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The coronavirus SARS-CoV-2 causes the severe disease COVID-19. SARS-CoV-2 infection is initiated by interaction of the viral spike protein and host receptor angiotensin-converting enzyme 2 (ACE2). We report an improved bright and reversible fluorogenic reporter, named SURF (split UnaG-based reversible and fluorogenic protein-protein interaction reporter), that we apply to monitor real-time interactions between spike and ACE2 in living cells. SURF has a large dynamic range with a dark-to-bright fluorescence signal that requires no exogenous cofactors. Utilizing this reporter, we carried out a high-throughput screening of small-molecule libraries. We identified three natural compounds that block replication of SARS-CoV-2 in both Vero cells and human primary nasal and bronchial epithelial cells. Cell biological and biochemical experiments validated all three compounds and showed that they block the early stages of viral infection. Two of the inhibitors, bruceine A and gamabufotalin, were also found to block replication of the Delta and Omicron variants of SARS-CoV-2. Both bruceine A and gamabufotalin exhibited potent antiviral activity in K18-hACE2 and wild-type C57BL6/J mice, as evidenced by reduced viral titres in the lung and brain, and protection from alveolar and peribronchial inflammation in the lung, thereby limiting disease progression. We propose that our fluorescent assay can be applied to identify antiviral compounds with potential as therapeutic treatment for COVID-19 and other respiratory diseases.

A graphene-base hot electron transistor integrated with a 2D material heterojunction is demonstrated as a frequency modulator. Our device can operate as a doubler or tripler with AC signals from 100 kHz to 10 MHz in single tunneling transistor.

We propose that the use of tightly stacked three-dimensional (3D) diamond-shaped Ge nanowire (NW) gate-all-around field-effect transistor (Ge-NW GAAFET) is a feasible approach to continuous scaling. The proposed devices with the Al2O3 dielectric exhibit high ISAT of 1200 μA/μm (pFET) and 1100 μA/μm (nFET), high ION/IOFF ratio of approximately 1×105, and steep subthreshold swing (SS) close to 70mV/dec. Superior gate control of the Ge-NW GAAFET was confirmed by the 3D TCAD simulation for the sub-3nm node applications. The formation of the tightly stacked Ge NWs is fully compatible with the complementary metal oxide semiconductor (CMOS) technology platform using only alternating isotropic and anisotropic dry etching, thus showing promising potential for extending CMOS scaling in the vertical direction.

Controlling the intensity of surface-enhanced Raman spectroscopy (SERS) in a systematic manner is the key to understanding, and even predicting, the dynamics of the imposing phenomenon. It has been...

High-Intensity Functional Training (HIFT) has become a popular mode of exercise. HIFT is a training style that involves performance of coordinated, whole-body exercises at high relative intensities...

Single-crystal silicon (Si) of six monolayer thickness was epitaxially grown on epi-germanium (Ge) in the (001) orientation at substrate temperatures lower than 300 °C, followed by direct depositio...

The lack of effective synthesis techniques for achieving wafer-scale uniformity and high crystallinity remains one of the major obstacles for two-dimensional (2D) layered materials in practical applications. 2D solid-phase crystallization (2DSPC) is proposed based on the area-scalable and semiconductor-process-compatible sputtering and thermal annealing techniques. It successfully synthesizes few-layer 2H-MoTe2 with a monocrystalline grain size exceeding half a centimeter on an amorphous substrate of silicon dioxide. The extremely large grain size is made possible through a two-step annealing process in an inert atmosphere. The initial rapid thermal annealing at high temperatures produces hexagonal monocrystalline 2H-MoTe2 seeds with low density and the subsequent long-duration furnace annealing at low temperatures enlarges the monocrystalline domains only from the pre-existing seeds. The 2DSPC mechanism and its morphological evolution agree with the classical nucleation theory and kinetic Wulff construction theory, respectively. Our result suggests the promising potential of 2DSPC as a simple yet effective route for synthesizing future wafer-scale, high-quality 2D materials.

