Unraveling Differences in the Effects of Ammonium/Amine-Based Additives on the Performance and Stability of Inverted Perovskite Solar Cells.

Additive engineering, with its excellent ability to passivate bulk or surface perovskite defects, has become a common strategy to improve the performance and stability of perovskite solar cells (PVSCs). Among the various additives reported so far, ammonium salts are considered an important branch. It is worth noting that although both ammonium-based additives (R-NH3 +) and amine-based additives (R-NH2) are derivatives of ammonia (NH3), the functions of the two can be easily confused due to their structural similarities. Moreover, there is no comprehensive comparative analysis of them in the literature. Here, the differences between phenethylammonium iodide (PEA+) and phenethylamine (PEA) additives are revealed experimentally and theoretically. The results clearly show that PEA outperforms PEA+ in terms of device performance and stability based on the following three factors: i) PEA's defect passivation capability is superior to that of PEA+; ii) PEA has better hydrophobicity to hinder water ingress; and iii) PEA completely improves the stability of PVSCs by enhancing thermal stability and inhibiting iodide migration in perovskite more effectively than PEA+. As a result, the power conversion efficiency (PCE) of the inverted methylammonium triiodide (MAPbI3) device using PEA increases by ≈15% to over 21%. More importantly, this device exhibits greater ability to prevent water invasion, thermal-induce degradation, and inhibit iodide ion migration, resulting in better long-term stability.

Continuous glucose monitoring versus conventional glucose monitoring in the ICU: A randomized controlled trial.

PURPOSE: This study evaluated the clinical utility of continuous glucose monitoring system (CGMS) in critically ill patients. METHODS: In this randomized controlled trial, we randomly assigned critically ill participants with diabetes or stress-induced hyperglycemia to the CGMS group (n = 48) or to the conventional point-of-care monitoring (POCM) group (n = 48). The glucose values and clinical outcome were compared between the two group. The primary endpoint was 28-day mortality after intensive care unit admission. RESULTS: The 28-day mortality was not significantly different between the CGMS and POCM group (20.8% vs 31.3%, P = 0.25). The mean glucose, time-weighted average glucose, glucose standard deviation and time in range (3.9-10.0) were significantly improved in the CGMS group (all P < 0.05). CONCLUSION: Compared with conventional POCM, CGMS did not decrease the 28-day mortality in critically ill participants with diabetes or stress-induced hyperglycemia. But CGMS may improve the glycemic control and may be increasingly used in critically ill patients.

Insights into the molecular mechanism of ParABS system in chromosome partition by HpParA and HpParB.

The ParABS system, composed of ParA (an ATPase), ParB (a DNA binding protein), and parS (a centromere-like DNA), regulates bacterial chromosome partition. The ParB-parS partition complex interacts with the nucleoid-bound ParA to form the nucleoid-adaptor complex (NAC). In Helicobacter pylori, ParA and ParB homologs are encoded as HpSoj and HpSpo0J (HpParA and HpParB), respectively. We determined the crystal structures of the ATP hydrolysis deficient mutant, HpParAD41A, and the HpParAD41A-DNA complex. We assayed the CTPase activity of HpParB and identified two potential DNA binding modes of HpParB regulated by CTP, one is the specific DNA binding by the DNA binding domain and the other is the non-specific DNA binding through the C-terminal domain under the regulation of CTP. We observed an interaction between HpParAD41A and the N-terminus fragment of HpParB (residue 1-10, HpParBN10) and determined the crystal structure of the ternary complex, HpParAD41A-DNA-HpParBN10 complex which mimics the NAC formation. HpParBN10 binds near the HpParAD41A dimer interface and is clamped by flexible loops, L23 and L34, through a specific cation-π interaction between Arg9 of HpParBN10 and Phe52 of HpParAD41A. We propose a molecular mechanism model of the ParABS system providing insight into chromosome partition in bacteria.

The combined effect of cardiorespiratory and muscular fitness on the incidence of metabolic syndrome before midlife.

