Combined transmission electron microscopy and x‐ray study of the microstructure and texture in sputtered Mo films

The microstructure and texture of thin Mo films sputtered onto the native oxide of Si(100) wafers were investigated with both conventional reflection x‐ray pole figures, and transmission electron microscopy and diffraction. Films were grown at two deposition rates (powers), 34 nm/min (1.5 kW) and 67 nm/min (3.9 kW), onto both moving and stationary substrates, under otherwise identical experimental conditions. The microstructure of the Mo films evolved into a zone 2 microstructure within the first 2 μm of growth. The development of both out‐of‐plane and in‐plane textures was found to be influenced by deposition rate and geometry. Films grown at the lower deposition rate exhibited predominantly {110} textures, while films grown at the higher rate exhibited predominantly {110} textures up to a film thickness of ∼0.5 μm and {111} textures above a film thickness of ∼1 μm. Films with the {110} textures developed grains with elongated footprints and faceted surfaces, while films with the {111} textures developed grains with elongated triangular footprints and faceted surfaces. In all of the films deposited onto moving substrates, an alignment of the grains normal to the tangent plane (defined by the substrate normal and the direction of platen rotation) was observed. In all of the films deposited onto stationary substrates, the development of an in‐plane texture was suppressed. These results suggest that a combination of geometric, energetic, and kinetic mechanisms are contributing to the evolution of the microstructure and texture in the Mo films.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/70000/2/JAPIAU-76-8-4610-1.pd

Growth anisotropy and self-shadowing: A model for the development of in-plane texture during polycrystalline thin-film growth

The development of a preferred crystallographic orientation in the plane of growth, an in-plane texture, is addressed in a model that incorporates anisotropic growth rates of a material and self-shadowing. Most crystalline materials exhibit fast growth along certain crystallographic directions and slow growth along others. This crystallographic growth anisotropy, which may be due to differences in surface free energy and surface diffusion, leads to the evolution of specific grain shapes in a material. In addition, self-shadowing due to an obliquely incident deposition flux leads to a variation in in-plane grain growth rates, where the “fast” growth direction is normal to the plane defined by the substrate normal and the incident flux direction. This geometric growth anisotropy leads to the formation of elongated grains in the plane of growth. Neither growth anisotropy alone can explain the development of an in-plane texture during polycrystalline thin-film growth. However, whenever both are present (i.e., oblique incidence deposition of anisotropic materials), an in-plane texture will develop. Grains that have “fast” crystallographic growth directions aligned with the “fast” geometric growth direction overgrow grains that do not exhibit this alignment. Furthermore, the rate of texturing increases with the degree of each anisotropy. This model was used to simulate in-plane texturing during thin-film deposition. The simulation results are in excellent quantitative agreement with recent experimental results concerning the development of in-plane texture in sputter deposited Mo films. © 1997 American Institute of Physics.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71031/2/JAPIAU-82-3-1397-1.pd

Controlling strength and toughness of multilayer films: A new multiscalar approach

Multiscalar films are produced in order to combine both toughness and strength into a multilayer film. These structures incorporate both a strengthening phase and a toughening phase in a compositionally modulated microcomposite. The mechanical properties and microstructure for thick (∼50 μm) Mo/W multiscalar films have been characterized. A detailed microstructural analysis (including transmission electron microscopy, scanning electron microscopy, and x‐ray techniques) of Mo/W multiscalar films has shown that large single‐crystal columns of Mo interspersed with epitaxial layers of W extend for the entire film thickness. The microstructure is a zone‐II‐type microstructure, yet the temperatures during deposition are well below the lower limit (0.3 T/Tm) previously reported for such microstructures. Hardness and tensile tests have shown that a multiscalar approach is capable of tailoring a desired strength and toughness into a multilayered film.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/70675/2/JAPIAU-74-2-1015-1.pd

Epstein–Barr Virus MicroRNAs Are Evolutionarily Conserved and Differentially Expressed

