Effects of monoglycerides of short and medium chain fatty acids and cinnamaldehyde blend on the growth, survival, immune responses, and tolerance to hypoxic stress of Pacific white shrimp (Litopenaeus vannamei).

Free fatty acids have long been used as dietary supplements in aquaculture, but the application of monoglycerides has increased interest in more recent times. The study aimed to investigate the effects of dietary short- and medium-chain fatty acid monoglyceride and cinnamaldehyde (SMMG) on the growth performance, survival, immune responses, and tolerance to hypoxic stress of Pacific white shrimp (Litopenaeus vannamei). In Experiment 1, shrimp post-larvae were divided into 4 groups with 6 replicates and fed with diets supplemented with 0 (control), 0.3, 0.4, and 0.5% diet for 30 days. The final body weight and survival rate were determined. In Experiment 2, the juvenile shrimp from Experiment 1 were subjected to hypoxic stress conditions (dissolved oxygen level 2-2.5 mg/L) for 14 days, then the specific growth rate (SGR), survival rate, intestinal Vibrio spp. count, immune responses, and histopathological change of the hepatopancreas were analyzed. Following the 30-day feeding trial, the results revealed that the final body weight and survival of the 0.3-0.5% SMMG groups (2.81-3.06 g and 74.00-84.33%, respectively) were significantly higher than the control shrimp (1.96 g and 68.33%, respectively). In the hypoxic stress experiment, the survival rates of shrimp fed 0.4-0.5% SMMG (71.67-80.00%) were significantly higher than the control (51.67%). Although the SGR were not affected by SMMG supplementation, all immune parameters evaluated were significantly enhanced, and the intestinal Vibrio spp. counts were significantly decreased in the 0.4-0.5% SMMG-fed shrimp; the histopathological structure of the hepatopancreas was also improved in these shrimp compared to the control. Our findings indicated that SMMG as a feed additive has beneficial effects in improving shrimp health and increasing tolerance to hypoxic conditions.

Isomeric Effects of Au28(S-c-C6H11)20 Nanoclusters on Photoluminescence: Roles of Electron-Vibration Coupling and Higher Triplet State.

The exploration of near-infrared photoluminescence (PL) from atomically precise nanoclusters is currently a prominent area of interest owing to its importance in both fundamental research and diverse applications. In this work, we investigate the near-infrared (NIR) photoluminescence mechanisms of two structural isomers of atomically precise gold nanoclusters of 28 atoms protected by cyclohexanethiolate (CHT) ligands, i.e., Au28i(CHT)20 and Au28ii(CHT)20. Based on their structures, analysis of 3O2 (triplet oxygen) quenching of the nanocluster triplet states, temperature-dependent photophysical studies, and theoretical calculations, we have elucidated the intricate processes governing the photoluminescence of these isomeric nanoclusters. For Au28i(CHT)20, its emission characteristics are identified as phosphorescence plus thermally activated delayed fluorescence (TADF) with a PL quantum yield (PLQY) of 0.3% in dichloromethane under ambient conditions. In contrast, the Au28ii(CHT)20 isomer exhibits exclusive phosphorescence with a PLQY of 3.7% in dichloromethane under ambient conditions. Theoretical simulations reveal a larger singlet (S1)-triplet (T1) gap in Au28ii than that in Au28i, and the higher T2 state plays a critical role in both isomers' photophysical processes. The insights derived from this investigation not only contribute to a more profound comprehension of the fundamental principles underlying the photoluminescence of atomically precise gold nanoclusters but also provide avenues for tailoring their optical properties for diverse applications.

Hetero and Homo Metal Exchange of Au25(SR)18 - and Ag25(SR)18 - Clusters with Metal-Thiolate Complexes: Ab Initio Molecular Dynamics Simulation Studies.

