Lactylation prediction models based on protein sequence and structural feature fusion.

Lysine lactylation (Kla) is a newly discovered posttranslational modification that is involved in important life activities, such as glycolysis-related cell function, macrophage polarization and nervous system regulation, and has received widespread attention due to the Warburg effect in tumor cells. In this work, we first design a natural language processing method to automatically extract the 3D structural features of Kla sites, avoiding potential biases caused by manually designed structural features. Then, we establish two Kla prediction frameworks, Attention-based feature fusion Kla model (ABFF-Kla) and EBFF-Kla, to integrate the sequence features and the structure features based on the attention layer and embedding layer, respectively. The results indicate that ABFF-Kla and Embedding-based feature fusion Kla model (EBFF-Kla), which fuse features from protein sequences and spatial structures, have better predictive performance than that of models that use only sequence features. Our work provides an approach for the automatic extraction of protein structural features, as well as a flexible framework for Kla prediction. The source code and the training data of the ABFF-Kla and the EBFF-Kla are publicly deposited at: https://github.com/ispotato/Lactylation_model.

Proteome, Lysine Acetylome, and Succinylome Identify Posttranslational Modification of STAT1 as a Novel Drug Target in Silicosis.

Inhalation of crystalline silica dust induces incurable lung damage, silicosis, and pulmonary fibrosis. However, the mechanisms of the lung injury remain poorly understood, with limited therapeutic options aside from lung transplantation. Posttranslational modifications can regulate the function of proteins and play an important role in studying disease mechanisms. To investigate changes in posttranslational modifications of proteins in silicosis, combined quantitative proteome, acetylome, and succinylome analyses were performed with lung tissues from silica-injured and healthy mice using liquid chromatography-mass spectrometry. Combined analysis was applied to the three omics datasets to construct a protein landscape. The acetylation and succinylation of the key transcription factor STAT1 were found to play important roles in the silica-induced pathophysiological changes. Modulating the acetylation level of STAT1 with geranylgeranylacetone effectively inhibited the progression of silicosis. This report revealed a comprehensive landscape of posttranslational modifications in silica-injured mouse and presented a novel therapeutic strategy targeting the posttranslational level for silica-induced lung diseases.

Global profiling of protein lactylation in Caenorhabditis elegans.

Lactylation, as a novel posttranslational modification, is essential for studying the functions and regulation of proteins in physiological and pathological processes, as well as for gaining in-depth knowledge on the occurrence and development of many diseases, including tumors. However, few studies have examined the protein lactylation of one whole organism. Thus, we studied the lactylation of global proteins in Caenorhabditis elegans to obtain an in vivo lactylome. Using an MS-based platform, we identified 1836 Class I (localization probabilities > 0.75) lactylated sites in 487 proteins. Bioinformatics analysis showed that lactylated proteins were mainly located in the cytoplasm and involved in the tricarboxylic acid cycle (TCA cycle) and other metabolic pathways. Then, we evaluated the conservation of lactylation in different organisms. In total, 41 C. elegans proteins were lactylated and homologous to lactylated proteins in humans and rats. Moreover, lactylation on H4K80 was conserved in three species. An additional 238 lactylated proteins were identified in C. elegans for the first time. This study establishes the first lactylome database in C. elegans and provides a basis for studying the role of lactylation.

Emodin ameliorates doxorubicin-induced cardiotoxicity by inhibiting ferroptosis through the remodeling of gut microbiota composition.