The pathogenic lymphocryptovirus Epstein–Barr virus (EBV) is shown to express at least 17 distinct microRNAs (miRNAs) in latently infected cells. These are arranged in two clusters: 14 miRNAs are located in the introns of the viral BART gene while three are located adjacent to BHRF1. The BART miRNAs are expressed at high levels in latently infected epithelial cells and at lower, albeit detectable, levels in B cells. In contrast to the tissue-specific expression pattern of the BART miRNAs, the BHRF1 miRNAs are found at high levels in B cells undergoing stage III latency but are essentially undetectable in B cells or epithelial cells undergoing stage I or II latency. Induction of lytic EBV replication was found to enhance the expression of many, but not all, of these viral miRNAs. Rhesus lymphocryptovirus, which is separated from EBV by ≥13 million years of evolution, expresses at least 16 distinct miRNAs, seven of which are closely related to EBV miRNAs. Thus, lymphocryptovirus miRNAs are under positive selection and are likely to play important roles in the viral life cycle. Moreover, the differential regulation of EBV miRNA expression implies distinct roles during infection of different human tissues

A robust mouse model of HPIV-3 infection and efficacy of GS-441524 against virus-induced lung pathology

Human parainfluenza virus type 3 (HPIV-3) can cause severe respiratory tract infections. There are no convenient small-animal infection models. Here, we show viral replication in the upper and lower airways of AG129 mice (double IFNα/β and IFNγ receptor knockout mice) upon intranasal inoculation. By multiplex fluorescence RNAscope and immunohistochemistry followed by confocal microscopy, we demonstrate viral tropism to ciliated cells and club cells of the bronchiolar epithelium. HPIV-3 causes a marked lung pathology. No virus transmission of the virus was observed by cohousing HPIV-3-infected AG129 mice with other mice. Oral treatment with GS-441524, the parent nucleoside of remdesivir, reduced infectious virus titers in the lung, with a relatively normal histology. Intranasal treatment also affords an antiviral effect. Thus, AG129 mice serve as a robust preclinical model for developing therapeutic and prophylactic strategies against HPIV-3. We suggest further investigation of GS-441524 and its prodrug forms to treat HPIV-3 infection in humans

The oral nucleoside prodrug GS-5245 is efficacious against SARS-CoV-2 and other endemic, epidemic, and enzootic coronaviruses

Despite the wide availability of several safe and effective vaccines that prevent severe COVID-19, the persistent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that can evade vaccine-elicited immunity remains a global health concern. In addition, the emergence of SARS-CoV-2 VOCs that can evade therapeutic monoclonal antibodies underscores the need for additional, variant-resistant treatment strategies. Here, we characterize the antiviral activity of GS-5245, obeldesivir (ODV), an oral prodrug of the parent nucleoside GS-441524, which targets the highly conserved viral RNA-dependent RNA polymerase (RdRp). We show that GS-5245 is broadly potent in vitro against alphacoronavirus HCoV-NL63, SARS-CoV, SARS-CoV-related bat-CoV RsSHC014, Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV-2 WA/1, and the highly transmissible SARS-CoV-2 BA.1 Omicron variant. Moreover, in mouse models of SARS-CoV, SARS-CoV-2 (WA/1 and Omicron B1.1.529), MERS-CoV, and bat-CoV RsSHC014 pathogenesis, we observed a dose-dependent reduction in viral replication, body weight loss, acute lung injury, and pulmonary function with GS-5245 therapy. Last, we demonstrate that a combination of GS-5245 and main protease (Mpro) inhibitor nirmatrelvir improved outcomes in vivo against SARS-CoV-2 compared with the single agents. Together, our data support the clinical evaluation of GS-5245 against coronaviruses that cause or have the potential to cause human disease

Therapeutic treatment with an oral prodrug of the remdesivir parental nucleoside is protective against SARS-CoV-2 pathogenesis in mice