The hetero and homo metal exchange of Au25(SR)18 - and Ag25(SR)18 - nanoclusters with metal-thiolate (M-SR) complexes (AuI(SR), AgI(SR), CuI(SR), and CuII(SR)2) are studied using ab initio molecular dynamics (AIMD) simulations. The AIMD simulation results unveil that the M-SR complexes directly displace Au(SR) or Ag(SR) units on the gold or silver core surface through an "anchoring effect". The whole process of metal-exchange reactions can be divided into three steps, including the adsorption of M-SR complexes on clusters, the formation of new staple motif, and the displacement of Au(SR) or Ag(SR) units by M-SR complexes. The key role of sulfur atoms in metal exchange reactions in M-SR complexes is revealed, which facilitates formation of new staple motifs and doping of M-SR complexes into gold and silver cores. This work provides a theoretical basis for further exploring the metal exchange reaction between noble metal nanoclusters and metal-thiolate complexes, as well as the isotope exchange reactions.

Theoretical calculations and simulations power the design of inorganic solid-state electrolytes.

Using solid-state electrolytes (SSEs) to build batteries helps improve the safety and lifespan of batteries, making it crucial to deeply understand the fundamental physical and chemical properties of SSEs. Theoretical calculations based on modern quantum chemical methods and molecular simulation techniques can explore the relationship between the structure and performance of SSEs at the atomic and molecular levels. In this review, we first comprehensively introduce theoretical methods used to assess the stability of SSEs, including mechanical, phase, and electrochemical stability, and summarize the significant progress achieved through these methods. Next, we outline the methods for calculating ion diffusion properties and discuss the advantages and limitations of these methods by combining the diffusion behaviors and mechanisms of ions in the bulk phase, grain boundaries, and electrode-solid electrolyte interfaces. Finally, we summarize the latest research progress in the discovery of high-quality SSEs through high-throughput screening and machine learning and discuss the application prospects of a new mode that incorporates machine learning into high-throughput screening.

TRIM7 ubiquitinates SARS-CoV-2 membrane protein to limit apoptosis and viral replication.

SARS-CoV-2 is a highly transmissible virus that causes COVID-19 disease. Mechanisms of viral pathogenesis include excessive inflammation and viral-induced cell death, resulting in tissue damage. We identified the host E3-ubiquitin ligase TRIM7 as an inhibitor of apoptosis and SARS-CoV-2 replication via ubiquitination of the viral membrane (M) protein. Trim7 -/- mice exhibited increased pathology and virus titers associated with epithelial apoptosis and dysregulated immune responses. Mechanistically, TRIM7 ubiquitinates M on K14, which protects cells from cell death. Longitudinal SARS-CoV-2 sequence analysis from infected patients revealed that mutations on M-K14 appeared in circulating variants during the pandemic. The relevance of these mutations was tested in a mouse model. A recombinant M-K14/K15R virus showed reduced viral replication, consistent with the role of K15 in virus assembly, and increased levels of apoptosis associated with the loss of ubiquitination on K14. TRIM7 antiviral activity requires caspase-6 inhibition, linking apoptosis with viral replication and pathology.

Novel shish-kebab structured nanofibrous decorating chitosan unidirectional scaffolds to mimic extracellular matrix for tissue engineering.

Electrospun nanofibrous scaffolds are renowned for their ability to mimic the microstructure of the extracellular matrix (ECM). However, they often fail to replicate the geometry of target tissues, and the biocompatibility of these scaffolds those made from synthetic polymers is always limited due to the lack of cell binding sites. To address these issues, we proposed an innovative approach that combined unidirectional freeze-drying and electrospinning. During this process, electrospun polycaprolactone (PCL) nanofibers were chopped into nanofibrils, which range in size up to several hundred micrometers, and were incorporated into the chitosan scaffolds via unidirectional freeze-drying. In these scaffolds, the chitosan phase was responsible for maintaining the structural integrity at the macroscale, while the embedded nanofibers enhanced the surface topography at the microscale. The resulting scaffolds exhibited a high porosity of 90% and an impressive water uptake capacity of 2500%. Furthermore, 3T3 fibroblast cells showed strong interactions with the scaffolds, characterized by high rates of cell proliferation and viability. The cells also displayed significant orientation along the direction of the pores, suggesting that the scaffolds effectively guided cellular growth.

Coordination engineering for iron-based hexacyanoferrate as a high-stability cathode for sodium-ion batteries.