How SARS-CoV-2 penetrates the airway barrier of mucus and periciliary mucins to infect nasal epithelium remains unclear. Using primary nasal epithelial organoid cultures, we found that the virus attaches to motile cilia via the ACE2 receptor. SARS-CoV-2 traverses the mucus layer, using motile cilia as tracks to access the cell body. Depleting cilia blocks infection for SARS-CoV-2 and other respiratory viruses. SARS-CoV-2 progeny attach to airway microvilli 24 h post-infection and trigger formation of apically extended and highly branched microvilli that organize viral egress from the microvilli back into the mucus layer, supporting a model of virus dispersion throughout airway tissue via mucociliary transport. Phosphoproteomics and kinase inhibition reveal that microvillar remodeling is regulated by p21-activated kinases (PAK). Importantly, Omicron variants bind with higher affinity to motile cilia and show accelerated viral entry. Our work suggests that motile cilia, microvilli, and mucociliary-dependent mucus flow are critical for efficient virus replication in nasal epithelia.

The crystal structure and magnetic, electronic, and thermal properties of a NdSbTe single crystal were examined by X-ray diffraction, magnetic and specific heat Cp(T) measurements, and density func...

The large bandgap and high p-type conductivity of sp2-bonded boron nitride (BN) make the compound very attractive for deep ultraviolet light-emitting diodes (DUV LEDs). However, integrating the pro...

In addition to the Ge-vacancy control of GeTe, the antimony (Sb) substitution of GeTe for the improvement of thermoelectric performance is explored for Ge1−xSbxTe with x = 0.08–0.12. The concomitant carrier concentration (n) and the aliovalent Sb ion substitution led to an optimal doping level of x = 0.10 to show ZT ∼ 2.35 near ∼800 K, which is significantly higher than those single- and multi-element substitution studies of the GeTe system reported in the literature. In addition, Ge0.9Sb0.1Te demonstrates an impressively high power factor of ∼36 μW cm−1 K−2 and a low thermal conductivity of ∼1.1 W m−1 K−1 at 800 K. The enhanced ZT level for Ge0.9Sb0.1Te is explained through a systematic investigation of micro-structural change and strain analysis from room temperature to 800 K. A significant reduction of lattice thermal conductivity (κlat) is identified and explained by the Sb substitution-introduced strained and widened domain boundaries for the herringbone domain structure of Ge0.9Sb0.1Te. The Sb substitution created multiple forms of strain near the defect centre, the herringbone domain structure, and widened tensile/compressive domain boundaries to support phonon scattering that covers a wide frequency range of the phonon spectrum to reduce lattice thermal conductivity effectively.

Understanding viral tropism is an essential step toward reducing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, decreasing mortality from coronavirus disease 2019 (COVID-19) and limiting opportunities for mutant strains to arise. Currently, little is known about the extent to which distinct tissue sites in the human head and neck region and proximal respiratory tract selectively permit SARS-CoV-2 infection and replication. In this translational study, we discover key variabilities in expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), essential SARS-CoV-2 entry factors, among the mucosal tissues of the human proximal airways. We show that SARS-CoV-2 infection is present in all examined head and neck tissues, with a notable tropism for the nasal cavity and tracheal mucosa. Finally, we uncover an association between smoking and higher SARS-CoV-2 viral infection in the human proximal airway, which may explain the increased susceptibility of smokers to developing severe COVID-19. This is at least partially explained by differences in interferon (IFN)-β1 levels between smokers and non-smokers., Graphical Abstract, Nakayama et al. discover key variabilities in expression of SARS-CoV-2 entry factors among human head and neck mucosal tissues. They demonstrate that SARS-CoV-2 preferentially infects the nasal cavity and trachea. They uncover an association between smoking and higher SARS-CoV-2 in the human proximal airway, in part because of differences in IFN-β1 expression.

The respiratory disease COVID-19 is caused by the coronavirus SARS-CoV-2. Here we report the discovery of ethacridine as a potent drug against SARS-CoV-2 (EC50 ~ 0.08 μM). Ethacridine was identified via high-throughput screening of an FDA-approved drug library in living cells using a fluorescence assay. Plaque assays, RT-PCR and immunofluorescence imaging at various stages of viral infection demonstrate that the main mode of action of ethacridine is through inactivation of viral particles, preventing their binding to the host cells. Consistently, ethacridine is effective in various cell types, including primary human nasal epithelial cells that are cultured in an air-liquid interface. Taken together, our work identifies a promising, potent, and new use of the old drug via a distinct mode of action for inhibiting SARS-CoV-2.

