Olgotrelvir, a dual inhibitor of SARS-CoV-2 Mpro and cathepsin L, as a standalone antiviral oral intervention candidate for COVID-19.

BACKGROUND: Oral antiviral drugs with improved antiviral potency and safety are needed to address current challenges in clinical practice for treatment of COVID-19, including the risks of rebound, drug-drug interactions, and emerging resistance. METHODS: Olgotrelvir (STI-1558) is designed as a next-generation antiviral targeting the SARS-CoV-2 main protease (Mpro), an essential enzyme for SARS-CoV-2 replication, and human cathepsin L (CTSL), a key enzyme for SARS-CoV-2 entry into host cells. FINDINGS: Olgotrelvir is a highly bioavailable oral prodrug that is converted in plasma to its active form, AC1115. The dual mechanism of action of olgotrelvir and AC1115 was confirmed by enzyme activity inhibition assays and co-crystal structures of AC1115 with SARS-CoV-2 Mpro and human CTSL. AC1115 displayed antiviral activity by inhibiting replication of all tested SARS-CoV-2 variants in cell culture systems. Olgotrelvir also inhibited viral entry into cells using SARS-CoV-2 Spike-mediated pseudotypes by inhibition of host CTSL. In the K18-hACE2 transgenic mouse model of SARS-CoV-2-mediated disease, olgotrelvir significantly reduced the virus load in the lungs, prevented body weight loss, and reduced cytokine release and lung pathologies. Olgotrelvir demonstrated potent activity against the nirmatrelvir-resistant Mpro E166 mutants. Olgotrelvir showed enhanced oral bioavailability in animal models and in humans with significant plasma exposure without ritonavir. In phase I studies (ClinicalTrials.gov: NCT05364840 and NCT05523739), olgotrelvir demonstrated a favorable safety profile and antiviral activity. CONCLUSIONS: Olgotrelvir is an oral inhibitor targeting Mpro and CTSL with high antiviral activity and plasma exposure and is a standalone treatment candidate for COVID-19. FUNDING: Funded by Sorrento Therapeutics.

Mechanical properties of cemented tailings backfill with chloride-free antifreeze.

In cold regions with sub-zero surface temperatures, the addition of chloride-free antifreeze (Ca(NO2)2, Ca(NO3)2, and CO(NH2)2) is an inexpensive method to prevent pipeline freezing during cemented tailings backfill (CTB) transport. However, the curing temperature of CTB after reaching the mine cavity tends to be above-zero. The mechanical properties of CTB with a chloride-free antifreeze in above-zero environments have not been investigated. Therefore, this study aimed at thoroughly exploring the effect of chloride-free antifreeze on the mechanical properties of CTB in above-zero environments. CTB samples with chloride-free antifreeze (Ca(NO2)2, Ca(NO3)2, and CO(NH2)2) and different concentrations (0, 5, 15, and 35 g/L) were prepared and cured in different above-zero environments (2, 20, and 35 °C). The unconfined compressive strength tests were performed after 1, 3, 7, and 28 days. In addition, a series of microstructural analyses and monitoring experiments were conducted. The results indicated that the addition of a 15-g/L chloride-free antifreeze decreased the strength of CTB curing at 20 °C after 1, 3, and 7 days and increased the strength after 28 days. Moreover, the CTB strength evolution with the curing time depends on the chloride-free antifreeze concentration and above-zero curing temperature. According to the TG/DTG analyses results, calcium ions had a promoting effect on the carbonation of calcium hydroxide. The findings of this study can provide a guideline for the application of chloride-free antifreeze on the mine backfill in cold regions.

Nonadiabatic dynamics studies of the H(2S) + RbH(X1Σ+) reaction: based on new diabatic potential energy surfaces.

The global diabatic potential energy surfaces (PESs) that correspond to the ground (12A') and first excited states (22A') of the RbH2 system PES are constructed based on 17 786 ab initio points. The neural network method is used to fit the PESs and the topographic features of the new diabatic PESs are discussed in detail. Based on the newly constructed diabatic PESs, the dynamics calculations of the H(2S) + RbH(X1Σ+) → Rb(52S) + H2(X1Σg +)/Rb(52P) + H2(X1Σg +) reactions are performed using the time-dependent wave packet method. The dynamics properties of these two channels such as the reaction probabilities, integral cross sections, and differential cross sections (DCSs) are calculated at state-to-state level of theory. The nonadiabatic effects are discussed in detail, and the results indicate that the adiabatic results are overestimated from the dynamics values. The DCSs of these two channels are forward biased, which indicates that the abstraction mechanism plays a dominant role in the reaction.