Iron-based hexacyanoferrate (Fe-HCF) are promising cathode materials for sodium-ion batteries (SIBs) due to their unique open-channel structure that facilitates fast ion transport and framework stability. However, practical implementation of SIBs has been hindered by low initial Coulombic efficiency (ICE), poor rate performance, and short lifespan. Herein, we report a coordination engineering to synthesize sodium-rich Fe-HCF as cathodes for SIBs through a uniquely designed 10-kg-scale chemical reactor. Our study systematically investigated the relationship between coordination surroundings and the electrochemical behavior. Building on this understanding, the cathode delivered a reversible capacity of 99.3 mAh g-1 at 5 C (1 C = 100 mA g-1), exceptional rate capability (51 mAh g-1 even at 100 C), long lifespan (over 15,000 times at 50 C), and a high ICE of 92.7%. A full cell comprising the Fe-HCF cathode and hard carbon (HC) anode exhibited an impressive cyclic stability with a high-capacity retention rate of 98.3% over 1,000 cycles. Meanwhile, this material can be readily scaled to the practical levels of yield. The findings underscore the potential of Fe-HCF as cathodes for SIBs and highlight the significance of controlling nucleation and morphology through coordination engineering for a sustainable energy storage system.

A single-gold-atom addition regulates sharp redshift in the fluorescence of atomically precise nanoclusters.

The manipulation of emission peaks at the atomic level and the investigation of the fluorescent origin mechanism are important issues. In this study, a phosphine-mediated modification method was employed on Au36(TBBT)24 nanocluster to produce a new gold nanocluster Au37(TBBT)21(TPP)2. The structural comparison revealed that Au37(TBBT)21(TPP)2 has a structural framework similar to that of Au36(TBBT)24 except for the reconstruction of its surface motifs, the addition of one gold atom into the kernel, and local structural distortion. Interestingly, compared with Au36(TBBT)24, the emission peak of Au37(TBBT)21(TPP)2 is red-shifted into the NIR-II windows (972 nm vs. 1152 nm in CDCl3) with a quantum yield of 1.5%. Furthermore, the origin of the NIR-II fluorescence in Au37(TBBT)21(TPP)2 and the red-shift mechanism of the emission peak were explored by combining the crystal structure and DFT calculations. The results reveal that the insertion of the 37th gold atom into the core can increase the contribution of the gold atoms to the HOMO orbitals and change the origin of their fluorescence from local excitation (LE) to inter fragment charge transfer (IFCT).

Utilizing cost-effective pyrocarbon for highly efficient gold retrieval from e-waste leachate.

Addressing burdens of electronic waste (E-waste) leachate while achieving sustainable and selective recovery of noble metals, such as gold, is highly demanded due to its limited supply and escalating prices. Here we demonstrate an environmentally-benign and practical approach for gold recovery from E-waste leachate using alginate-derived pyrocarbon sorbent. The sorbent demonstrates potent gold recovery performance compared to most previously reported advanced sorbents, showcasing high recovery capacity of 2829.7 mg g-1, high efficiency (>99.5%), remarkable selectivity (Kd ~ 3.1 × 108 mL g-1), and robust anti-interference capabilities within environmentally relevant contexts. The aromatic structures of pyrocarbon serve as crucial electrons sources, enabling a hydroxylation process that simultaneously generates electrons and phenolic hydroxyls for the reduction of gold ions. Our investigations further uncover a "stepwise" nucleation mechanism, in which gold ions are reduced as intermediate gold-chlorine clusters, facilitating rapid reduction process by lowering energy barriers from 1.08 to -21.84 eV. Technoeconomic analysis demonstrates its economic viability with an input-output ratio as high as 1370%. Our protocol obviates the necessity for organic reagents whilst obtaining 23.96 karats gold product from real-world central processing units (CPUs) leachates. This work introduces a green sorption technique for gold recovery, emphasizing its role in promoting a circular economy and environmental sustainability.

Chiral Inversion of Au40(SR)24 Nanocluster Driven by Rotation of Gold Tetrahedra in the Kekulé-like Core.

