Genomic investigations of unexplained acute hepatitis in children.

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children.

Understanding of multiple resistance states by current sweeping in MoS2-based non-volatile memory devices.

Recently, various two-dimensional materials have been reported to exhibit non-volatile resistance switching phenomenon. The atomristors, featuring memristor effect in atomically thin nanomaterials such as monolayer transition metal dichalcogenides and hexagonal boron nitride, have drawn much attention due to the extremely thin active layer thickness with the advantages of forming-free characteristic, large on/off resistance ratio and fast switching speed. To investigate the switching mechanisms in the 2D monolayers, we introduced an electrical characterization method by current sweeping to illustrate the detailed information hidden in the commonly used voltage-sweep curves. Multiple transition steps have been observed in the SET process of MoS2-based resistance switching devices. The different behaviors of transition steps were attributed to the number of defects or vacancies associated with the switching phenomenon, which is consistent with the previously reported conductive-bridge-like model for 2D atomristors. This work provides an approach using current sweeping to precisely characterize the resistance switching effect and inspires further research to optimize the defect distribution in 2D materials for the applications in multi-bit non-volatile memory and neuromorphic computing.

High-Performance Photodetectors Based on Solution-Processed Epitaxial Grown Hybrid Halide Perovskites.

Hybrid organic-inorganic halide perovskites (HOIPs) have recently attracted tremendous attention because of their excellent semiconducting and optoelectronic properties, which exist despite their morphology and crystallinity being far inferior to those of more mature semiconductors, such as silicon and III-V compound semiconductors. Heteroepitaxy can provide a route to achieving high-performance HOIP devices when high crystalline quality and smooth morphology are required, but work on heteroepitaxial HOIPs has not previously been reported. Here, we demonstrate epitaxial growth of methylammonium lead iodide (MAPbI3) on single crystal KCl substrates with smooth morphology and the highest carrier recombination lifetime (∼213 ns) yet reported for nonsingle crystalline MAPbI3. Experimental Raman spectra agree well with theoretical calculations, presenting in particular a sharp peak at 290 cm-1 for the torsional mode of the organic cations, a marker of orientational order and typically lacking in previous reports. Photodetectors were fabricated showing excellent performance, confirming the high quality of the epitaxial MAPbI3 thin films. This work provides a new strategy to enhance the performance of all HOIPs-based devices.

Atomristor: Nonvolatile Resistance Switching in Atomic Sheets of Transition Metal Dichalcogenides.

Recently, two-dimensional (2D) atomic sheets have inspired new ideas in nanoscience including topologically protected charge transport,1,2 spatially separated excitons,3 and strongly anisotropic heat transport.4 Here, we report the intriguing observation of stable nonvolatile resistance switching (NVRS) in single-layer atomic sheets sandwiched between metal electrodes. NVRS is observed in the prototypical semiconducting (MX2, M = Mo, W; and X = S, Se) transitional metal dichalcogenides (TMDs),5 which alludes to the universality of this phenomenon in TMD monolayers and offers forming-free switching. This observation of NVRS phenomenon, widely attributed to ionic diffusion, filament, and interfacial redox in bulk oxides and electrolytes,6-9 inspires new studies on defects, ion transport, and energetics at the sharp interfaces between atomically thin sheets and conducting electrodes. Our findings overturn the contemporary thinking that nonvolatile switching is not scalable to subnanometre owing to leakage currents.10 Emerging device concepts in nonvolatile flexible memory fabrics, and brain-inspired (neuromorphic) computing could benefit substantially from the wide 2D materials design space. A new major application, zero-static power radio frequency (RF) switching, is demonstrated with a monolayer switch operating to 50 GHz.

High-Throughput Ligand Screening Enables the Enantioselective Conjugate Borylation of Cyclobutenones to Access Synthetically Versatile Tertiary Cyclobutylboronates.

