An AI-guided screen identifies probucol as an enhancer of mitophagy through modulation of lipid droplets.

Failures in mitophagy, a process by which damaged mitochondria are cleared, results in neurodegeneration, while enhancing mitophagy promotes the survival of dopaminergic neurons. Using an artificial intelligence platform, we employed a natural language processing approach to evaluate the semantic similarity of candidate molecules to a set of well-established mitophagy enhancers. Top candidates were screened in a cell-based mitochondrial clearance assay. Probucol, a lipid-lowering drug, was validated across several orthogonal mitophagy assays. In vivo, probucol improved survival, locomotor function, and dopaminergic neuron loss in zebrafish and fly models of mitochondrial damage. Probucol functioned independently of PINK1/Parkin, but its effects on mitophagy and in vivo depended on ABCA1, which negatively regulated mitophagy following mitochondrial damage. Autophagosome and lysosomal markers were elevated by probucol treatment in addition to increased contact between lipid droplets (LDs) and mitochondria. Conversely, LD expansion, which occurs following mitochondrial damage, was suppressed by probucol and probucol-mediated mitophagy enhancement required LDs. Probucol-mediated LD dynamics changes may prime the cell for a more efficient mitophagic response to mitochondrial damage.

CFAP53 regulates mammalian cilia-type motility patterns through differential localization and recruitment of axonemal dynein components.

Motile cilia can beat with distinct patterns, but how motility variations are regulated remain obscure. Here, we have studied the role of the coiled-coil protein CFAP53 in the motility of different cilia-types in the mouse. While node (9+0) cilia of Cfap53 mutants were immotile, tracheal and ependymal (9+2) cilia retained motility, albeit with an altered beat pattern. In node cilia, CFAP53 mainly localized at the base (centriolar satellites), whereas it was also present along the entire axoneme in tracheal cilia. CFAP53 associated tightly with microtubules and interacted with axonemal dyneins and TTC25, a dynein docking complex component. TTC25 and outer dynein arms (ODAs) were lost from node cilia, but were largely maintained in tracheal cilia of Cfap53-/- mice. Thus, CFAP53 at the base of node cilia facilitates axonemal transport of TTC25 and dyneins, while axonemal CFAP53 in 9+2 cilia stabilizes dynein binding to microtubules. Our study establishes how differential localization and function of CFAP53 contributes to the unique motion patterns of two important mammalian cilia-types.

Conservation as well as divergence in Mcidas function underlies the differentiation of multiciliated cells in vertebrates.

Multiciliated cells (MCCs) differentiate hundreds of motile cilia that beat to drive fluid movement over various kinds of epithelia. In Xenopus, mice and human, the coiled-coil containing protein Mcidas (Mci) has been shown to be a key transcriptional regulator of MCC differentiation. We have examined Mci function in the zebrafish, another model organism that is widely used to study ciliary biology. We show that zebrafish mci is expressed specifically in the developing MCCs of the kidney tubules, but surprisingly, not in those of the nasal placodes. Mci proteins lack a DNA binding domain and associate with the cell-cycle transcription factors E2f4/5 for regulating MCC-specific gene expression. We found that while the zebrafish Mci protein can complex with the E2f family members, its sequence as well as the requirement and sufficiency for MCC differentiation has diverged significantly from Mci homologues of the tetrapods. We also provide evidence that compared to Gmnc, another related coiled-coil protein that has recently been shown to regulate MCC development upstream of Mci, the Mci protein originated later within the vertebrate lineage. Based on these data, we argue that in contrast to Gmnc, which has a vital role in the genetic circuitry that drives MCC formation, the requirement of Mci, at least in the zebrafish, is not obligatory.

Composition-Controlled Atomic Layer Deposition of Phase-Change Memories and Ovonic Threshold Switches with High Performance.

Chalcogenide compounds are the main characters in a revolution in electronic memories. These materials are used to produce ultrafast ovonic threshold switches (OTSs) with good selectivity and moderate leakage current and phase-change memories (PCMs) with excellent endurance and short read/write times when compared with state-of-the-art flash-NANDs. The combination of these two electrical elements is used to fabricate nonvolatile memory arrays with a write/access time orders of magnitude shorter than that of state-of-the-art flash-NANDs. These devices have a pivotal role for the advancement of fields such as artificial intelligence, machine learning, and big-data. Chalcogenide films, at the moment, are deposited by using physical vapor deposition (PVD) techniques that allow for fine control over the stoichiometry of solid solutions but fail in providing the conformality required for developing large-memory-capacity integrated 3D structures. Here we present conformal ALD chalcogenide films with control over the composition of germanium, antimony, and tellurium (GST). By developing a technique to grow elemental Te we demonstrate the ability to deposit conformal, smooth, composition-controlled GST films. We present a thorough physical and chemical characterization of the solids and an in-depth electrical test. We demonstrate the ability to produce both OTS and PCM materials. GeTe4 OTSs exhibit fast switching times of ∼13 ns. Ge2Sb2Te5 ALD PCMs exhibit a wide memory window exceeding two orders of magnitude, short write times (∼100 ns), and a reset current density as low as ∼107 A/cm2-performance matching or improving upon state-of-the-art PVD PCM devices.