Studying the chiral characteristics and chiral inversion mechanisms of gold nanoclusters is important to promote their applications in the field of chiral catalysis and chiral recognition. Herein, we investigated the chiral inversion process of the Au40(SR)24 nanocluster and its derivatives using density functional theory calculations. The results showed that the chiral inversion process can be achieved by rotation of tetrahedra units in the gold core without breaking the Au-S bond. This work found that Au40 nanoclusters protected by different ligands have different chiral inversion mechanisms, and the difference is mainly attributable to the steric effects of the ligands. Moreover, the chiral inversion of the derivative clusters (Au34, Au28, and Au22) of the Au40 nanocluster can also be accomplished by the rotation of the Au4 tetrahedra units in the gold core. The energy barrier in the chiral inversion process of gold nanoclusters increases with the decrease of Au4 tetrahedra units in the gold core. This work identifies a chiral inversion mechanism with lower reaction energy barriers and provided a theoretical basis for the study of gold nanocluster chirality.

The alarmin IL-33 exacerbates pulmonary inflammation and immune dysfunction in SARS-CoV-2 infection.

Dysregulated host immune responses contribute to disease severity and worsened prognosis in COVID-19 infection and the underlying mechanisms are not fully understood. In this study, we observed that IL-33, a damage-associated molecular pattern molecule, is significantly increased in COVID-19 patients and in SARS-CoV-2-infected mice. Using IL-33-/- mice, we demonstrated that IL-33 deficiency resulted in significant decreases in bodyweight loss, tissue viral burdens, and lung pathology. These improved outcomes in IL-33-/- mice also correlated with a reduction in innate immune cell infiltrates, i.e., neutrophils, macrophages, natural killer cells, and activated T cells in inflamed lungs. Lung RNA-seq results revealed that IL-33 signaling enhances activation of inflammatory pathways, including interferon signaling, pathogen phagocytosis, macrophage activation, and cytokine/chemokine signals. Overall, these findings demonstrate that the alarmin IL-33 plays a pathogenic role in SARS-CoV-2 infection and provides new insights that will inform the development of effective therapeutic strategies for COVID-19.

The participation of ferroptosis in fibrosis of the heart and kidney tissues in Dahl salt-sensitive hypertensive rats.

BACKGROUND: Salt-sensitive hypertension is often more prone to induce damage to target organs such as the heart and kidneys. Abundant recent studies have demonstrated a close association between ferroptosis and cardiovascular diseases.Therefore, we hypothesize that ferroptosis may be closely associated with organ damage in salt-sensitive hypertension. This study aimed to investigate whether ferroptosis is involved in the occurrence and development of myocardial fibrosis and renal fibrosis in salt-sensitive hypertensive rats. METHODS: Ten 7-week-old male Dahl salt-sensitive (Dahl-SS) rats were adaptively fed for 1 week, then randomly divided into two groups and fed either a normal diet (0.3% NaCl, NDS group) or a high-salt diet (8% NaCl, HDS group) for 8 weeks. Blood pressure of the rats was observed, and analysis of the hearts and kidneys of Dahl-SS rats was conducted via HE-staining, Masson-staining, Prussian-blue-staining, TEM, tissue iron content detection, MDA content detection, immunofluorescence, and Western blot. RESULTS: Compared to the NDS group, rats in the HDS group increases in systolic blood pressure(SBP) and diastolic blood pressure(DBP)(P<0.05);collagen fiber accumulation was observed in the heart and kidney tissues (P<0.01), accompanied by alterations in mitochondrial ultrastructure,reduced mitochondrial volume, and increased density of the mitochondrial double membrane. Additionally,there were significant increases in both iron content and MDA levels(P<0.05). Immunofluorescence and Western blot results both indicated significant downregulation (P<0.05) of xCT and GPX4 proteins associated with ferroptosis in the HDS group. CONCLUSION: Ferroptosis is involved in the damage and fibrosis of the heart and kidney tissues in salt-sensitive hypertensive rats.

A murine model of post-acute neurological sequelae following SARS-CoV-2 variant infection.