BACKGROUND: Cardiorespiratory fitness (CRF) could reduce the risk of metabolic syndrome (MetS) while the association between muscular endurance capacity (MEC) and incident MetS has rarely been investigated in young adults. METHODS: A total of 2890 military men and women, aged 18-39 years, free of baseline MetS in Taiwan, were followed for incident MetS from baseline (2014) until the end of 2020. All subjects received annual health examinations for assessment of MetS. Physical fitness was assessed by CRF (estimated maximal oxygen uptake, VO2 max [mL/kg/min], in a 3000-m run) and MEC (numbers of 2-min push-ups). MetS was defined according to the International Diabetes Federation (IDF) criteria. Multiple Cox regression analysis was conducted with adjustments for baseline age, sex, substance use status and physical activity to determine the associations of CRF and MEC with incidences of new-onset MetS and related features, for example, central obesity, hypertension, dyslipidaemia and prediabetes or diabetes. To examine the combined effects of CRF and MEC status on incidence of MetS, high and low levels of CRF and MEC were separately defined by over and under the sex-specific median in each exercise test. RESULTS: During a median follow-up of 5.8 years, there were 673 (23.3%) new-onset MetS. Higher CRF was associated with a lower incidence of MetS (hazard ratio [HR] and 95% confidence interval: 0.905 [0.877-0.933]), and its components separately, except hypertension. No association was observed between MEC and incident MetS, and its components separately, except hypertension. When evaluating the combined effects of MEC and CRF status on the incidence of MetS, it was observed that compared with the low CRF/low MEC, the high CRF/high MEC (HR: 0.553 [0.439-0.697]) and the high CRF/low MEC (HR: 0.730 [0.580-0.918]) had a lower incidence of new-onset MetS (P value for the intergroup difference = 0.04). There was no significant result for the low CRF/high MEC. CONCLUSIONS: This study highlights that although the protective effects of MEC to reduce the incidence of MetS and most of its related features were mainly driven by CRF in young adults, there was an addictive effect of greater MEC on CRF to prevent the development of new-onset MetS before midlife.

Integrated-omics profiling unveils the disparities of host defense to ECM scaffolds during wound healing in aged individuals.

Extracellular matrix (ECM) scaffold membranes have exhibited promising potential to better the outcomes of wound healing by creating a regenerative microenvironment around. However, when compared to the application in younger individuals, the performance of the same scaffold membrane in promoting re-epithelialization and collagen deposition was observed dissatisfying in aged mice. To comprehensively explore the mechanisms underlying this age-related disparity, we conducted the integrated analysis, combing single-cell RNA sequencing (scRNA-Seq) with spatial transcriptomics, and elucidated six functionally and spatially distinctive macrophage groups and lymphocytes surrounding the ECM scaffolds. Through intergroup comparative analysis and cell-cell communication, we characterized the dysfunction of Spp1+ macrophages in aged mice impeded the activation of the type Ⅱ immune response, thus inhibiting the repair ability of epidermal cells and fibroblasts around the ECM scaffolds. These findings contribute to a deeper understanding of biomaterial applications in varied physiological contexts, thereby paving the way for the development of precision-based biomaterials tailored specifically for aged individuals in future therapeutic strategies.

Diagnostic Value of 99mTc-MIBI Myocardial Perfusion Imaging in Detecting Myocardial Ischemia of Children with Kawasaki Disease and Coronary Artery Lesions.

Pediatric patients with coronary artery lesions (CALs) after Kawasaki disease (KD) may be complicated with myocardial ischemia. Although previous studies in adults have proven the diagnostic value of 99mTc-MIBI myocardial perfusion imaging (MPI) for ischemic heart disease, its feasibility and accuracy in this pediatric population remain uncertain. In this retrospective study, we collected data of 177 pediatric patients (Age range: 6 months to 14 years) who had undergone MPI and coronary artery angiography (CAG) between July 2019 and February 2023. Using the positive result of CAG as the reference standard of myocardial ischemia, we compared the results of 99mTc-MIBI MPI with other non-invasive examinations, including cardiac magnetic resonance imaging (CMRI), echocardiogram, and comprehensive electrocardiogram-related examinations. All patients finished adenosine triphosphate stress MPI without major side effects. The sensitivity of MPI was 79.17%, which was greater than CMRI and echocardiogram (P < 0.05). The negative predictive value and the accuracy of MPI were 89.9% and 71.75%, indicating the advantages over others. Composite monitoring strategy of MPI and CMRI effectively improved the diagnostic performance (P < 0.001). In 4 cases diagnosed with myocardial ischemia by "MPI + CMRI," despite the absence of significant stenosis, multiple giant coronary artery aneurysms (GCAA) were all observed in CAG. 99mTc-MIBI MPI is the preferred non-invasive examination for detecting myocardial ischemia in pediatric patients with CAL after KD. When combined with CMRI, it can enhance diagnostic accuracy. Multiple GCAAs without stenosis may be an isolated risk factor of myocardial ischemia.