Cyclobutane rings are important in medicinal chemistry, yet few enantioselective methods exist to access this scaffold. In particular, cyclobutylboronates are receiving increasing attention in the literature due to the synthetic versatility of alkylboronic esters and the increasing role of boronic acids in drug discovery. Herein, a conjugate borylation of α-alkyl,ß-aryl/alkyl cyclobutenones is reported leading to the first synthesis of enantioenriched tertiary cyclobutylboronates. Cyclobutanones with two stereogenic centers are obtained in good to high yield, with high enantioselectivity and diastereoselectivity. Vital to this advance are the development of a novel approach to α,ß unsymmetrically disubstituted cyclobutenone substrates and the use of a high-throughput chiral ligand screening platform. The synthetic utility of both the boronic ester and ketone functionalities is displayed, with remarkable chemoselectivity for either group being possible in this small ring scaffold.

Localized dielectric breakdown and antireflection coating in metal-oxide-semiconductor photoelectrodes.

Silicon-based photoelectrodes for solar fuel production have attracted great interest over the past decade, with the major challenge being silicon's vulnerability to corrosion. A metal-insulator-semiconductor architecture, in which an insulator film serves as a protection layer, can prevent corrosion but must also allow low-resistance carrier transport, generally leading to a trade-off between stability and efficiency. In this work, we propose and demonstrate a general method to decouple the two roles of the insulator by employing localized dielectric breakdown. This approach allows the insulator to be thick, which enhances stability, while enabling low-resistance carrier transport as required for efficiency. This method can be applied to various oxides, such as SiO2 and Al2O3. In addition, it is suitable for silicon, III-V compounds, and other optical absorbers for both photocathodes and photoanodes. Finally, the thick metal-oxide layer can serve as a thin-film antireflection coating, which increases light absorption efficiency.

A Copper-Mediated Conjugate Addition Approach to Analogues of Aconitine-Type Diterpenoid Alkaloids.

A copper-mediated conjugate addition of electron-rich aryl groups into a complex vinyl nitrile using arylmagnesium bromides is reported. The conjugate addition adducts were advanced toward the synthesis of designed aconitine-type analogues. The variation in oxygenation patterns on the arene coupling partner, introduced through the current conjugate addition approach, may ultimately provide insight into structure-activity relationships of the diterpenoid alkaloids.

A Unifying Synthesis Approach to the C18-, C19-, and C20-Diterpenoid Alkaloids.

The secondary metabolites that comprise the diterpenoid alkaloids are categorized into C18, C19, and C20 families depending on the number of contiguous carbon atoms that constitute their central framework. Herein, we detail our efforts to prepare these molecules by chemical synthesis, including a photochemical approach, and ultimately a bioinspired strategy that has resulted in the development of a unifying synthesis of one C18 (weisaconitine D), one C19 (liljestrandinine), and three C20 (cochlearenine, paniculamine, and N-ethyl-1α-hydroxy-17-veratroyldictyzine) natural products from a common intermediate.

Syntheses of Denudatine Diterpenoid Alkaloids: Cochlearenine, N-Ethyl-1α-hydroxy-17-veratroyldictyzine, and Paniculamine.

The denudatine-type diterpenoid alkaloids cochlearenine, N-ethyl-1α-hydroxy-17-veratroyldictyzine, and paniculamine have been synthesized for the first time (25, 26, and 26 steps from 16, respectively). These syntheses take advantage of a common intermediate (8) that we have previously employed in preparing aconitine-type natural products. The syntheses reported herein complete the realization of a unified strategy for the preparation of C20, C19, and C18 diterpenoid alkaloids.

A study of the interfacial resistive switching mechanism by proton exchange reactions on the SiO(x) layer.

In this work, we investigated SiO(x)-based interfacial resistive switching in planar metal-insulator-metal structures using physical/chemical/electrical analyses. This work helps clarify the interfacial reaction process and mechanism in SiO(x), and also shows the potential for high temperature operation in future nonvolatile memory applications.

Integrated one diode-one resistor architecture in nanopillar SiOx resistive switching memory by nanosphere lithography.