Viral variant is one known risk factor associated with post-acute sequelae of COVID-19 (PASC), yet the pathogenesis is largely unknown. Here, we studied SARS-CoV-2 Delta variant-induced PASC in K18-hACE2 mice. The virus replicated productively, induced robust inflammatory responses in lung and brain tissues, and caused weight loss and mortality during the acute infection. Longitudinal behavior studies in surviving mice up to 4 months post-acute infection revealed persistent abnormalities in neuropsychiatric state and motor behaviors, while reflex and sensory functions recovered over time. In the brain, no detectable viral RNA and minimal residential immune cell activation was observed in the surviving mice post-acute infection. Transcriptome analysis revealed persistent activation of immune pathways, including humoral responses, complement, and phagocytosis, and gene expression levels associated with ataxia telangiectasia, impaired cognitive function and memory recall, and neuronal dysfunction and degeneration. Furthermore, surviving mice maintained potent systemic T helper 1 prone cellular immune responses and strong sera neutralizing antibodies against Delta and Omicron variants months post-acute infection. Overall, our findings suggest that infection in K18-hACE2 mice recapitulates the persistent clinical symptoms reported in long-COVID patients and provides new insights into the role of systemic and brain residential immune factors in PASC pathogenesis.

Discovering of Atomically Precise Metal Nanoclusters by High-Throughput Syntheses Platform.

Understanding the complete structure of noble metal nanoclusters is both academically and practically significant. However, progress has been hindered by the low synthetic efficiency of many nanocluster syntheses. In this study, we present the first high-throughput syntheses of homo-gold, homo-copper, and gold-copper alloy nanoclusters in dichloromethane at room temperature. Through high-throughput screening, we successfully obtained three nanoclusters in a single reaction: Au18(SC6H11)14, [Au41Cu66(SC6H11)44](SbF6)3, and an unidentified copper cluster (referred to as Au18, Au41Cu66 , and Cu-NC). The optimized synthesis route was achieved with the assistance of machine learning for experimental data analysis, which also guided the synthesis of other metal nanoclusters such as Au40Cu34(4-S-PhF)40 (Au40Cu34), [Au6Cu6(SPh)12]n ([Au6Cu6]n), and Au18Cu32(3,5-C8H9S)36 (Au18Cu32)). This research demonstrates that high-throughput screening can be a valuable tool in accelerating the development of nanocluster syntheses.

Efficacy and Safety of Bufei Jiedu Granules in Treating Multidrug-Resistant Pulmonary Tuberculosis: A Multi-center, Double-Blinded and Randomized Controlled Trial.

OBJECTIVE: To assess the efficacy and safety of Bufei Jiedu (BFJD) ranules as adjuvant therapy for patients with multidrug-resistant pulmonary tuberculosis (MDR-PTB). METHODS: A large-scale, multi-center, double-blinded, and randomized controlled trial was conducted in 18 sentinel hospitals in China from December 2012 to December 2016. A total of 312 MDR-PTB patients were randomly assigned to BFJD Granules or placebo groups (1:1) using a stratified randomization method, which both received the long-course chemotherapy regimen for 18 months (6 Am-Lfx-P-Z-Pto, 12 Lfx-P-Z-Pto). Meanwhile, patients in both groups also received BFJD Granules or placebo twice a day for a total of 18 months, respectively. The primary outcome was cure rate. The secondary outcomes included time to sputum-culture conversion, changes in lung cavities and quality of life (QoL) of patients. Adverse reactions were monitored during and after the trial. RESULTS: A total of 216 cases completed the trial, 111 in the BFJD Granules group and 105 in the placebo group. BFJD Granules, as an adjuvant treatment, increased the cure rate by 13.6% at the end of treatment, compared with the placebo (58.4% vs. 44.8%, P=0.02), and accelerated the median time to sputum-culture conversion (5 months vs. 11 months). The cavity closure rate of the BFJD Granules group (50.6%, 43/85) was higher than that of the placebo group (32.1%, 26/81; P=0.02) in patients who completed the treatment. At the end of the intensive treatment, according to the 36-item Short Form, the BFJD Granules significantly improved physical functioning, general health, and vitality of patients relative to the placebo group (all P<0.01). Overall, the death rates in the two groups were not significantly different; 5.1% (8/156) in the BFJD Granules group and 2.6% (4/156) in the placebo group. CONCLUSIONS: Supplementing BFJD Granules with the long-course chemotherapy regimen significantly increased the cure rate and cavity closure rates, and rapidly improved QoL of patients with MDR-PTB (Registration No. ChiCTR-TRC-12002850).

