematical technicalities often accompanying stability analysis in the literature. The method delivers the stability index and can be straightforwardly applied to other elastic stability problems.

UnrealHaptics: Plugins for Advanced VR Interactions in Modern Game Engines

We present UnrealHaptics, a plugin-architecture that enables advanced virtual reality (VR) interactions, such as haptics or grasping in modern game engines. The core is a combination of a state-of-the-art collision detection library with support for very fast and stable force and torque computations and a general device plugin for communication with different input/output hardware devices, such as haptic devices or Cybergloves. Our modular and lightweight architecture makes it easy for other researchers to adapt our plugins to their requirements. We prove the versatility of our plugin architecture by providing two use cases implemented in the Unreal Engine 4 (UE4). In the first use case, we have tested our plugin with a haptic device in different test scenes. For the second use case, we show a virtual hand grasping an object with precise collision detection and handling multiple contacts. We have evaluated the performance in our use cases. The results show that our plugin easily meets the requirements of stable force rendering at 1 kHz for haptic rendering even in highly non-convex scenes, and it can handle the complex contact scenarios of virtual grasping.