A Bond-Wire Drift Offset Minimized Capacitance-to-Digital Interface for MEMS Accelerometer with Gain-Enhanced VCO-Based Quantization and Nested Digital Chopping Feedback Loops.

This paper presents an output offset minimized capacitance-to-digital interface for a MEMS accelerometer. With a gain-enhanced voltage-controlled oscillator (VCO)-based quantization loop, the interface is able to output a digital signal with improved dynamic range. For optimizing the output offset caused by nonideal factors (e.g., the bond-wire drift), a nested digital chopping feedback loop is embedded in the VCO-based quantization loop. It enables the interface to minimize the output offset without digital filtering and digital-to-analog conversion. The proposed architecture is well suited for dynamic range and offset improvements with low cost. Fabricated with a 0.18 µm Global Foundry (GF) CMOS process, the interface offers a 78 dB dynamic range with 0.4% nonlinearity from a single 2 V supply. With the input referred offset up to 1.3 pF, the offset cancellation loop keeps the DC output offset within 40 mV. The power dissipation is 6.5 mW with a bandwidth of 4 kHz.

Tuning Surface Wettability of Buffer Layers by Incorporating Polyethylene Glycols for Enhanced Performance of Perovskite Solar Cells.

Phenyl-C61-butyric acid methyl ester (PCBM) has been widely researched as a passivate electron transport layer in planar n-i-p-type perovskite solar cells (PSCs). However, due to the terrible wettability of PCBM, the growth of perfect large-area perovskite films on the electron transport layer treated by PCBM is a huge challenge, which limits the commercial application of PSCs. Herein, we incorporate a hydrophilic polymer polyethylene glycol (PEG) into PCBM to ameliorate its wettability. A high-quality perovskite film can be prepared on a 2 × 2 cm substrate. Hydrogen-bonding effects between the PEG-PCBM buffer layer and the perovskite layer can further stabilize the electron transport layer/perovskite interface. Based on the improved electron transport and suppressed carrier recombination, a device with an active area of 1.03 cm2 achieves an efficiency of 18.25%. In addition, the first-principles calculations indicate that PEG has stronger adsorption (Eads = -0.37) toward H2O than the MAPbI3 perovskite (Eads = -0.25), which can prevent water molecules from infiltrating the perovskite. The unsealed device still maintains 90% of the initial efficiency under ambient conditions, with 30-40% relative humidity for 22 days. These outstanding properties are attributed to the unique molecular structure and prominent wettability of PEG.

Analysis and design of a 3rd order velocity-controlled closed-loop for MEMS vibratory gyroscopes.

The time-average method currently available is limited to analyzing the specific performance of the automatic gain control-proportional and integral (AGC-PI) based velocity-controlled closed-loop in a micro-electro-mechanical systems (MEMS) vibratory gyroscope, since it is hard to solve nonlinear functions in the time domain when the control loop reaches to 3rd order. In this paper, we propose a linearization design approach to overcome this limitation by establishing a 3rd order linear model of the control loop and transferring the analysis to the frequency domain. Order reduction is applied on the built linear model's transfer function by constructing a zero-pole doublet, and therefore mathematical expression of each control loop's performance specification is obtained. Then an optimization methodology is summarized, which reveals that a robust, stable and swift control loop can be achieved by carefully selecting the system parameters following a priority order. Closed-loop drive circuits are designed and implemented using 0.35 µm complementary metal oxide semiconductor (CMOS) process, and experiments carried out on a gyroscope prototype verify the optimization methodology that an optimized stability of the control loop can be achieved by constructing the zero-pole doublet, and disturbance rejection capability (D.R.C) of the control loop can be improved by increasing the integral term.

[Primary clinical outcome of the tongue mobility via deep cervical nerve or accessory nerve-restored sublingual nerve].

OBJECTIVE: To explore the clinical prognosis of sublingual nerve anastomosis with a branch of the deep cervical nerves or accessory nerve. METHOD: To retrospectively analyze 2 cases of paraganglion tumor,in which the sublingual nerve were disconnected because of overdrawing of surrounding tissue and tumor invasion. One branch of deep cervical nerve or accessory nerve was dissected and anastomosed to the distal end of sublingual nerve. Steroids and nerve nutritional chemicals were given after operation, and early functional physical exercise was recommended for the two patients. RESULT: The lingual mobility of the two patients was restored partially 1 to 2 months after operation, while the tongue of lesion side suffered from slight atrophy especially in the posterior 1/2 part. The patients experienced better and better mobility of the tongue. CONCLUSION: Sublingual nerve anastomosis with a branch of the deep cervical nerves or accessory nerve is viable. It could be a reconstructive modality for patients suffered from sublingual nerve disconnected.