Summary RNA viruses generate defective viral genomes (DVG) that can interfere with replication of the parental wild-type virus. To examine their therapeutic potential, we created a DVG by deleting the capsid-coding region of poliovirus. Strikingly, intraperitoneal or intranasal administration of this genome, which we termed eTIP1, elicits an antiviral response, inhibits replication and protects mice from several RNA viruses, including enteroviruses, influenza and SARS-CoV-2. While eTIP1 replication following intranasal administration is limited to the nasal cavity, its antiviral action extends non-cell-autonomously to the lungs. eTIP1 broad-spectrum antiviral effects are mediated by both local and distal type I interferon responses. Importantly, while a single eTIP1 dose protects animals from SARS-CoV-2 infection, it also stimulates production of SARS-CoV-2 neutralizing antibodies that afford long-lasting protection from SARS-CoV-2 reinfection. Thus, eTIP1 is a safe and effective broad-spectrum antiviral generating short- and long-term protection against SARS-CoV-2 and other respiratory infections in animal models.

Emerging evidence points toward an intricate relationship between the pandemic of coronavirus disease 2019 (COVID-19) and diabetes. While preexisting diabetes is associated with severe COVID-19, it is unclear whether COVID-19 severity is a cause or consequence of diabetes. To mechanistically link COVID-19 to diabetes, we tested whether insulin-producing pancreatic β cells can be infected by SARS-CoV-2 and cause β cell depletion. We found that the SARS-CoV-2 receptor, ACE2, and related entry factors (TMPRSS2, NRP1, and TRFC) are expressed in β cells, with selectively high expression of NRP1. We discovered that SARS-CoV-2 infects human pancreatic β cells in patients who succumbed to COVID-19 and selectively infects human islet β cells in vitro. We demonstrated that SARS-CoV-2 infection attenuates pancreatic insulin levels and secretion and induces β cell apoptosis, each rescued by NRP1 inhibition. Phosphoproteomic pathway analysis of infected islets indicates apoptotic β cell signaling, similar to that observed in type 1 diabetes (T1D). In summary, our study shows SARS-CoV-2 can directly induce β cell killing., Graphical abstract, Diabetic patients are at risk for severe COVID-19, but the virus may further damage insulin-secreting β cells. Wu et al. found that patient β cells are virally infected and the highly expressed neuropilin-1 receptor is critical for viral entry, causing cell death and reduced insulin secretion, exacerbating diabetes in patients.

We demonstrate that the upconversion nanoparticles (UCNPs) fluoresce 50 times more on a gold (Au) coated Cicada wing. UCNPs are attractive bioimaging, and therapeutic materials as it is excited in the infrared, limited only by the low fluorescence quantum yield. Here, a plasmonic effect, coupled with an anti-reflecting (AR) Cicada wing substrate coated with Au is demonstrated to enhance the fluorescence of the UCNPs. Silica (SiO2) coated Erbium doped green emitting core-shell UCNPs (NaYF4: Yb3+, Er3+@SiO2) show conventional metal enhanced fluorescence. The AR property of the Cicada wing (R ~0.2% @ 1000 nm) contributes >6-fold enhancement as compared to flat (silicon, and quartz) substrates (R~10–30% @ 1000 nm). Upon plasmon coupling, with an optimally sputtered Au coating, an unprecedented enhancement of >50-fold for the 520, and 655 nm emission was obtained on the Au coated Cicada wings, vis-a-vis planar uncoated (silicon, and quartz) substrates. The enhancement was also confirmed by direct fluorescence imaging of the photonic substrates used. The fluorescence lifetime of the core, and the core-shell UCNPs (~300 μs) decreased by ~30–40%, and 10–30%, respectively, when placed on Au coated substrates.