The coronavirus disease 2019 (COVID-19) pandemic remains uncontrolled despite the rapid rollout of safe and effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines, underscoring the need to develop highly effective antivirals. In the setting of waning immunity from infection and vaccination, breakthrough infections are becoming increasingly common and treatment options remain limited. Additionally, the emergence of SARS-CoV-2 variants of concern, with their potential to escape neutralization by therapeutic monoclonal antibodies, emphasizes the need to develop second-generation oral antivirals targeting highly conserved viral proteins that can be rapidly deployed to outpatients. Here, we demonstrate the in vitro antiviral activity and in vivo therapeutic efficacy of GS-621763, an orally bioavailable prodrug of GS-441524, the parent nucleoside of remdesivir, which targets the highly conserved virus RNA-dependent RNA polymerase. GS-621763 exhibited antiviral activity against SARS-CoV-2 in lung cell lines and two different human primary lung cell culture systems. GS-621763 was also potently antiviral against a genetically unrelated emerging coronavirus, Middle East Respiratory Syndrome CoV (MERS-CoV). The dose-proportional pharmacokinetic profile observed after oral administration of GS-621763 translated to dose-dependent antiviral activity in mice infected with SARS-CoV-2. Therapeutic GS-621763 administration reduced viral load and lung pathology; treatment also improved pulmonary function in COVID-19 mouse model. A direct comparison of GS-621763 with molnupiravir, an oral nucleoside analog antiviral which has recently received EUA approval, proved both drugs to be similarly efficacious in mice. These data support the exploration of GS-441524 oral prodrugs for the treatment of COVID-19

Remdesivir Inhibits SARS-CoV-2 in Human Lung Cells and Chimeric SARS-CoV Expressing the SARS-CoV-2 RNA Polymerase in Mice

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the novel viral disease COVID-19. With no approved therapies, this pandemic illustrates the urgent need for broad-spectrum antiviral countermeasures against SARS-CoV-2 and future emerging CoVs. We report that remdesivir (RDV) potently inhibits SARS-CoV-2 replication in human lung cells and primary human airway epithelial cultures (EC50 = 0.01 μM). Weaker activity is observed in Vero E6 cells (EC50 = 1.65 μM) because of their low capacity to metabolize RDV. To rapidly evaluate in vivo efficacy, we engineered a chimeric SARS-CoV encoding the viral target of RDV, the RNA-dependent RNA polymerase of SARS-CoV-2. In mice infected with the chimeric virus, therapeutic RDV administration diminishes lung viral load and improves pulmonary function compared with vehicle-treated animals. These data demonstrate that RDV is potently active against SARS-CoV-2 in vitro and in vivo, supporting its further clinical testing for treatment of COVID-19

Author Correction: Federated learning enables big data for rare cancer boundary detection.

10.1038/s41467-023-36188-7NATURE COMMUNICATIONS14

Federated learning enables big data for rare cancer boundary detection.

Although machine learning (ML) has shown promise across disciplines, out-of-sample generalizability is concerning. This is currently addressed by sharing multi-site data, but such centralization is challenging/infeasible to scale due to various limitations. Federated ML (FL) provides an alternative paradigm for accurate and generalizable ML, by only sharing numerical model updates. Here we present the largest FL study to-date, involving data from 71 sites across 6 continents, to generate an automatic tumor boundary detector for the rare disease of glioblastoma, reporting the largest such dataset in the literature (n = 6, 314). We demonstrate a 33% delineation improvement for the surgically targetable tumor, and 23% for the complete tumor extent, over a publicly trained model. We anticipate our study to: 1) enable more healthcare studies informed by large diverse data, ensuring meaningful results for rare diseases and underrepresented populations, 2) facilitate further analyses for glioblastoma by releasing our consensus model, and 3) demonstrate the FL effectiveness at such scale and task-complexity as a paradigm shift for multi-site collaborations, alleviating the need for data-sharing