We report on a highly compact, one diode-one resistor (1D-1R) nanopillar device architecture for SiOx-based ReRAM fabricated using nanosphere lithography (NSL). The intrinsic SiOx-based resistive switching element and Si diode are self-aligned on an epitaxial silicon wafer using NSL and a deep-Si-etch process without conventional photolithography. AC-pulse response in 50 ns regime, multibit operation, and good reliability are demonstrated. The NSL process provides a fast and economical approach to large-scale patterning of high-density 1D-1R ReRAM with good potential for use in future applications.

Post-annealing optimization of the heteroepitaxial La-doped SrSnO3 integrated on silicon via ALD.

Wide band gap (WBG) alkaline-earth stannate transparent oxide semiconductors (TOSs) have attracted increasing attention in recent years for their high carrier mobility and outstanding optoelectronic properties, and have been applied widely in various devices, such as flat-panel displays. Most alkaline-earth stannates are grown by molecular beam epitaxy (MBE); there are some intractable issues with the tin source including the volatility with SnO and Sn sources and the decomposition of the SnO2 source. In contrast, atomic layer deposition (ALD) serves as an ideal technique for the growth of complex stannate perovskites with precise stoichiometry control and tunable thickness at the atomic scale. Herein, we report the La-SrSnO3/BaTiO3 perovskite heterostructure heterogeneously integrated on Si (001), which uses ALD-grown La-doped SrSnO3 (LSSO) as a channel material and MBE-grown BaTiO3 (BTO) as a dielectric material. The reflective high-energy electron diffraction and X-ray diffraction results indicate the crystallinity of each epitaxial layer with a full width at half maximum (FWHM) of 0.62°. In situ X-ray photoelectron spectroscopy results confirm that there was no Sn0 state in ALD-deposited LSSO. Besides, we report a strategy for the post-treatment of LSSO/BTO perovskite heterostructures by controlling the oxygen annealing temperature and time, with a maximum oxide capacitance Cox of 0.31 µF cm-2 and a minimum low-frequency dispersion for the devices with 7 h oxygen annealing at 400 °C. The enhancement of capacitance properties is primarily attributed to a decrease of oxygen vacancies in the films and interface defects in the heterostructure interfaces during an additional ex situ excess oxygen annealing. This work expands current optimization methods for reducing defects in epitaxial LSSO/BTO perovskite heterostructures and shows that excess oxygen annealing is a powerful tool for enhancing the capacitance properties of LSSO/BTO heterostructures.

Use of a sample-to-result shotgun metagenomics platform for the detection and quantification of viral pathogens in paediatric immunocompromised patients.

Background: Infections by several DNA viruses can severely impact outcomes in paediatric immunocompromised patients. Current testing, which is generally limited to singleplex qPCR assays, can miss both common and rarer viruses if they are not targeted. Objectives: To evaluate the performance of the Galileo Viral Panel (Galileo), a sample-to-result shotgun metagenomics platform for the detection and quantification of 12 DNA viruses, compared to standard of care qPCR assays. Study design: A clinical performance evaluation was carried out using 43 prospectively collected EDTA plasma samples positive for one or more DNA viruses. Agreement between assays was assessed by overall, positive, and negative percent agreement, as well as quantitative agreement by linear regression and Bland-Altman analysis. Results: Overall positive percent agreement was 84% (95% CI: 76%-90%), and negative percent agreement was 95% (95% CI: 92%-97%). There was a high correlation between Galileo and qPCR for ADV, CMV, EBV, and VZV (R2  = 0.91) and a mean difference by Bland Altman of -0.43 log10 IU or cp/ml (95% limits of agreement, -1.37 to 0.51). In addition, there was a high correlation between Galileo Signal Score and qPCR for TTV (R2  = 0.85). Conclusion: We observed high qualitative and quantitative agreement between qPCR and Galileo. Galileo identified additional viruses that were not tested with routine qPCR and could impact clinical outcomes.

Wafer-Scalable Single-Layer Amorphous Molybdenum Trioxide.