A highly reproducible sample preparation method for pure GeTe in a rhombohedral structure without converting to the cubic structure up to ∼500 °C is reported to show control of the Ge-vacancy level and the corresponding herringbone-structured microdomains. The thermoelectric figure-of-merit (ZT) for GeTe powder could be raised from ∼0.8 to 1.37 at high temperature (HT) near ∼500 °C by tuning the Ge-vacancy level through the applied reversible in situ route, which made it highly controllable and reproducible. The enhanced ZT of GeTe was found to be strongly correlated with both its significantly increased Seebeck coefficient (∼161 μV K−1 at 500 °C) and reduced thermal conductivity (∼2.62 W m−1 K−1 at 500 °C) for a sample with nearly vacancy-free thicker herringbone-structured microdomains in the suppressed rhombohedral-to-cubic structure phase transformation. The microdomain and crystal structures were identified with HR-TEM (high-resolution transmission electron microscopy) and powder X-ray diffraction (XRD), while electron probe micro-analysis (EPMA) was used to confirm the stoichiometry changes of Ge : Te. Theoretical calculations for GeTe with various Ge-vacancy levels suggested that the Fermi level shifts toward the valence band as a function of increasing the Ge-vacancy level, which is consistent with the increased hole-type carrier concentration (n) and effective mass (m*) deduced from the Hall measurements. The uniquely prepared sample of a near-vacancy-free GeTe in a rhombohedral structure at high temperature favoured an enhanced Seebeck coefficient in view of the converging L- and Σ-bands of the heavy effective mass at the Fermi level, while the high density domain boundaries for the domain of low carrier density were shown to reduce the total thermal conductivity effectively.

Multiple G protein-coupled receptors (GPCRs) are expressed in pancreatic islet cells, but the majority have unknown functions. We observed specific GPCRs localized to primary cilia, a prominent signaling organelle, in pancreatic α and β cells. Loss of cilia disrupts β-cell endocrine function, but the molecular drivers are unknown. Using functional expression, we identified multiple GPCRs localized to cilia in mouse and human islet α and β cells, including FFAR4, PTGER4, ADRB2, KISS1R, and P2RY14. Free fatty acid receptor 4 (FFAR4) and prostaglandin E receptor 4 (PTGER4) agonists stimulate ciliary cAMP signaling and promote glucagon and insulin secretion by α- and β-cell lines and by mouse and human islets. Transport of GPCRs to primary cilia requires TULP3, whose knockdown in primary human and mouse islets relocalized ciliary FFAR4 and PTGER4 and impaired regulated glucagon or insulin secretion, without affecting ciliary structure. Our findings provide index evidence that regulated hormone secretion by islet α and β cells is controlled by ciliary GPCRs providing new targets for diabetes.

For the first time, we demonstrate heterogeneous complementary FETs (hCFETs) with Ge and Si channels fabricated with a layer transfer technique. The 3D channel stacking integration particularly employs a low-temperature (200 °C) hetero-layers bonding technique (LT-HBT) realized by a surface activating chemical treatment at room temperature, enabling Ge channels bonded onto Si wafers. Furthermore, to obtain symmetric performance in n/p FETs, a multi-channel structure of two-channel Si and one-channel Ge is also implemented. Wafer-scale LT-HBT is demonstrated successfully, showing new opportunities for the ultimate device footprint scaling with heterogeneous integration.

The coronavirus SARS-CoV-2 is the causative agent of the ongoing severe acute respiratory disease pandemic COVID-19. Tissue and cellular tropism is one key to understanding the pathogenesis of SARS-CoV-2. We investigate the expression and subcellular localization of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), within the upper (nasal) and lower (pulmonary) respiratory tracts of human donors using a diverse panel of banked tissues. Here, we report our discovery that the ACE2 receptor protein robustly localizes within the motile cilia of airway epithelial cells, which likely represents the initial or early subcellular site of SARS-CoV-2 viral entry during host respiratory transmission. We further determine whether ciliary ACE2 expression in the upper airway is influenced by patient demographics, clinical characteristics, comorbidities, or medication use, and show the first mechanistic evidence that the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs) does not increase susceptibility to SARS-CoV-2 infection through enhancing the expression of ciliary ACE2 receptor. These findings are crucial to our understanding of the transmission of SARS-CoV-2 for prevention and control of this virulent pathogen., Understanding how SARS-CoV-2 gains initial entry into the human body is a key step towards the development of prophylaxes and therapeutics for COVID-19. Here, the authors show that ACE2, the receptor for SARS-CoV-2, is abundantly expressed in the motile cilia of the human nasal and respiratory tract and is not affected by the use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers.