Computational Investigation of the Potential and Limitations of Machine Learning with Neural Network Circuits Based on Synaptic Transistors.

Synaptic transistors have been proposed to implement neuron activation functions of neural networks (NNs). While promising to enable compact, fast, inexpensive, and energy-efficient dedicated NN circuits, they also have limitations compared to digital NNs (realized as codes for digital processors), including shape choices of the activation function using particular types of transistor implementation, and instabilities due to noise and other factors present in analog circuits. We present a computational study of the effects of these factors on NN performance and find that, while accuracy competitive with traditional NNs can be realized for many applications, there is high sensitivity to the instability in the shape of the activation function, suggesting that, when highly accurate NNs are required, high-precision circuitry should be developed beyond what has been reported for synaptic transistors to date.

LC-MS/MS and EMIT measure the whole blood concentration of cyclosporine A: The two methods yield concordant results within the dynamic range of the latter, but the former shows broader application scenarios.

Cyclosporine A (CsA) is a widely used immunosuppressive drug with a narrow therapeutic index and large individual differences. Its therapeutic and toxic effects are closely related to blood drug concentrations, requiring routine therapeutic drug monitoring (TDM). The current main methods for TDM of CsA are enzyme multiplied immunoassay technique (EMIT) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). However, few study on the method comparison of the EMIT and LC-MS/MS for the measurement of whole blood CsA concentration in children has been reported. In this study, we developed a simple and sensitive LC-MS/MS assay for the determination of CsA, and 657 cases of CsA concentrations were determined from 197 pediatric patients by a routine EMIT assay and by the validated in-house LC-MS/MS method on the same batch of samples, aimed to address the aforementioned concern. Consistency between the two assays was evaluated using linear regression and Bland-Altman analysis. The linear range of LC-MS/MS was 0.500-2000 ng/mL and that of the EMIT was 40-500 ng/mL, respectively. Overall, the correlation between the two methods was significant (r-value ranging from 0.8842 to 0.9441). Unsatisfactory consistency was observed in the concentrations < 40 ng/mL (r = 0.7325) and 200-500 ng/mL (r = 0.6851). Bland-Altman plot showed a mean bias of -18.0 % (±1.96 SD, -73.8 to 37.8 %) between EMIT and LC-MS/MS. For Passing-Bablok regression between EMIT and LC-MS/MS did not differ significantly (p > 0.05). In conclusion, the two methods were closely correlated, but the CsA concentration by LC-MS/MS assay was slightly higher than that by EMIT method. Switching from the EMIT assay to the LC-MS/MS method was acceptable, and the LC-MS/MS method will receive broader application in clinical settings due to its better analytical capabilities, but the results need to be further verified in different laboratories.

Piperidine and Pyridine Series Lead-Free Dion-Jacobson Phase Tin Perovskite Single Crystals and Their Applications for Field-Effect Transistors.

Two-dimensional (2D) organic-inorganic metal halide perovskites have gained immense attention as alternatives to three-dimensional (3D) perovskites in recent years. The hydrophobic spacers in the layered structure of 2D perovskites make them more moisture-resistant than 3D perovskites. Moreover, they exhibit unique anisotropic electrical transport properties due to a structural confinement effect. In this study, four lead-free Dion-Jacobson (DJ) Sn-based phase perovskite single crystals, 3AMPSnI4, 4AMPSnI4, 3AMPYSnI4, and 4AMPYSnI4 [AMP = (aminomethyl)-piperidinium, AMPY = (aminomethyl)pyridinium] are reported. Results reveal structural differences between them impacting the resulting optical properties. Namely, higher octahedron distortion results in a higher absorption edge. Density functional theory (DFT) is also performed to determine the trends in energy band diagrams, exciton binding energies, and formation energies due to structural differences among the four single crystals. Finally, a field-effect transistor (FET) based on 4AMPSnI4 is demonstrated with a respectable hole mobility of 0.57 cm2 V-1 s-1 requiring a low threshold voltage of only -2.5 V at a drain voltage of -40 V. To the best of our knowledge, this is the third DJ-phase perovskite FET reported to date.

Structures and dynamics of Rpd3S complex bound to nucleosome.