The relationship between gut microbiota and doxorubicin-induced cardiotoxicity (DIC) is becoming increasingly clear. Emodin (EMO), a naturally occurring anthraquinone, exerts cardioprotective effects and plays a protective role by regulating gut microbiota composition. Therefore, the protective effect of EMO against DIC injury and its underlying mechanisms are worth investigating. In this study, we analyzed the differences in the gut microbiota in recipient mice transplanted with different flora using 16S-rDNA sequencing, analyzed the differences in serum metabolites among groups of mice using a nontargeted gas chromatography-mass spectrometry coupling system, and assessed cardiac function based on cardiac morphological staining, cardiac injury markers, and ferroptosis indicator assays. We found EMO ameliorated DIC and ferroptosis, as evidenced by decreased myocardial fibrosis, cardiomyocyte hypertrophy, and myocardial disorganization; improved ferroptosis indicators; and the maintenance of normal mitochondrial morphology. The protective effect of EMO was eliminated by the scavenging effect of antibiotics on the gut microbiota. Through fecal microbiota transplantation (FMT), we found that EMO restored the gut microbiota disrupted by doxorubicin (DOX) to near-normal levels. This was evidenced by an increased proportion of Bacteroidota and a decreased proportion of Verrucomicrobiota. FMT resulted in changes in the composition of serum metabolites. Mice transplanted with EMO-improved gut microbiota showed better cardiac function and ferroptosis indices; however, these beneficial effects were not observed in Nrf2 (Nfe2l2)-/- mice. Overall, EMO exerted a protective effect against DIC by attenuating ferroptosis, and the above effects occurred by remodeling the composition of gut microbiota perturbed by DOX and required Nrf2 mediation.NEW & NOTEWORTHY This study demonstrated for the first time the protective effect of emodin against DIC and verified by FMT that its cardioprotective effect was achieved by remodeling gut microbiota composition, resulting in attenuation of ferroptosis. Furthermore, we demonstrated that these effects were mediated by the redox-related gene Nrf2.

RTA 408 ameliorates diabetic cardiomyopathy by activating Nrf2 to regulate mitochondrial fission and fusion and inhibiting NF-κB-mediated inflammation.

Diabetic cardiomyopathy (dCM) is a major complication of diabetes; however, specific treatments for dCM are currently lacking. RTA 408, a semisynthetic triterpenoid, has shown therapeutic potential against various diseases by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. We established in vitro and in vivo models using high glucose toxicity and db/db mice, respectively, to simulate dCM. Our results demonstrated that RTA 408 activated Nrf2 and alleviated various dCM-related cardiac dysfunctions, both in vivo and in vitro. Additionally, it was found that silencing the Nrf2 gene eliminated the cardioprotective effect of RTA 408. RTA 408 ameliorated oxidative stress in dCM mice and high glucose-exposed H9C2 cells by activating Nrf2, inhibiting mitochondrial fission, exerting anti-inflammatory effects through the Nrf2/NF-κB axis, and ultimately suppressing apoptosis, thereby providing cardiac protection against dCM. These findings provide valuable insights for potential dCM treatments.NEW & NOTEWORTHY We demonstrated first that the nuclear factor erythroid 2-related factor 2 (Nrf2) activator RTA 408 has a protective effect against diabetic cardiomyopathy. We found that RTA 408 could stimulate the nuclear entry of Nrf2 protein, regulate the mitochondrial fission-fusion balance, and redistribute p65, which significantly alleviated the oxidative stress level in cardiomyocytes, thereby reducing apoptosis and inflammation, and protecting the systolic and diastolic functions of the heart.

Paeoniflorin confers ferroptosis resistance by regulating the gut microbiota and its metabolites in diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM) is closely related to ferroptosis, a new type of cell death that mainly manifests as intracellular iron accumulation and lipid peroxidation. Paeoniflorin (PA) helps to improve impaired glucose tolerance, influences the distribution of the intestinal flora, and induces significant resistance to ferroptosis in several models. In this study, we found that PA improved cardiac dysfunction in mice with DCM by alleviating myocardial damage, resisting oxidative stress and ferroptosis, and changing the community composition and structure of the intestinal microbiota. Metabolomics analysis revealed that PA-treated fecal microbiota transplantation affected metabolites in DCM mice. Based on in vivo and in vitro experiments, 11,12-epoxyeicosatrienoic acid (11,12-EET) may serve as a key contributor that mediates the cardioprotective and antiferroptotic effects of PA-treated fecal microbiota transplantation (FMT) in DCM mice.NEW & NOTEWORTHY This study demonstrated for the first time that paeoniflorin (PA) exerts protective effects in diabetic cardiomyopathy mice by alleviating myocardial damage, resisting ferroptosis, and changing the community composition and structure of the intestinal microbiota, and 11,12-epoxyeicosatrienoic acid (11,12-EET) may serve as a key contributor in its therapeutic efficacy.

