Potential COVID-19 therapeutics from a rare disease: weaponizing lipid dysregulation to combat viral infectivity.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2 has resulted in the death of more than 328,000 persons worldwide in the first 5 months of 2020. Herculean efforts to rapidly design and produce vaccines and other antiviral interventions are ongoing. However, newly evolving viral mutations, the prospect of only temporary immunity, and a long path to regulatory approval pose significant challenges and call for a common, readily available, and inexpensive treatment. Strategic drug repurposing combined with rapid testing of established molecular targets could provide a pause in disease progression. SARS-CoV-2 shares extensive structural and functional conservation with SARS-CoV-1, including engagement of the same host cell receptor (angiotensin-converting enzyme 2) localized in cholesterol-rich microdomains. These lipid-enveloped viruses encounter the endosomal/lysosomal host compartment in a critical step of infection and maturation. Niemann-Pick type C (NP-C) disease is a rare monogenic neurodegenerative disease caused by deficient efflux of lipids from the late endosome/lysosome (LE/L). The NP-C disease-causing gene (NPC1) has been strongly associated with viral infection, both as a filovirus receptor (e.g., Ebola) and through LE/L lipid trafficking. This suggests that NPC1 inhibitors or NP-C disease mimetics could serve as anti-SARS-CoV-2 agents. Fortunately, there are such clinically approved molecules that elicit antiviral activity in preclinical studies, without causing NP-C disease. Inhibition of NPC1 may impair viral SARS-CoV-2 infectivity via several lipid-dependent mechanisms, which disturb the microenvironment optimum for viral infectivity. We suggest that known mechanistic information on NPC1 could be utilized to identify existing and future drugs to treat COVID-19.

A nearby neutron-star merger explains the actinide abundances in the early Solar System.

A growing body of evidence indicates that binary neutron-star mergers are the primary origin of heavy elements produced exclusively through rapid neutron capture1-4 (the 'r-process'). As neutron-star mergers occur infrequently, their deposition of radioactive isotopes into the pre-solar nebula could have been dominated by a few nearby events. Although short-lived r-process isotopes-with half-lives shorter than 100 million years-are no longer present in the Solar System, their abundances in the early Solar System are known because their daughter products were preserved in high-temperature condensates found in meteorites5. Here we report that abundances of short-lived r-process isotopes in the early Solar System point to their origin in neutron-star mergers, and indicate substantial deposition by a single nearby merger event. By comparing numerical simulations with the early Solar System abundance ratios of actinides produced exclusively through the r-process, we constrain the rate of occurrence of their Galactic production sites to within about 1-100 per million years. This is consistent with observational estimates of neutron-star merger rates6-8, but rules out supernovae and stellar sources. We further find that there was probably a single nearby merger that produced much of the curium and a substantial fraction of the plutonium present in the early Solar System. Such an event may have occurred about 300 parsecs away from the pre-solar nebula, approximately 80 million years before the formation of the Solar System.

A gut microbial factor modulates locomotor behaviour in Drosophila.

While research into the biology of animal behaviour has primarily focused on the central nervous system, cues from peripheral tissues and the environment have been implicated in brain development and function1. There is emerging evidence that bidirectional communication between the gut and the brain affects behaviours including anxiety, cognition, nociception and social interaction1-9. Coordinated locomotor behaviour is critical for the survival and propagation of animals, and is regulated by internal and external sensory inputs10,11. However, little is known about how the gut microbiome influences host locomotion, or the molecular and cellular mechanisms involved. Here we report that germ-free status or antibiotic treatment results in hyperactive locomotor behaviour in the fruit fly Drosophila melanogaster. Increased walking speed and daily activity in the absence of a gut microbiome are rescued by mono-colonization with specific bacteria, including the fly commensal Lactobacillus brevis. The bacterial enzyme xylose isomerase from L. brevis recapitulates the locomotor effects of microbial colonization by modulating sugar metabolism in flies. Notably, thermogenetic activation of octopaminergic neurons or exogenous administration of octopamine, the invertebrate counterpart of noradrenaline, abrogates the effects of xylose isomerase on Drosophila locomotion. These findings reveal a previously unappreciated role for the gut microbiome in modulating locomotion, and identify octopaminergic neurons as mediators of peripheral microbial cues that regulate motor behaviour in animals.

