Maximizing Free Energy Gain.

Maximizing the amount of work harvested from an environment is important for a wide variety of biological and technological processes, from energy-harvesting processes such as photosynthesis to energy storage systems such as fuels and batteries. Here, we consider the maximization of free energy-and by extension, the maximum extractable work-that can be gained by a classical or quantum system that undergoes driving by its environment. We consider how the free energy gain depends on the initial state of the system while also accounting for the cost of preparing the system.

Multiple cell types support productive infection and dynamic translocation of infectious Ebola virus to the surface of human skin.

Ebola virus (EBOV) causes severe human disease. During late infection, EBOV virions are on the skin's surface; however, the permissive skin cell types and the route of virus translocation to the epidermal surface are unknown. We describe a human skin explant model and demonstrate that EBOV infection of human skin via basal media increases in a time-dependent and dose-dependent manner.

Hippo signaling pathway regulates Ebola virus transcription and egress.

Filovirus-host interactions play important roles in all stages of the virus lifecycle. Here, we identify LATS1/2 kinases and YAP, key components of the Hippo pathway, as critical regulators of EBOV transcription and egress. Specifically, we find that when YAP is phosphorylated by LATS1/2, it localizes to the cytoplasm (Hippo "ON") where it sequesters VP40 to prevent egress.

Ebola Virus Uses Tunneling Nanotubes as an Alternate Route of Dissemination.

Ebola virus (EBOV) disease is marked by rapid virus replication and spread. EBOV enters the cell by macropinocytosis and replicates in the cytoplasm, and nascent virions egress from the cell surface to infect neighboring cells. Here, we show that EBOV uses an alternate route to disseminate: tunneling nanotubes (TNTs).

Contrasting effects of filamin A and B proteins in modulating filovirus entry.

Ebola (EBOV) and Marburg viruses (MARV) cause severe hemorrhagic fever associated with high mortality rates in humans. A better understanding of filovirus-host interactions that regulate the EBOV and MARV lifecycles can provide biological and mechanistic insight critical for therapeutic development. EBOV glycoprotein (eGP) and MARV glycoprotein (mGP) mediate entry into host cells primarily by actin-dependent macropinocytosis.

Observing and braiding topological Majorana modes on programmable quantum simulators.

Electrons are indivisible elementary particles, yet paradoxically a collection of them can act as a fraction of a single electron, exhibiting exotic and useful properties. One such collective excitation, known as a topological Majorana mode, is naturally stable against perturbations, such as unwanted local noise, and can thereby robustly store quantum information. As such, Majorana modes serve as the basic primitive of topological quantum computing, providing resilience to errors.

Chaperone-assisted selective autophagy targets filovirus VP40 as a client and restricts egress of virus particles.

The filovirus VP40 protein directs virion egress, which is regulated either positively or negatively by select VP40-host interactions. We demonstrate that host BAG3 and HSP70 recognize VP40 as a client and inhibit the egress of VP40 virus-like particles (VLPs) by promoting degradation of VP40 via Chaperone-assisted selective autophagy (CASA). Pharmacological inhibition of either the early stage formation of the VP40/BAG3/HSP70 tripartite complex, or late stage formation of autolysosomes, rescued VP40 VLP egress back to WT levels.

Non-canonical proline-tyrosine interactions with multiple host proteins regulate Ebola virus infection.

The Ebola virus VP30 protein interacts with the viral nucleoprotein and with host protein RBBP6 via PPxPxY motifs that adopt non-canonical orientations, as compared to other proline-rich motifs. An affinity tag-purification mass spectrometry approach identified additional PPxPxY-containing host proteins hnRNP L, hnRNPUL1, and PEG10, as VP30 interactors. hnRNP L and PEG10, like RBBP6, inhibit viral RNA synthesis and EBOV infection, whereas hnRNPUL1 enhances.

Compound FC-10696 Inhibits Egress of Marburg Virus.

Marburg virus (MARV) VP40 protein (mVP40) directs egress and spread of MARV, in part, by recruiting specific host WW domain-containing proteins via its conserved PPxY late (L) domain motif to facilitate efficient virus-cell separation. We reported previously that small-molecule compounds targeting the viral PPxY/host WW domain interaction inhibited VP40-mediated egress and spread. Here, we report on the antiviral potency of novel compound FC-10696, which emerged from extensive structure-activity relationship (SAR) of a previously described series of PPxY inhibitors.

Unitary Subharmonic Response and Floquet Majorana Modes.

Detection and manipulation of excitations with non-Abelian statistics, such as Majorana fermions, are essential for creating topological quantum computers. To this end, we show the connection between the existence of such localized particles and the phenomenon of unitary subharmonic response (SR) in periodically driven systems. In particular, starting from highly nonequilibrium initial states, the unpaired Majorana modes exhibit spin oscillations with twice the driving period, are localized, and can have exponentially long lifetimes in clean systems.

Frontline Science: CD40 signaling restricts RNA virus replication in Mϕs, leading to rapid innate immune control of acute virus infection.

Many acute viral infections target tissue Mϕs, yet the mechanisms of Mϕ-mediated control of viruses are poorly understood. Here, we report that CD40 expressed by peritoneal Mϕs restricts early infection of a broad range of RNA viruses. Loss of CD40 expression enhanced virus replication as early as 12-24 h of infection and, conversely, stimulation of CD40 signaling with an agonistic Ab blocked infection.

Angiomotin regulates budding and spread of Ebola virus.

The Ebola virus (EBOV) VP40 matrix protein (eVP40) orchestrates assembly and budding of virions in part by hijacking select WW-domain-bearing host proteins via its PPxY late (L)-domain motif. Angiomotin (Amot) is a multifunctional PPxY-containing adaptor protein that regulates angiogenesis, actin dynamics, and cell migration/motility. Amot also regulates the Hippo signaling pathway via interactions with the WW-domain-containing Hippo effector protein Yes-associated protein (YAP).