Multi-omics profiling reveal cells with novel oncogenic cluster, TRAP1low/CAMSAP3low, emerge more aggressive behavior and poor-prognosis in early-stage endometrial cancer.

The clinical heterogeneity of early-stage endometrial cancer (EC) is worthy of further study to identify high-quality prognostic markers and their potential role in aggressive tumor behavior. Mutation of TP53 was considered as an important primary triage in modified molecular typing for EC, it still cannot precisely predict the prognosis of EC. After proteomic analysis of cancer and para-cancerous tissues from 24 early-stage endometrioid EC patients with different survival outcomes, 13 differentially expressed proteins were screen out while 2 proteins enriched in p53 signaling pathway were further identified by single-cell transcriptome (scRNA-seq). Interestingly, tumor necrosis factor type-1 receptor-associated protein (TRAP1) and calmodulin-regulated spectrin-associated protein family member 3 (CAMSAP3) were found to be significantly downregulated in the specific cell cluster. Expectedly, the signature genes of TRAP1low/CAMSAP3low cluster included classical oncogenes. Moreover, close cellular interactions were observed between myeloid cells and the TRAP1low/CAMSAP3low cluster after systematically elucidating their relationship with tumor microenvironment (TME). The expression of TRAP1 and CAMSAP3 was verified by immunohistochemistry. Thus, a novel prediction model combining TRAP1, CAMSAP3 and TP53 was construct by multi-omics. Compared with the area under the curve, it demonstrated a significantly improvemrnt in the diagnostic efficacy in EC patients from TCGA bank. In conclusion, this work improved the current knowledge regarding the prognosis of early-stage EC through proteomics and scRNA-seq. These findings may lead to improvements in precise risk stratification of early-stage EC patients.

Repeated acute coronary syndrome caused by a mind-bending mural thrombus in ascending aorta: a case report and review of the literature.

BACKGROUND: Acute coronary syndrome due to coronary artery embolism in the setting of ascending aortic thrombus is an uncommon condition, even rarer when there is no aortic pathology such as aneurysm, severe atherosclerosis, aortic dissection, or thrombophilia (whether inherited or acquired). CASE PRESENTATION: We report a case of a 58-year-old male presented with acute chest pain, electrocardiogram showing non-ST-elevation acute coronary syndrome. The computed tomography angiography of coronary artery revealed a mural thrombus in the proximal part of ascending aorta, located above the left coronary artery ostium, without any aortic pathologies. With the exception of hypertension and cigarette smoking, no other risk factors were identified in this patient that may increase the risk of thrombosis. Given the life-threatening risk of interventional therapy and surgery, the patient determinedly opted for anticoagulant and dual antiplatelet therapy. Then he experienced the reoccurrence of chest pain after 6-day treatment, progressed to anterior and inferior ST-segment elevation myocardial infarction. Coronary artery embolism originating from the ascending aortic thrombus was suspected. Considering the hemodynamic instability of the patient, the medical treatment was continued and bridged to warfarin and aspirin after discharge. Follow-up computed tomography angiography at 6 months showed no obstruction in coronary artery and complete resolution of the thrombus. No thromboembolic events occurred henceforward. CONCLUSIONS: Acute coronary syndrome could be a manifestation of secondary coronary embolism due to ascending aortic thrombus. Currently, there is no standardized guideline for the treatment of aortic mural thrombus, individualized treatment is recommended. When surgical therapy is not applicable for the patient, anticoagulation and dual antiplatelet treatment are alternative treatments that may successfully lead to the resolution of the aortic thrombus.