Infused ice can multiply IceCube's sensitivity.

The IceCube Neutrino Observatory is the world's largest neutrino detector with a cubic-kilometer instrumented volume at the South Pole. It is preparing for a major upgrade that will significantly increase its sensitivity. A promising technological innovation investigated for this upgrade is wavelength shifting optics. Augmenting sensors with such optics could increase the photo-collection area of IceCube's digital optical modules, and shift the incoming photons' wavelength to where these modules are the most sensitive. Here we investigate the use of IceCube's drill holes as wavelength shifting optics. We calculate the sensitivity enhancement due to increasing the ice's refractive index in the holes, and infusing wavelength-shifting substrate into the ice. We find that, with adequate wavelength-shifter infusion, every ~0.05 increase in the ice's refractive index will increase IceCube's photon sensitivity by 100%, opening the possibility for the substantial, cost-effective expansion of IceCube's reach.

Environmental Stress Causes Lethal Neuro-Trauma during Asymptomatic Viral Infections.

Asymptomatic infections often proceed undetected, yet can still prime the host to be sensitive to secondary environmental stress. While the mechanisms underlying disease caused by asymptomatic infections are unknown, it is believed that productive pathogen replication is required. We report that the environmental stress of carbon dioxide (CO2) anesthesia converts an asymptomatic rhabdovirus infection in Drosophila to one that is lethal. This lethality results from a pool of infectious virus in glial cells and is regulated by the antiviral RNAi pathway of the host. CO2 sensitivity is caused by the fusogenic activity of the viral glycoprotein, which results in fusion of neurons and glia. Expression of the viral glycoprotein, but not a fusion defective mutant, is sufficient to cause CO2 sensitivity, which can occur even in the absence of productive viral replication. These findings highlight how viral proteins, independent of pathogen replication, may predispose hosts to life-threatening environmental stress.

Quantification of gait parameters in freely walking rodents.

BACKGROUND: Qualitative and quantitative measurements of motor performance are essential for characterizing perturbations of motor systems. Although several methods exist for analyzing specific motor tasks, few behavioral assays are readily available to researchers that provide a complete set of kinematic parameters in rodents. RESULTS: Here we present MouseWalker, an integrated hardware and software system that provides a comprehensive and quantitative description of kinematic features in freely walking rodents. Footprints are visualized with high spatial and temporal resolution by a non-invasive optical touch sensor coupled to high-speed imaging. A freely available and open-source software package tracks footprints and body features to generate a comprehensive description of many locomotion features, including static parameters such as footprint position and stance patterns and dynamic parameters, such as step and swing cycle duration, and inter-leg coordination. Using this method, we describe walking by wild-type mice including several previously undescribed parameters. For example, we demonstrate that footprint touchdown occurs instantaneously by the entire paw with no obvious rostral-caudal or lateral-medial bias. CONCLUSIONS: The readily available MouseWalker system and the large set of readouts it generates greatly increases the currently available toolkit for the analysis of wild type and aberrant locomotion in rodents.

Kinematic responses to changes in walking orientation and gravitational load in Drosophila melanogaster.

Walking behavior is context-dependent, resulting from the integration of internal and external influences by specialized motor and pre-motor centers. Neuronal programs must be sufficiently flexible to the locomotive challenges inherent in different environments. Although insect studies have contributed substantially to the identification of the components and rules that determine locomotion, we still lack an understanding of how multi-jointed walking insects respond to changes in walking orientation and direction and strength of the gravitational force. In order to answer these questions we measured with high temporal and spatial resolution the kinematic properties of untethered Drosophila during inverted and vertical walking. In addition, we also examined the kinematic responses to increases in gravitational load. We find that animals are capable of shifting their step, spatial and inter-leg parameters in order to cope with more challenging walking conditions. For example, flies walking in an inverted orientation decreased the duration of their swing phase leading to increased contact with the substrate and, as a result, greater stability. We also find that when flies carry additional weight, thereby increasing their gravitational load, some changes in step parameters vary over time, providing evidence for adaptation. However, above a threshold that is between 1 and 2 times their body weight flies display locomotion parameters that suggest they are no longer capable of walking in a coordinated manner. Finally, we find that functional chordotonal organs are required for flies to cope with additional weight, as animals deficient in these proprioceptors display increased sensitivity to load bearing as well as other locomotive defects.