Resistance mechanisms of SARS-CoV-2 3CLpro to the non-covalent inhibitor WU-04.

Drug resistance poses a significant challenge in the development of effective therapies against SARS-CoV-2. Here, we identified two double mutations, M49K/M165V and M49K/S301P, in the 3C-like protease (3CLpro) that confer resistance to a novel non-covalent inhibitor, WU-04, which is currently in phase III clinical trials (NCT06197217). Crystallographic analysis indicates that the M49K mutation destabilizes the WU-04-binding pocket, impacting the binding of WU-04 more significantly than the binding of 3CLpro substrates. The M165V mutation directly interferes with WU-04 binding. The S301P mutation, which is far from the WU-04-binding pocket, indirectly affects WU-04 binding by restricting the rotation of 3CLpro's C-terminal tail and impeding 3CLpro dimerization. We further explored 3CLpro mutations that confer resistance to two clinically used inhibitors: ensitrelvir and nirmatrelvir, and revealed a trade-off between the catalytic activity, thermostability, and drug resistance of 3CLpro. We found that mutations at the same residue (M49) can have distinct effects on the 3CLpro inhibitors, highlighting the importance of developing multiple antiviral agents with different skeletons for fighting SARS-CoV-2. These findings enhance our understanding of SARS-CoV-2 resistance mechanisms and inform the development of effective therapeutics.

Atomically Precise Mo2Cu17 Bimetallic Nanocluster: Synergistic Mo2O4-Coupled Copper Alkynyl Cluster for the Improved Hydrogen Evolution Reaction Performance.

Electrolytic hydrogen production via water splitting holds significant promise for the future of the energy revolution. The design of efficient and abundant catalysts, coupled with a comprehensive understanding of the hydrogen evolution reaction (HER) mechanism, is of paramount importance. In this study, we propose a strategy to craft an atomically precise cluster catalyst with superior HER performance by cocoupling a Mo2O4 structural unit and a Cu(I) alkynyl cluster into a structured framework. The resulting bimetallic cluster, Mo2Cu17, encapsulates a distinctive structure [Mo2O4Cu17(TC4A)4(PhC≡C)6], comprising a binuclear Mo2O4 subunit and a {Cu17(TC4A)2(PhC≡C)6} cluster, both shielded by thiacalix[4]arene (TC4A) and phenylacetylene (PhC≡CH). Expanding our exploration, we synthesized two homoleptic CuI alkynyl clusters coprotected by the TC4A and PhC≡C- ligands: Cu13 and Cu22. Remarkably, Mo2Cu17 demonstrates superior HER efficiency compared to its counterparts, achieving a current density of 10 mA cm-2 in alkaline solution with an overpotential as low as 120 mV, significantly outperforming Cu13 (178 mV) and Cu22 (214 mV) nanoclusters. DFT calculations illuminate the catalytic mechanism and indicate that the intrinsically higher activity of Mo2Cu17 may be attributed to the synergistic Mo2O4-Cu(I) coupling.

Mechanism Insight into Metal Exchange between Au25(SR)18-/Ag25(SR)18- Clusters and Metal Ions from Ab Initio Molecular Dynamics Simulations.

The metal exchange reaction has emerged as an efficient method to synthesize ligand-protected alloy nanoclusters with precise compositions and structure. However, the understanding of the mechanism of these metal exchange processes is quite limited. Herein, the dynamic process of metal exchange of Au25(SR)18- and Ag25(SR)18- (R = CH3) nanoclusters with metal ions (Au+, Ag+, Cu2+, Cu+, Cd2+, and Hg2+) is investigated using ab initio molecular dynamics simulations. Computational results unveiled a multifaceted nature of the metal exchange process, dictated by several variables, including thermodynamic stability, electrochemical activity, metal affinity to ligand, and the coordination mode of metal ions. As a result of these factors, metal ions may either directly exchange with Au or Ag atoms on the icosahedral core surface by a "knock-off" mechanism or be stably adsorbed at the core-motif interface of Au25(SR)18- and Ag25(SR)18- nanoclusters. Meanwhile, we also discovered that counterions can promote adsorbed Ag and Cu atoms to diffuse into the gold core. Finally, the driving force of the galvanic reduction and antigalvanic reduction reactions is discussed. The formation of a more stable core-doping product nanocluster is the major driving force of metal exchange reactions.