The Novel Small Molecule TRVA242 Stabilizes Neuromuscular Junction Defects in Multiple Animal Models of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder in which the neuromuscular junction progressively degenerates, leading to movement difficulties, paralysis, and eventually death. ALS is currently being treated by only two FDA-approved drugs with modest efficacy in slowing disease progression. Often, the translation of preclinical findings to bedside terminates prematurely as the evaluation of potential therapeutic compounds focuses on a single study or a single animal model. To circumscribe these issues, we screened 3,765 novel small molecule derivatives of pimozide, a recently identified repurposed neuroleptic for ALS, in Caenorhabditis elegans, confirmed the hits in zebrafish and validated the most active compounds in mouse genetic models. Out of the 27 small molecules identified from the high-throughput screen in worms, 4 were found to recover locomotor defects in C. elegans and genetic zebrafish models of ALS. TRVA242 was identified as the most potent compound as it significantly improved efficiency in rescuing locomotor, motorneuron, and neuromuscular junction synaptic deficits in a C. elegans TDP-43 model and in multiple zebrafish genetic (TDP-43, SOD1, and C9ORF72) models of ALS. The actions of TRVA242 were also conserved in a mammalian model as it also stabilized neuromuscular junction deficits in a mouse SOD1 model of ALS. Compounds such as TRVA242 therefore represent new potential therapeutics for the treatment of ALS.

Engineering of Ferroelectric HfO2-ZrO2 Nanolaminates.

In this work, the ferroelectric properties of nanolaminates made of HfO2 and ZrO2 were studied as a function of the deposition temperature and the individual HfO2/ZrO2 layer thickness before and after electrical field cycling. The ferroelectric response was found to depend on the structure of the nanolaminates before any postdeposition annealing treatment. After annealing with a TiN cap, an "antiferroelectric-like" response was obtained from nanolaminates deposited in an amorphous state at a lower temperature, whereas a ferroelectric response was obtained from nanolaminates deposited at a higher temperature, where crystallites were detected in thick films before annealing. As the individual layer thicknesses were decreased, an increased lattice distortion and a concurrent increase in remanent polarization were observed from the nanolaminates deposited at high temperatures. After field cycling, nanolaminates deposited at lower temperatures exhibited an antiferroelectric-like to ferroelectric transition, whereas those deposited at higher temperatures exhibited a larger remanent polarization. Finally, we demonstrate that by leveraging the proper choice of process conditions and layer thickness, remanent polarizations exceeding those of the HfZrO4 solid solution can be obtained.

Schottky Barrier Catalysis Mechanism in Metal-Assisted Chemical Etching of Silicon.

Metal-assisted chemical etching (MACE) is a versatile anisotropic etch for silicon although its mechanism is not well understood. Here we propose that the Schottky junction formed between metal and silicon plays an essential role on the distribution of holes in silicon injected from hydrogen peroxide. The proposed mechanism can be used to explain the dependence of the etching kinetics on the doping level, doping type, crystallographic surface direction, and etchant solution composition. We used the doping dependence of the reaction to fabricate a novel etch stop for the reaction.

Hybrid Metal-Semiconductor Nanostructure for Ultrahigh Optical Absorption and Low Electrical Resistance at Optoelectronic Interfaces.

Engineered optoelectronic surfaces must control both the flow of light and the flow of electrons at an interface; however, nanostructures for photon and electron management have typically been studied and optimized separately. In this work, we unify these concepts in a new hybrid metal-semiconductor surface that offers both strong light absorption and high electrical conductivity. We use metal-assisted chemical etching to nanostructure the surface of a silicon wafer, creating an array of silicon nanopillars protruding through holes in a gold film. When coated with a silicon nitride anti-reflection layer, we observe broad-band absorption of up to 97% in this structure, which is remarkable considering that metal covers 60% of the top surface. We use optical simulations to show that Mie-like resonances in the nanopillars funnel light around the metal layer and into the substrate, rendering the metal nearly transparent to the incoming light. Our results show that, across a wide parameter space, hybrid metal-semiconductor surfaces with absorption above 90% and sheet resistance below 20 Ω/□ are realizable, suggesting a new paradigm wherein transparent electrodes and photon management textures are designed and fabricated together to create high-performance optoelectronic interfaces.

Cilia: Organelles at the Heart of Heart Disease.

Genetic disorders, such as heterotaxy, first provided a link between cilia and developmental heart defects. Now, a genetic screen in mice shows that ciliary dysfunction may indeed be the major contributing factor in the etiology of congenital heart disease.

Gmnc Is a Master Regulator of the Multiciliated Cell Differentiation Program.