Gas cloud G2 can illuminate the black hole population near the galactic center.

Galactic nuclei are expected to be densely populated with stellar- and intermediate-mass black holes. Exploring this population will have important consequences for the observation prospects of gravitational waves as well as understanding galactic evolution. The gas cloud G2 currently approaching Sgr A* provides an unprecedented opportunity to probe the black hole and neutron star population of the Galactic nucleus. We examine the possibility of a G2-cloud-black-hole encounter and its detectability with current x-ray satellites, such as Chandra and NuSTAR. We find that multiple encounters are likely to occur close to the pericenter, which may be detectable upon favorable circumstances. This opportunity provides an additional important science case for leading x-ray observatories to closely follow G2 on its way to the nucleus.

Quantification of gait parameters in freely walking wild type and sensory deprived Drosophila melanogaster.

Coordinated walking in vertebrates and multi-legged invertebrates [corrected] such as Drosophila melanogaster requires a complex neural network coupled to sensory feedback. An understanding of this network will benefit from systems such as Drosophila that have the ability to genetically manipulate neural activities. However, the fly's small size makes it challenging to analyze walking in this system. In order to overcome this limitation, we developed an optical method coupled with high-speed imaging that allows the tracking and quantification of gait parameters in freely walking flies with high temporal and spatial resolution. Using this method, we present a comprehensive description of many locomotion parameters, such as gait, tarsal positioning, and intersegmental and left-right coordination for wild type fruit flies. Surprisingly, we find that inactivation of sensory neurons in the fly's legs, to block proprioceptive feedback, led to deficient step precision, but interleg coordination and the ability to execute a tripod gait were unaffected.DOI:http://dx.doi.org/10.7554/eLife.00231.001.

Exploring the birth and death of black holes and other creatures.

Astronomers and physicists of diverse interest are teaming up to study enigmatic cosmic phenomena, such as the life cycle of black holes. A "disruptive innovation" is about to emerge during the next decade: Advanced gravitational-wave observatories. The emergence of gravitational-wave physics as a viable observational channel is expected to improve our understanding of the Universe in unprecedented and plausibly unexpected ways, and to enhance the capabilities of the astrophysics community. Detecting cosmic counterparts to gravitational-wave events would revolutionize our understanding of violent astrophysical processes, such as the birth and death of black holes and neutron stars. Although the vanguard of joint observational work with electromagnetic observatories has already rewarded us with a glimpse of the power of gravitational-wave astronomy, the most interesting science is yet to come. Many sources of gravitational-waves are expected to be observable through a broad set of messengers, including γ-rays, X-rays, optical, radio, and neutrino emission. Multimessenger investigations may be crucial for the first detection of gravitational-waves, and could provide the broadest scientific impact afterwards. This paper outlines some exciting aspects of transient multimessenger astronomy with gravitational-waves and highlights open questions that might be resolvable by Advanced or third generation gravitational-wave detector networks. In addition, we will use examples from current research to illustrate that the toolkit of fundamental research can enrich other fields, and that synergistic science can expand horizons here on Earth.

Observational constraints on multimessenger sources of gravitational waves and high-energy neutrinos.

Many astronomical sources of intense bursts of photons are also predicted to be strong emitters of gravitational waves (GWs) and high-energy neutrinos (HENs). Moreover some suspected classes, e.g., choked gamma-ray bursts, may only be identifiable via nonphoton messengers. Here we explore the reach of current and planned experiments to address this question. We derive constraints on the rate of GW and HEN bursts based on independent observations by the initial LIGO and Virgo GW detectors and the partially completed IceCube (40-string) HEN detector. We then estimate the reach of joint GW+HEN searches using advanced GW detectors and the completed km(3) IceCube detector to probe the joint parameter space. We show that searches undertaken by advanced detectors will be capable of detecting, constraining, or excluding, several existing models with 1 yr of observation.