The Rpd3S complex plays a pivotal role in facilitating local histone deacetylation in the transcribed regions to suppress intragenic transcription initiation. Here, we present the cryo-electron microscopy structures of the budding yeast Rpd3S complex in both its apo and three nucleosome-bound states at atomic resolutions, revealing the exquisite architecture of Rpd3S to well accommodate a mononucleosome without linker DNA. The Rpd3S core, containing a Sin3 Lobe and two NB modules, is a rigid complex and provides three positive-charged anchors (Sin3_HCR and two Rco1_NIDs) to connect nucleosomal DNA. In three nucleosome-bound states, the Rpd3S core exhibits three distinct orientations relative to the nucleosome, assisting the sector-shaped deacetylase Rpd3 to locate above the SHL5-6, SHL0-1, or SHL2-3, respectively. Our work provides a structural framework that reveals a dynamic working model for the Rpd3S complex to engage diverse deacetylation sites.

Oral health and physical performance in Asian military males: The cardiorespiratory fitness and health in armed forces.

Background/purpose: It is unclear about whether the oral health has impact on physical performance. Therefore, this study aimed to examine the association between oral health and physical performance in 300 military adults in Taiwan. Materials and methods: Oral health was assessed by the presence of periodontitis and dental caries. The status of cardiorespiratory and muscular endurance capacity was respectively assessed by tertiles of time for a 3000-m run and 2-min push-up numbers. Multivariable logistic and linear regression analyses with adjustments for age, smoking, alcohol drinking, blood pressure, anthropometric variables, lipid profile, fasting glucose and physical activity were used to determine the association. Results: Participants with periodontitis were more likely to have worse 3000-m running performance classified in the lowest tertile [odds ratio (OR) and 95% confidence interval: 1.94 (1.03, 3.66)]. Participants with any dental caries were more likely to have worse push-ups performance classified in the lowest tertile [OR: 2.50 (1.27, 4.92)]. In linear regression analyses, dental caries numbers were inversely correlated with 2-min push-ups numbers [ß = -1.04 (-2.07, -0.01)]. Conclusion: This study suggests that oral health is crucial to maintain physical fitness, and dental caries and periodontitis may affect differently on aerobic and muscular endurance capacities.

Prediction of various insulin resistance indices for the risk of hypertension among military young adults: the CHIEF cohort study, 2014-2020.

BACKGROUND: Non-insulin-based insulin resistance (NI-IR) indices have been reported to have an association with prevalent hypertension, however, no cohort studies to date have compared their prediction of hypertension among young adults. METHODS: A total of 2,448 military men and women, aged 18-39 years, without baseline hypertension in Taiwan were followed for incident hypertension events from 2014 until the end of 2020. All subjects underwent annual health examinations including measurements of blood pressure (BP) in mmHg. Systolic BP (SBP) 130-139/diastolic BP (DBP) < 80, SBP < 130/DBP 80-89, and SBP 130-139/DBP 80-89 were respectively defined as stage I isolated systolic hypertension (ISH), isolated diastolic hypertension (IDH) and combined hypertension (CH). The cut-off levels of stage II hypertension for SBP and DBP were 140-159 and 90-99, respectively. Four NI-IR indices included the ratio of serum triglycerides (TG) to high-density lipoprotein cholesterol (HDL-C), TyG index defined as ln[TG* fasting glucose (FG)/2], Metabolic Score for IR (METS-IR) defined as ln[(2* FG) + TG)* body mass index (BMI)/(ln(HDL-C))], and ZJU index defined as BMI + FG + TG + 3* alanine transaminase/aspartate transaminase (+ 2 if female). Multivariable Cox regression analysis was performed with adjustments for baseline age, sex, body mass index, BP, substance use, family history for early onset cardiovascular diseases or hypertension, low-density lipoprotein cholesterol, kidney function, serum uric acid and physical activity to determine the associations. RESULTS: During a median follow-up of 6.0 years, there were 920 hypertension events (37.6%). Greater TyG, TG/HDL-C and METS-IR indices were associated with a higher risk of stage I IDH (hazard ratios (HRs) and 95% confidence intervals: 1.376 (1.123-1.687), 1.082 (1.039-1.127) and 3.455 (1.921-6.214), respectively), whereas only greater ZJU index was associated with a higher risk of stage II IDH [HRs: 1.011 (1.001-1.021)]. In addition, greater ZJU index was associated with a higher risk of stage II ISH [HR: 1.013 (1.003-1.023)], and greater TyG index was associated with a higher risk of stage II CH [HR: 2.821 (1.244-6.395)]. CONCLUSION: Insulin resistance assessed by various NI-IR indices was associated with a higher risk of hypertension in young adults, while the assessment ability for specific hypertension category may differ by NI-IR indices.

Biological characterization and complete genome analysis of the newly isolated Serratia liquefaciens phage vB_SlqS_ZDD2.