Molybdenum trioxide (MoO3), an important transition metal oxide (TMO), has been extensively investigated over the past few decades due to its potential in existing and emerging technologies, including catalysis, energy and data storage, electrochromic devices, and sensors. Recently, the growing interest in two-dimensional (2D) materials, often rich in interesting properties and functionalities compared to their bulk counterparts, has led to the investigation of 2D MoO3. However, the realization of large-area true 2D (single to few atom layers thick) MoO3 is yet to be achieved. Here, we demonstrate a facile route to obtain wafer-scale monolayer amorphous MoO3 using 2D MoS2 as a starting material, followed by UV-ozone oxidation at a substrate temperature as low as 120 °C. This simple yet effective process yields smooth, continuous, uniform, and stable monolayer oxide with wafer-scale homogeneity, as confirmed by several characterization techniques, including atomic force microscopy, numerous spectroscopy methods, and scanning transmission electron microscopy. Furthermore, using the subnanometer MoO3 as the active layer sandwiched between two metal electrodes, we demonstrate the thinnest oxide-based nonvolatile resistive switching memory with a low voltage operation and a high ON/OFF ratio. These results (potentially extendable to other TMOs) will enable further exploration of subnanometer stoichiometric MoO3, extending the frontiers of ultrathin flexible oxide materials and devices.

A Library of Atomically Thin 2D Materials Featuring the Conductive-Point Resistive Switching Phenomenon.

Non-volatile resistive switching (NVRS) is a widely available effect in transitional metal oxides, colloquially known as memristors, and of broad interest for memory technology and neuromorphic computing. Until recently, NVRS was not known in other transitional metal dichalcogenides (TMDs), an important material class owing to their atomic thinness enabling the ultimate dimensional scaling. Here, various monolayer or few-layer 2D materials are presented in the conventional vertical structure that exhibit NVRS, including TMDs (MX2 , M = transitional metal, e.g., Mo, W, Re, Sn, or Pt; X = chalcogen, e.g., S, Se, or Te), TMD heterostructure (WS2 /MoS2 ), and an atomically thin insulator (h-BN). These results indicate the universality of the phenomenon in 2D non-conductive materials, and feature low switching voltage, large ON/OFF ratio, and forming-free characteristic. A dissociation-diffusion-adsorption model is proposed, attributing the enhanced conductance to metal atoms/ions adsorption into intrinsic vacancies, a conductive-point mechanism supported by first-principle calculations and scanning tunneling microscopy characterizations. The results motivate further research in the understanding and applications of defects in 2D materials.

Wafer-Scale Synthesis of WS2 Films with In Situ Controllable p-Type Doping by Atomic Layer Deposition.

Wafer-scale synthesis of p-type TMD films is critical for its commercialization in next-generation electro/optoelectronics. In this work, wafer-scale intrinsic n-type WS2 films and in situ Nb-doped p-type WS2 films were synthesized through atomic layer deposition (ALD) on 8-inch α-Al2O3/Si wafers, 2-inch sapphire, and 1 cm2 GaN substrate pieces. The Nb doping concentration was precisely controlled by altering cycle number of Nb precursor and activated by postannealing. WS2 n-FETs and Nb-doped p-FETs with different Nb concentrations have been fabricated using CMOS-compatible processes. X-ray photoelectron spectroscopy, Raman spectroscopy, and Hall measurements confirmed the effective substitutional doping with Nb. The on/off ratio and electron mobility of WS2 n-FET are as high as 105 and 6.85 cm2 V-1 s-1, respectively. In WS2 p-FET with 15-cycle Nb doping, the on/off ratio and hole mobility are 10 and 0.016 cm2 V-1 s-1, respectively. The p-n structure based on n- and p- type WS2 films was proved with a 104 rectifying ratio. The realization of controllable in situ Nb-doped WS2 films paved a way for fabricating wafer-scale complementary WS2 FETs.

Growth Mechanisms and Morphology Engineering of Atomic Layer-Deposited WS2.