The respiratory disease COVID-19 is caused by the coronavirus SARS-CoV-2. Here we report the discovery of ethacridine as a potent drug against SARS-CoV-2 (EC50 ~ 0.08 μM). Ethacridine was identified via high-throughput screening of an FDA-approved drug library in living cells using a fluorescence assay. Plaque assays, RT-PCR and immunofluorescence imaging at various stages of viral infection demonstrate that the main mode of action of ethacridine is through inactivation of viral particles, preventing their binding to the host cells. Consistently, ethacridine is effective in various cell types, including primary human nasal epithelial cells that are cultured in an air-liquid interface. Taken together, our work identifies a promising, potent, and new use of the old drug via a distinct mode of action for inhibiting SARS-CoV-2., Author summary To identify inhibitors against SARS-CoV-2, here we have designed and demonstrated a high throughput screening system that works in living cells at BSL2. To repurpose existing drugs, we have screened an FDA-approved drug library and identified several drugs that inhibit Mpro and block SARS-CoV-2 in cells. Interestingly, one of the identified drugs, ethacridine, shows ~40-fold higher antiviral activity than its antiprotease activity. Further studies unveil that ethacridine inhibits the coronavirus by inactivating the viral particles. Our work demonstrated a powerful tool to screen protease inhibitors to inhibit coronavirus, as well as other diseases in the future.

SummaryMultiple G protein coupled receptors (GPCRs) are expressed in pancreatic islet cells but the majority have unknown functions. We observe specific GPCRs localized to primary cilia, a prominent signaling organelle, in pancreatic α- and β-cells. Loss of cilia disrupts β-cell endocrine function, but the molecular drivers are unknown. Using functional expression, we identified multiple GPCRs localized to cilia in mouse and human islet α- and β-cells, including FFAR4, PTGER4, DRD5, ADRB2, KISS1R, and P2RY14. Free fatty acid receptor 4 (FFAR4) and prostaglandin E receptor 4 (PTGER4) agonists stimulate ciliary cAMP signaling and promote glucagon and insulin secretion by α- and β-cell lines, and by mouse and human islets. Transport of GPCRs to primary cilia requires TULP3, whose knockdown in primary human and mouse islets depleted ciliary FFAR4 and PTGER4, and impaired regulated glucagon or insulin secretion, without affecting ciliary structure. Our findings provide index evidence that regulated hormone secretion by islet α- and β-cells is regulated by ciliary GPCRs providing new targets for diabetes.

The role of an atomic-layer thick periodic Y&ndash, O array in inducing the epitaxial growth of single-crystal hexagonal YAlO3 perovskite (H-YAP) films was studied using high-angle annular dark-field and annular bright-field scanning transmission electron microscopy in conjunction with a spherical aberration-corrected probe and in situ reflection high-energy electron diffraction. We observed the Y&ndash, O array at the interface of amorphous atomic layer deposition (ALD) sub-nano-laminated (snl) Al2O3/Y2O3 multilayers and GaAs(111)A, with the first film deposition being three cycles of ALD-Y2O3. This thin array was a seed layer for growing the H-YAP from the ALD snl multilayers with 900 &deg, C rapid thermal annealing (RTA). The annealed film only contained H-YAP with an excellent crystallinity and an atomically sharp interface with the substrate. The initial Y&ndash, O array became the bottom layer of H-YAP, bonding with Ga, the top layer of GaAs. Using a similar ALD snl multilayer, but with the first film deposition of three ALD-Al2O3 cycles, there was no observation of a periodic atomic array at the interface. RTA of the sample to 900 &deg, C resulted in a non-uniform film, mixing amorphous regions and island-like H-YAP domains. The results indicate that the epitaxial H-YAP was induced from the atomic-layer thick periodic Y&ndash, O array, rather than from GaAs(111)A.