Acute Plasmodium Infection Promotes Interferon-Gamma-Dependent Resistance to Ebola Virus Infection.

During the 2013-2016 Ebola virus (EBOV) epidemic, a significant number of patients admitted to Ebola treatment units were co-infected with Plasmodium falciparum, a predominant agent of malaria. However, there is no consensus on how malaria impacts EBOV infection. The effect of acute Plasmodium infection on EBOV challenge was investigated using mouse-adapted EBOV and a biosafety level 2 (BSL-2) model virus.

Modular mimicry and engagement of the Hippo pathway by Marburg virus VP40: Implications for filovirus biology and budding.

Ebola (EBOV) and Marburg (MARV) are members of the Filoviridae family, which continue to emerge and cause sporadic outbreaks of hemorrhagic fever with high mortality rates. Filoviruses utilize their VP40 matrix protein to drive virion assembly and budding, in part, by recruitment of specific WW-domain-bearing host proteins via its conserved PPxY Late (L) domain motif. Here, we screened an array of 115 mammalian, bacterially expressed and purified WW-domains using a PPxY-containing peptide from MARV VP40 (mVP40) to identify novel host interactors.

Emergent Prethermalization Signatures in Out-of-Time Ordered Correlations.

How a many-body quantum system thermalizes-or fails to do so-under its own interaction is a fundamental yet elusive concept. Here we demonstrate nuclear magnetic resonance observation of the emergence of prethermalization by measuring out-of-time ordered correlations. We exploit Hamiltonian engineering techniques to tune the strength of spin-spin interactions and of a transverse magnetic field in a spin chain system, as well as to invert the Hamiltonian sign to reveal out-of-time ordered correlations.

DABMA: A Derivative of ABMA with Improved Broad-Spectrum Inhibitory Activity of Toxins and Viruses.

The small molecule ABMA has been previously shown to protect cells against multiple toxins and pathogens including virus, intracellular bacteria, and parasite. Its mechanism of action is directly associated with host endolysosomal pathway rather than targeting toxin or pathogen itself. However, the relationship of its broad-spectrum anti-infection activity and chemical structure is not yet resolved.

Protein Interaction Mapping Identifies RBBP6 as a Negative Regulator of Ebola Virus Replication.

Ebola virus (EBOV) infection often results in fatal illness in humans, yet little is known about how EBOV usurps host pathways during infection. To address this, we used affinity tag-purification mass spectrometry (AP-MS) to generate an EBOV-host protein-protein interaction (PPI) map. We uncovered 194 high-confidence EBOV-human PPIs, including one between the viral transcription regulator VP30 and the host ubiquitin ligase RBBP6.

Stability of Periodically Driven Topological Phases against Disorder.

In recent experiments, time-dependent periodic fields are used to create exotic topological phases of matter with potential applications ranging from quantum transport to quantum computing. These nonequilibrium states, at high driving frequencies, exhibit the quintessential robustness against local disorder similar to equilibrium topological phases. However, proving the existence of such topological phases in a general setting is an open problem.

Autophagy-Associated Proteins Control Ebola Virus Internalization Into Host Cells.

Ebola virus (EBOV) enters host cells by macropinocytosis, a poorly understood process. Recent studies have suggested that cell factors involved in autophagy, an evolutionally conserved pathway leading to the lysosomal degradation of protein aggregates and organelles during cellular stress, also have roles in macropinocytosis. Here, we demonstrate that autophagy-associated proteins are required for trafficking of EBOV into the cell body.

Robustness and universality of surface states in Dirac materials.

Ballistically propagating topologically protected states harbor exotic transport phenomena of wide interest. Here we describe a nontopological mechanism that produces such states at the surfaces of generic Dirac materials, giving rise to propagating surface modes with energies near the bulk band crossing. The robustness of surface states originates from the unique properties of Dirac-Bloch wavefunctions which exhibit strong coupling to generic boundaries.

Retro-2 and its dihydroquinazolinone derivatives inhibit filovirus infection.

Members of the family Filoviridae cause severe, often fatal disease in humans, for which there are no approved vaccines and only a few experimental drugs tested in animal models. Retro-2, a small molecule that inhibits retrograde trafficking of bacterial and plant toxins inside host cells, has been demonstrated to be effective against a range of bacterial and virus pathogens, both in vitro and in animal models. Here, we demonstrated that Retro-2 and its derivatives, Retro-2.

Observation of Electron Coherence and Fabry-Perot Standing Waves at a Graphene Edge.

Electron surface states in solids are typically confined to the outermost atomic layers and, due to surface disorder, have negligible impact on electronic transport. Here, we demonstrate a very different behavior for surface states in graphene. We probe the wavelike character of these states by Fabry-Perot (FP) interferometry and find that, in contrast to theoretical predictions, these states can propagate ballistically over micron-scale distances.

Mechanisms of Filovirus Entry.

Filovirus entry into cells is complex, perhaps as complex as any viral entry mechanism identified to date. However, over the past 10 years, the important events required for filoviruses to enter into the endosomal compartment and fuse with vesicular membranes have been elucidated (Fig. 1).

Inhibitors of retrograde trafficking active against ricin and Shiga toxins also protect cells from several viruses, Leishmania and Chlamydiales.

Medical countermeasures to treat biothreat agent infections require broad-spectrum therapeutics that do not induce agent resistance. A cell-based high-throughput screen (HTS) against ricin toxin combined with hit optimization allowed selection of a family of compounds that meet these requirements. The hit compound Retro-2 and its derivatives have been demonstrated to be safe in vivo in mice even at high doses.