Transition-metal dichalcogenides (TMDs) have attracted intense research interest for a broad range of device applications. Atomic layer deposition (ALD), a CMOS compatible technique, can enable the preparation of high-quality TMD films on 8 to 12 in. wafers for large-scale circuit integration. However, the ALD growth mechanisms are still not fully understood. In this work, we systematically investigated the growth mechanisms for WS2 and found them to be strongly affected by nucleation density and film thickness. Transmission electron microscope imaging reveals the coexistence and competition of lateral and vertical growth mechanisms at different growth stages, and the critical thicknesses for each mechanism are obtained. The in-plane lateral growth mode dominates when the film thickness remains less than 5.6 nm (8 layers), while the vertical growth mode dominates when the thickness is greater than 20 nm. From the resulting understanding of these growth mechanisms, the conditions for film deposition were optimized and a maximum grain size of 108 nm was achieved. WS2-based field-effect transistors were fabricated with electron mobility and on/off current ratio up to 3.21 cm2 V-1 s-1 and 105, respectively. Particularly, this work proves the capability of synthesis of TMD films in a wafer scale with excellent controllability of thickness and morphology, enabling many potential applications other than transistors, such as nanowire- or nanosheet-based supercapacitors, batteries, sensors, and catalysis.

An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19.

The worldwide outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. Alongside vaccines, antiviral therapeutics are an important part of the healthcare response to countering the ongoing threat presented by COVID-19. Here, we report the discovery and characterization of PF-07321332, an orally bioavailable SARS-CoV-2 main protease inhibitor with in vitro pan-human coronavirus antiviral activity and excellent off-target selectivity and in vivo safety profiles. PF-07321332 has demonstrated oral activity in a mouse-adapted SARS-CoV-2 model and has achieved oral plasma concentrations exceeding the in vitro antiviral cell potency in a phase 1 clinical trial in healthy human participants.

Resistance state evolution under constant electric stress on a MoS2 non-volatile resistive switching device.

MoS2 has been reported to exhibit a resistive switching phenomenon in a vertical metal-insulator-metal (MIM) structure and has attracted much attention due to its ultra-thin active layer thickness. Here, the resistance evolutions in the high resistance state (HRS) and low resistance state (LRS) are investigated under constant voltage stress (CVS) or constant current stress (CCS) on MoS2 resistive switching devices. Interestingly, compared with bulk transition metal oxides (TMO), MoS2 exhibits an opposite characteristic in the fresh or pre-RESET device in the "HRS" wherein the resistance will increase to an even higher resistance after applying CVS, a unique phenomenon only accessible in 2D-based resistive switching devices. It is inferred that instead of in the highest resistance state, the fresh or pre-RESET devices are in an intermediate state with a small amount of Au embedded in the MoS2 film. Inspired by the capability of both bipolar and unipolar operation, positive and negative CVS measurements are performed and show similar characteristics. In addition, it is observed that the resistance state transition is faster when using higher electric stress. Numerical simulations have been performed to study the temperature effect with small-area integration capability. These results can be explained by a modified conductive-bridge-like model based on Au migration, uncovering the switching mechanisms in the ultrathin 2D materials and inspiring future studies in this area.

Thinnest Nonvolatile Memory Based on Monolayer h-BN.

2D materials have attracted much interest over the past decade in nanoelectronics. However, it was believed that the atomically thin layered materials are not able to show memristive effect in vertically stacked structure, until the recent discovery of monolayer transition metal dichalcogenide (TMD) atomristors, overcoming the scaling limit to sub-nanometer. Herein, the nonvolatile resistance switching (NVRS) phenomenon in monolayer hexagonal boron nitride (h-BN), a typical 2D insulator, is reported. The h-BN atomristors are studied using different electrodes and structures, featuring forming-free switching in both unipolar and bipolar operations, with large on/off ratio (up to 107 ). Moreover, fast switching speed (<15 ns) is demonstrated via pulse operation. Compared with monolayer TMDs, the one-atom-thin h-BN sheet reduces the vertical scaling to ≈0.33 nm, representing a record thickness for memory materials. Simulation results based on ab-initio method reveal that substitution of metal ions into h-BN vacancies during electrical switching is a likely mechanism. The existence of NVRS in monolayer h-BN indicates fruitful interactions between defects, metal ions and interfaces, and can advance emerging applications on ultrathin flexible memory, printed electronics, neuromorphic computing, and radio frequency switches.