A novel lytic phage named vB_SlqS_ZDD2 was isolated from hospital sewage using the double-layer agar method with Serratia liquefaciens ATCC 27592 as the host. BLASTn analysis showed that the genome sequence of phage vB_SlqS_ZDD2 did not resemble any other phages in the NCBI database. Phenotype and phylogeny analysis indicated that this phage might be a new member of the class Caudoviricetes. Phage vB_SlqS_ZDD2 has a dsDNA genome of 49,178 bp with 55% GC content and has 73 open reading frames. This phage exhibited strong lytic activity and a wide range of pH (3-12) and temperature tolerance (below 70℃).

Scleroglucan protects the intestine from irradiation-induced injury by targeting the IL-17 signaling pathway.

BACKGROUND: Intestinal tissue is extremely sensitive to ionizing radiation (IR), which is easy to cause intestinal radiation sickness, and the mortality rate is very high after exposure. Recent studies have found that intestinal immune cells and intestinal stem cells (ISCs) may play a key role in IR-induced intestinal injury. METHODS: C57BL6 mice matched for age, sex and weight were randomly grouped and intraperitoneal injected with PBS, Scleroglucan (125.0 mg/kg) or Anti-mouse IL-17A -InVivo (10 mg/kg), the number of mice in each group was n ≥ 3.Survival time, body weight, pathology, organoids and immune cell markers of the mice after IR (10.0 Gy) were compared, and the mechanism of action in intestinal tissues was verified by transcriptome sequencing. RESULTS: Scleroglucan has significant radiation protective effects on the intestine, including improving the survival rate of irradiated mice, inhibiting the radiation damage of intestinal tissue, and promoting the proliferation and differentiation of intestinal stem cells (ISCs). The results of RNA sequencing suggested that Scleroglucan could significantly activate the immune system and up-regulate the IL-17 and NF-κB signaling pathways. Flow cytometry showed that Scleroglucan could significantly up-regulate the number of Th17 cells and the level of IL-17A in the gut. IL-17A provides radiation protection. After intraperitoneal injection of Scleroglucan and Anti-mouse IL-17A -InVivo, mice can significantly reverse the radiation protection effect of Scleroglucan, down-regulate the molecular markers of intestinal stem cells and the associated markers of DC, Th1 and Th17 cells, and up-regulate the associated markers of Treg and Macrophage cells. CONCLUSION: Scleroglucan may promote the proliferation and regeneration of ISCs by regulating the activation of intestinal immune function mediated by IL-17 signaling pathway and play a protective role in IR-induced injury.

Enhancing the Performance of 2D Tin-Based Pure Red Perovskite Light-Emitting Diodes through the Synergistic Effect of Natural Antioxidants and Cyclic Molecular Additives.

Tin (Sn)-based perovskites are being investigated in many optoelectronic applications given their similar valence electron configuration to that of lead-based perovskites and the potential environmental hazards of lead-based perovskites. However, the formation of high-quality Sn-based perovskite films faces several challenges, mainly due to the easy oxidation of Sn2+ to Sn4+ and the fast crystallization rate. Here, to develop an environmentally friendly process for Sn-based perovskite fabrication, a series of natural antioxidants are studied as additives and ascorbic acid (VitC) is found to have a superior ability to inhibit the oxidation problem. A common cyclic molecule, 18-Crown-6, is further added as a second additive, which synergizes with VitC to significantly reduce the nonradiative recombination pathways in the PEA2SnI4 film. This synergistic effect greatly improves the performance of 2D red Sn-based PeLED, with a maximum external quantum efficiency of 1.87% (≈9 times that of the pristine device), a purer color, and better bias stability. This work demonstrates the potential of the dual-additive approach in enhancing the performance of 2D Sn-based PeLEDs, while the use of these environmentally friendly additives contributes to their future sustainability.

Investigating the Mobility-Compressibility Properties of Conjugated Polymers by the Contact Film Transfer Method with Prestrain.