Defects in primary cilia result in syndromes collectively called “ciliopathies”, which often present with obesity and diabetes. Although glucose is the primary mediator of GSIS, circulating factors including free fatty acids, amino acids, and various hormones also play critical roles. At the interface between these circulating factors and GSIS, GPCR signaling is often central. The primary cilium is a membrane and microtubule-based sensory organelle and is highly enriched with specialized GPCRs. Cilia are present on pancreatic β-cells, but the role of cilia in β-cell function remains unclear. To discover ciliary GPCRs important for β-cell function, we compiled a list of candidate β-cell specific or highly expressed GPCRs based on human pancreatic gene expression profiles. We identified 66 β-cell specific GPCRs comparing with α-cells and acinar-cells. These 66 candidate GPCRs was expressed as C-terminally tagged GFP fusion proteins and screened for ciliary localization in a mouse pancreatic β-cell line, MIN6. To date, we have identified the following GPCRs localize to cilia in MIN6 cells: FFAR4, PTGER4, ADRB2, KISS1R, and P2RY14. To validate ciliary localization of GPCRs, we also used antibodies against the endogenous GPCRs. We have confirmed that the free fatty acid receptor 4 (Ffar4) and the prostaglandin E receptor 4 (Ptger4) are localized to the primary cilium of mouse and human β-cells. In addition, the treatment of each of agonists of these receptors promote glucose-stimulated insulin secretion (GSIS) in mouse and human islet. Tulp3 is required for transporting GPCRs into the primary cilium. We used shRNA targeting Tulp3 delivered by lentivirus to knock-down Tulp3 in mouse and human islet cells. Tulp3 depletion leaves ciliary structure intact but impairs the localization of Ffar4 and Ptger4 in cilia and disrupts agonist-stimulated GSIS in mouse and human pseudo-islets. Together, these data suggest that primary cilia and ciliary GPCRs are important for the circulating factors-regulated GSIS in β-cell. Disclosure C. Wu: None. K. Hilgendorf: None. Y. Hang: None. R.J. Bevacqua: None. C.T. Johnson: None. C.A. Chang: None. S. Park: None. K. Tellez: None. S. Kim: None. P.K. Jackson: None. Funding Stanford Diabetes Research Center

We investigated the expression and subcellular localization of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), within the upper (nasal) and lower (pulmonary) respiratory tracts of healthy human donors. We detected ACE2 protein expression within the cilia organelle of ciliated airway epithelial cells, which likely represents the initial or early subcellular site of SARS-CoV-2 viral entry during respiratory transmission. We further determined whether ACE2 expression in the cilia of upper respiratory cells was influenced by patient demographics, clinical characteristics, co-morbidities, or medication use, and found no evidence that the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs) increases ACE2 protein expression.

For the first time, CMOS inverters and 6T-SRAM cells based on vertically stacked gate-all-around complementary FETs (CFETs) are experimentally demonstrated. Manufacturing difficulties of vertically stacked source and drain electrodes of the CFETs have been overcome by using junctionless transistors, thereby reducing the number of lithographic steps required. Furthermore, with post metallization treatments, both the voltage transfer characteristics (VTCs) of CMOS inverters and butterfly curves of SRAM show significant improvements due to the symmetry of nMOS and pMOS threshold voltages. Simulation shows that 3-dimensional CFET inverters have lower input parasitic capacitance than standard 2-dimensional CMOS, leading to reduced gate delay and lower power consumption.

For the first time, below 400°C-fabricated gate-all-around (GAA) transistor fabrication process was demonstrated with monolithic computing-in-memory (CIM) circuit. Key enablers are plasma-assisted atomic layer etching (PA-ALE), plasma immersion ion implantation (PIII) and far-infrared laser activation (FIR-LA). The 3D stackable single-grained Si GAA MOSFETs thus fabricated exhibit record-high I on /I off ratio (~108) with low I off (pFETs