Targeting G9a translational mechanism of SARS-CoV-2 pathogenesis for multifaceted therapeutics of COVID-19 and its sequalae.

By largely unknown mechanism(s), SARS-CoV-2 hijacks the host translation apparatus to promote COVID-19 pathogenesis. We report that the histone methyltransferase G9a noncanonically regulates viral hijacking of the translation machinery to bring about COVID-19 symptoms of hyperinflammation, lymphopenia, and blood coagulation. Chemoproteomic analysis of COVID-19 patient peripheral mononuclear blood cells (PBMC) identified enhanced interactions between SARS-CoV-2-upregulated G9a and distinct translation regulators, particularly the N 6 -methyladenosine (m 6 A) RNA methylase METTL3. These interactions with translation regulators implicated G9a in translational regulation of COVID-19. Inhibition of G9a activity suppressed SARS-CoV-2 replication in human alveolar epithelial cells. Accordingly, multi-omics analysis of the same alveolar cells identified SARS-CoV-2-induced changes at the transcriptional, m 6 A-epitranscriptional, translational, and post-translational (phosphorylation or secretion) levels that were reversed by inhibitor treatment. As suggested by the aforesaid chemoproteomic analysis, these multi-omics-correlated changes revealed a G9a-regulated translational mechanism of COVID-19 pathogenesis in which G9a directs translation of viral and host proteins associated with SARS-CoV-2 replication and with dysregulation of host response. Comparison of proteomic analyses of G9a inhibitor-treated, SARS-CoV-2 infected cells, or ex vivo culture of patient PBMCs, with COVID-19 patient data revealed that G9a inhibition reversed the patient proteomic landscape that correlated with COVID-19 pathology/symptoms. These data also indicated that the G9a-regulated, inhibitor-reversed, translational mechanism outperformed G9a-transcriptional suppression to ultimately determine COVID-19 pathogenesis and to define the inhibitor action, from which biomarkers of serve symptom vulnerability were mechanistically derived. This cell line-to-patient conservation of G9a-translated, COVID-19 proteome suggests that G9a inhibitors can be used to treat patients with COVID-19, particularly patients with long-lasting COVID-19 sequelae.

Metformin blocks BIK1-mediated CPK28 phosphorylation and enhances plant immunity.

INTRODUCTION: Metformin (MET), derived from Galega officinalis, stands as the primary first-line medication for the treatment of type 2 diabetes (T2D). Despite its well-documented benefits in mammalian cellular processes, its functions and underlying mechanisms in plants remain unclear. OBJECTIVES: This study aimed to elucidate MET's role in inducing plant immunity and investigate the associated mechanisms. METHODS: To investigate the impact of MET on enhancing plant immune responses, we conducted assays measuring defense gene expression, reactive oxygen species (ROS) accumulation, mitogen-activated protein kinase (MAPK) phosphorylation, and pathogen infection. Additionally, surface plasmon resonance (SPR) and microscale thermophoresis (MST) techniques were employed to identify MET targets. Protein-protein interactions were analyzed using a luciferase complementation assay and a co-immunoprecipitation assay. RESULTS: Our findings revealed that MET boosts plant disease resistance by activating MAPKs, upregulating the expression of downstream defense genes, and fortifying the ROS burst. CALCIUM-DEPENDENT PROTEIN KINASE 28 (CPK28) was identified as a target of MET. It inhibited the interaction between BOTRYTIS-INDUCED KINASE 1 (BIK1) and CPK28, blocking CPK28 threonine 76 (T76) transphosphorylation by BIK1, and alleviating the negative regulation of immune responses by CPK28. Moreover, MET enhanced disease resistance in tomato, pepper, and soybean plants. CONCLUSION: Collectively, our data suggest that MET enhances plant immunity by blocking BIK1-mediated CPK28 phosphorylation.