An ACE2 decoy can be administered by inhalation and potently targets omicron variants of SARS-CoV-2.

Monoclonal antibodies targeting the SARS-CoV-2 spike (S) neutralize infection and are efficacious for the treatment of COVID-19. However, SARS-CoV-2 variants, notably sublineages of B.1.1.529/omicron, have emerged that escape antibodies in clinical use. As an alternative, soluble decoy receptors based on the host entry receptor ACE2 broadly bind and block S from SARS-CoV-2 variants and related betacoronaviruses. The high-affinity and catalytically active decoy sACE22 .v2.4-IgG1 was previously shown to be effective against SARS-CoV-2 variants when administered intravenously. Here, inhalation of aerosolized sACE22 .v2.4-IgG1 increased survival and ameliorated lung injury in K18-hACE2 mice inoculated with P.1/gamma virus. Loss of catalytic activity reduced the decoy's therapeutic efficacy, which was further confirmed by intravenous administration, supporting dual mechanisms of action: direct blocking of S and turnover of ACE2 substrates associated with lung injury and inflammation. Furthermore, sACE22 .v2.4-IgG1 tightly binds and neutralizes BA.1, BA.2, and BA.4/BA.5 omicron and protects K18-hACE2 mice inoculated with a high dose of BA.1 omicron virus. Overall, the therapeutic potential of sACE22 .v2.4-IgG1 is demonstrated by the inhalation route and broad neutralization potency persists against highly divergent SARS-CoV-2 variants.

Steering Molecular Activity with Optogenetics: Recent Advances and Perspectives.

Optogenetics utilizes photosensitive proteins to manipulate the localization and interaction of molecules in living cells. Because light can be rapidly switched and conveniently confined to the sub-micrometer scale, optogenetics allows for controlling cellular events with an unprecedented resolution in time and space. The past decade has witnessed an enormous progress in the field of optogenetics within the biological sciences. The ever-increasing amount of optogenetic tools, however, can overwhelm the selection of appropriate optogenetic strategies. Considering that each optogenetic tool may have a distinct mode of action, a comparative analysis of the current optogenetic toolbox can promote the further use of optogenetics, especially by researchers new to this field. This review provides such a compilation that highlights the spatiotemporal accuracy of current optogenetic systems. Recent advances of optogenetics in live cells and animal models are summarized, the emerging work that interlinks optogenetics with other research fields is presented, and exciting clinical and industrial efforts to employ optogenetic strategy toward disease intervention are reported.

Comparative Determination of Cytotoxicity of Sub-10 nm Copper Nanoparticles to Prokaryotic and Eukaryotic Systems.

Copper nanoparticles demonstrate antibacterial activity, but their toxicity to eukaryotic systems is less understood. Here, we carried out a comparative study to determine the biocompatibility and cytotoxicity of sub-10 nm copper nanoparticles to a variety of biological systems, including prokaryotic cells (Escherichia coli), yeast, mammalian cell lines (HEK293T, PC12), and zebrafish embryos. We determined the bearing threshold for the cell-death-inducing concentration of copper nanoparticles by probing cell growth, viability, as well as embryological features. To exclude the partial toxicity effect from the remnant reactants, we developed a purification approach using agarose gel electrophoresis. Purified CuONP solution inhibits bacterial growth and causes eukaryotic cell death at 170 and 122.5 ppm (w/w) during the 18 h of treatment, respectively. CuONP significantly reduces the pigmentation of retina pigmented epithelium of zebrafish embryos at 85 ppm. The cytotoxicity of CuONP in eukaryotic cells could arise from the oxidative stress induced by CuONP. This result suggests that small copper nanoparticles exert cytotoxicity in both prokaryotic and eukaryotic systems, and therefore, caution should be used to avoid direct contact of copper nanoparticles to human tissues considering the potential use of copper nanoparticles in the clinical setting.

Optical control of ERK and AKT signaling promotes axon regeneration and functional recovery of PNS and CNS in Drosophila.

Neuroregeneration is a dynamic process synergizing the functional outcomes of multiple signaling circuits. Channelrhodopsin-based optogenetics shows the feasibility of stimulating neural repair but does not pin down specific signaling cascades. Here, we utilized optogenetic systems, optoRaf and optoAKT, to delineate the contribution of the ERK and AKT signaling pathways to neuroregeneration in live Drosophila larvae. We showed that optoRaf or optoAKT activation not only enhanced axon regeneration in both regeneration-competent and -incompetent sensory neurons in the peripheral nervous system but also allowed temporal tuning and proper guidance of axon regrowth. Furthermore, optoRaf and optoAKT differ in their signaling kinetics during regeneration, showing a gated versus graded response, respectively. Importantly in the central nervous system, their activation promotes axon regrowth and functional recovery of the thermonociceptive behavior. We conclude that non-neuronal optogenetics targets damaged neurons and signaling subcircuits, providing a novel strategy in the intervention of neural damage with improved precision.

Most cells have a built-in regeneration signaling program that allows them to divide and repair. But, in the cells of the central nervous system, which are called neurons, this program is ineffective. This is why accidents and illnesses affecting the brain and spinal cord can cause permanent damage. Reactivating regeneration in neurons could help them repair, but it is not easy. Certain small molecules can switch repair signaling programs back on. Unfortunately, these molecules diffuse easily through tissues, spreading around the body and making it hard to target individual damaged cells. This both hampers research into neuronal repair and makes treatments directed at healing damage to the nervous system more likely to have side-effects. It is unclear whether reactivating regeneration signaling in individual neurons is possible. One way to address this question is to use optogenetics. This technique uses genetic engineering to fuse proteins that are light-sensitive to proteins responsible for relaying signals in the cell. When specific wavelengths of light hit the light-sensitive proteins, the fused signaling proteins switch on, leading to the activation of any proteins they control, for example, those involved in regeneration. Wang et al. used optogenetic tools to determine if light can help repair neurons in fruit fly larvae. First, a strong laser light was used to damage an individual neuron in a fruit fly larva that had been genetically modified so that blue light would activate the regeneration program in its neurons. Then, Wang et al. illuminated the cell with dim blue light, switching on the regeneration program. Not only did this allow the neuron to repair itself, it also allowed the light to guide its regeneration. By focusing the blue light on the damaged end of the neuron, it was possible to guide the direction of the cell's growth as it regenerated. Regeneration programs in flies and mammals involve similar signaling proteins, but blue light does not penetrate well into mammalian tissues. This means that further research into LEDs that can be implanted may be necessary before neuronal repair experiments can be performed in mammals. In any case, the ability to focus treatment on individual neurons paves the way for future work into the regeneration of the nervous system, and the combination of light and genetics could reveal more about how repair signals work.