Multiciliated cells (MCCs) differentiate hundreds of motile cilia that generate mechanical force required to drive fluid movement over epithelia [1, 2]. For example, metachronal beating of MCC cilia in the mammalian airways clears mucus that traps inhaled pathogens and pollutants. Consequently, abnormalities in MCC differentiation or ciliary motility have been linked to an expanding spectrum of human airway diseases [3­6]. The current view posits that MCC precursors are singled out by the inhibition of Notch signaling. MCC precursors then support an explosive production of basal bodies, which migrate to the apical surface, dock with the plasma membrane, and seed the growth of multiple motile cilia. At the center of this elaborate differentiation program resides the coiled-coil-containing protein Multicilin, which transcriptionally activates genes for basal body production and the gene for FoxJ1, the master regulator for basal body docking, cilia formation, and motility [7, 8]. Here, using genetic analysis in the zebrafish embryo, we discovered that Gmnc is a novel determinant of the MCC fate. Like Multicilin, Gmnc is a coiled-coil-containing protein of the Geminin family. We show that Gmnc functions downstream of Notch signaling, but upstream of Multicilin in the developmental pathway controlling MCC specification. Moreover, we find that loss of Gmnc in Xenopus embryos also causes loss of MCC differentiation and that overexpression of the protein is sufficient to induce supernumerary MCCs. Together, our data identify Gmnc as an evolutionarily conserved master regulator functioning at the top of the hierarchy of transcription factors involved in MCC differentiation.

Optical transmission enhancement through chemically tuned two-dimensional bismuth chalcogenide nanoplates.

Layer-structured two-dimensional nanomaterials are a family of materials with strong covalent bonding within layers and weak van der Waals interaction between layers, whose vertical thickness can be thinned down to few nanometer and even single atomic layer. Bismuth chalcogenides are examples of such two-dimensional materials. Here, we present our discovery of significant enhancement of light transmission through thin nanoplates of layered bismuth chalcogenides by intercalation of copper atoms, which is on the contrary to most bulk materials in which doping reduces the light transmission. This surprising behaviour results from two mechanisms: chemical tuning effect of substantial reduction of material absorption after intercalation and nanophotonic effect of zero-wave anti-reflection unique to ultra-small thickness of nanoplates. We demonstrate that the synergy of these two effects in two-dimensional nanostructures can be exploited for various optoelectronic applications including transparent electrode. The intercalation mechanism allows potential dynamic tuning capability.

Improving lithium-sulphur batteries through spatial control of sulphur species deposition on a hybrid electrode surface.

Lithium-sulphur batteries are attractive owing to their high theoretical energy density and reasonable kinetics. Despite the success of trapping soluble polysulphides in a matrix with high surface area, spatial control of solid-state sulphur and lithium sulphide species deposition as a critical aspect has not been demonstrated. Herein, we show a clear visual evidence that these solid species deposit preferentially onto tin-doped indium oxide instead of carbon during electrochemical charge/discharge of soluble polysuphides. To incorporate this concept of spatial control into more practical battery electrodes, we further prepare carbon nanofibers with tin-doped indium oxide nanoparticles decorating the surface as hybrid three-dimensional electrodes to maximize the number of deposition sites. With 12.5 µl of 5 M Li2S8 as the catholyte and a rate of C/5, we can reach the theoretical limit of Li2S8 capacity ~\n1,470 mAh g(-1) (sulphur weight) under the loading of hybrid electrode only at 4.3 mg cm(-2).

Performance enhancement of metal nanowire transparent conducting electrodes by mesoscale metal wires.

For transparent conducting electrodes in optoelectronic devices, electrical sheet resistance and optical transmittance are two of the main criteria. Recently, metal nanowires have been demonstrated to be a promising type of transparent conducting electrode because of low sheet resistance and high transmittance. Here we incorporate a mesoscale metal wire (1-5 µm in diameter) into metal nanowire transparent conducting electrodes and demonstrate at least a one order of magnitude reduction in sheet resistance at a given transmittance. We realize experimentally a hybrid of mesoscale and nanoscale metal nanowires with high performance, including a sheet resistance of 0.36 Ω sq(-1) and transmittance of 92%. In addition, the mesoscale metal wires are applied to a wide range of transparent conducting electrodes including conducting polymers and oxides with improvement up to several orders of magnitude. The metal mesowires can be synthesized by electrospinning methods and their general applicability opens up opportunities for many transparent conducting electrode applications.

Broadband light management using low-Q whispering gallery modes in spherical nanoshells.

Light trapping across a wide band of frequencies is important for applications such as solar cells and photodetectors. Here, we demonstrate a new approach to light management by forming whispering-gallery resonant modes inside a spherical nanoshell structure. The geometry of the structure gives rise to a low quality-factor, facilitating the coupling of light into the resonant modes and substantial enhancement of the light path in the active material, thus dramatically improving absorption. Using nanocrystalline silicon (nc-Si) as a model system, we observe broadband absorption enhancement across a large range of incident angles. The absorption of a single layer of 50-nm-thick spherical nanoshells is equivalent to a 1-µm-thick planar nc-Si film. This light-trapping structure could enable the manufacturing of high-throughput ultra-thin film absorbers in a variety of material systems that demand shorter deposition time, less material usage and transferability to flexible substrates.