Up to now, researches on the mobility-stretchability of semiconducting polymers are extensively investigated, but little attention was  paid to their morphology and field-effect transistor characteristics under compressive strains, which is equally crucial in wearable electronic applications. In this work, a contact film transfer method is applied to evaluate the mobility-compressibility properties of conjugated polymers. A series of isoindigo-bithiophene conjugated polymers with symmetric carbosilane side chains (P(SiSi)), siloxane-terminated alkyl side chains (P(SiOSiO)), and combined asymmetric side chains (P(SiOSi)) are investigated. Accordingly, a compressed elastomer slab is used to transfer and compress the polymer films by releasing prestrain, and the morphology and mobility evolutions of these polymers are tracked. It is found that P(SiOSi) outperforms the other symmetric polymers including P(Si─Si) and P(SiO─SiO), having the ability to dissipate strain with its shortened lamellar spacing and orthogonal chain alignment. Notably, the mechanical durability of P(SiOSi) is also enhanced after consecutive compress-release cycles. In addition, the contact film transfer technique is demonstrated to be applicable to investigate the compressibility of different semiconducting polymers. These results demonstrate a comprehensive approach to understand the mobility-compressibility properties of semiconducting polymers under tensile and compressive strains.

Short-term exposure to ozone may trigger the onset of Kawasaki disease: An individual-level, case-crossover study in East China.

Kawasaki disease (KD) is an acute, systemic vasculitis that primarily affects children aged under the age of 5. While environmental factors have been linked to the development of KD, the specific role of ozone (O3) pollution in triggering the disease onset remains uncertain. This study aimed to examine the associations between short-term O3 exposure and KD onset in children. Utilizing a satellite-based model with a spatial resolution of 1 × 1 km, we matched 1808 KD patients (out of a total of 6115 eligible individuals) to pre-onset ozone exposures based on their home addresses in East China between 2013 and 2020. Our findings revealed a significant association of O3 exposure with KD onset on the day of onset (lag 0 day). However, this association attenuated and became statistically insignificant on lag 1 and lag 2 days. Each interquartile range (52.32 µg/m3) increase in O3 concentration at lag 0 day was associated with a 16.2% (95% CI: 3.6%, 30.3%) increased risk of KD onset. The E-R curve for O3 exhibited a plateau at low concentrations and then increased rapidly at concentrations ≥75 µg/m3. Notably, these associations were stronger in male children, younger children (<2 years of age) and patients experiencing KD onset during the warm season. This study provides novel epidemiological evidence indicating that short-term O3 exposure is associated with an increased risk of childhood KD onset. These findings emphasized the importance of considering this environmental risk factor in KD prevention strategies.

Valorization of spent coffee grounds through integrated bioprocess of fermentable sugars, volatile fatty acids, yeast-based single-cell protein and biofuels production.

Recovering nutrients from waste for biological processes aligns with sustainability principles. This study aimed to convert spent coffee grounds (SCG) into valuable products, including fermentable sugars, volatile fatty acids (VFAs), yeast-based single-cell protein and biofuels. Alkaline pretreatment was conducted before enzymatic hydrolysis, in which the pretreated SCG was hydrolyzed with varying enzyme loadings (20-60 filter paper units (FPU)/g-solid) and solid loadings (3-15 % w/v). The hydrolyzed slurry was utilized for VFAs and hydrogen production, yielding high values of 0.66 g/g-volatile solids (VS) and 109 mL/g-VS, respectively, using an enzyme loading of 50 FPU/g-solid and a solid loading of 3 % (w/v). The derived VFAs were used to cultivate a newly isolated yeast, Candida maltosa KKU-ARY2, resulting in an accumulated protein content of 43.7 % and a biomass concentration of 4.6 g/L. This study highlights the conversion of SCG into essential components, emphasizing the benefits of waste utilization through cascade bioprocesses.

USP2 inhibition prevents infection with ACE2-dependent coronaviruses in vitro and is protective against SARS-CoV-2 in mice.

Targeting angiotensin-converting enzyme 2 (ACE2) represents a promising and effective approach to combat not only the COVID-19 pandemic but also potential future pandemics arising from coronaviruses that depend on ACE2 for infection. Here, we report ubiquitin specific peptidase 2 (USP2) as a host-directed antiviral target; we further describe the development of MS102, an orally available USP2 inhibitor with viable antiviral activity against ACE2-dependent coronaviruses. Mechanistically, USP2 serves as a physiological deubiquitinase of ACE2, and targeted inhibition with specific small-molecule inhibitor ML364 leads to a marked and reversible reduction in ACE2 protein abundance, thereby blocking various ACE2-dependent coronaviruses tested. Using human ACE2 transgenic mouse models, we further demonstrate that ML364 efficiently controls disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as evidenced by reduced viral loads and ameliorated lung inflammation. Furthermore, we improved the in vivo performance of ML364 in terms of both pharmacokinetics and antiviral activity. The resulting lead compound, MS102, holds promise as an oral therapeutic option for treating infections with coronaviruses that are reliant on ACE2.