Polyurethane foam dressing with non-adherent membrane improves negative pressure wound therapy in pigs.

OBJECTIVE: Negative pressure wound therapy (NPWT) is considered to be an effective technique to promote the healing of various wounds. The aim of this study was to evaluate different wound dressings combined with NPWT in treating wounds in Wuzhishan pigs. METHOD: Excisions were made in the backs of the pigs and were covered with polyvinyl alcohol (PVA) dressing, polyurethane (PU) dressing or PU dressing with non-adherent membrane (PU-non-ad). NPWT was applied to the wound site. In the control group, basic occlusive dressing (gauze) without NPWT was applied. On days 0, 3, 7, 14, 21 and 28 post-surgery, the wound size was measured during dressing change, and wound healing rate (WHR) was calculated. In addition, blood perfusion within 2cm of the surrounding wound was measured by laser doppler flowmetry. Dressing specimen was collected and microbiology was analysed. Granulation tissues from the central part of the wounds were analysed for histology, vascular endothelial growth factor (VEGF) and cluster of differentiation 31 (CD31) mRNA expression. RESULTS: The PU-non-ad-NPWT significantly (p<0.01) accelerated wound healing in the pigs. Further pathological analysis revealed that the non-adherent membrane effectively protected granulation tissue formation in PU-NPWT treated wounds. The blood perfusion analysis suggested that the non-adherent membrane improved the blood supply to the wound area. Microbiological analysis showed that non-adherent membrane decreased the bacterial load in the PU-NPWT dressing. VEGF and CD31 mRNA expression was upregulated in the wound tissue from the PU-non-ad-NPWT treated groups. CONCLUSION: In this study, the PU dressing with non-adherent membrane was an ideal dressing in NPWT-assisted wound healing.

[Identification of Protein-Coding Gene Markers in Breast Invasive Carcinoma Based on Machine Learning].

Objective To screen out the biomarkers linked to prognosis of breast invasive carcinoma based on the analysis of transcriptome data by random forest (RF),extreme gradient boosting (XGBoost),light gradient boosting machine (LightGBM),and categorical boosting (CatBoost). Methods We obtained the expression data of breast invasive carcinoma from The Cancer Genome Atlas and employed DESeq2,t-test,and Cox univariate analysis to identify the differentially expressed protein-coding genes associated with survival prognosis in human breast invasive carcinoma samples.Furthermore,RF,XGBoost,LightGBM,and CatBoost models were established to mine the protein-coding gene markers related to the prognosis of breast invasive cancer and the model performance was compared.The expression data of breast cancer from the Gene Expression Omnibus was used for validation. Results A total of 151 differentially expressed protein-coding genes related to survival prognosis were screened out.The machine learning model established with C3orf80,UGP2,and SPC25 demonstrated the best performance. Conclusions Three protein-coding genes (UGP2,C3orf80,and SPC25) were screened out to identify breast invasive carcinoma.This study provides a new direction for the treatment and diagnosis of breast invasive carcinoma.

Global profiling of lysine lactylation in human lungs.

Lactate is closely related to various cellular processes, such as angiogenesis, responses to hypoxia, and macrophage polarization, while regulating natural immune signaling pathways and promoting neurogenesis and cognitive function. Lysine lactylation (Kla) is a novel posttranslational modification, the examination of which may lead to new understanding of the nonmetabolic functions of lactate and the various physiological and pathological processes in which lactate is involved, such as infection, tumorigenesis and tumor development. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), researchers have identified lactylation in human gastric cancer cells and some other species, but no research on lactylation in human lungs has been reported. In this study, we performed global profiling of lactylation in human lungs under normal physiological conditions, and 724 Kla sites in 451 proteins were identified. After comparing the identified proteins with those reported in human lactylation datasets, 141 proteins that undergo lactylation were identified for the first time in this study. Our work expands the database on human lactylation and helps advance the study on lactylation function and regulation under physiological and pathological conditions.

Global analysis of lysine acetylation in the brain cortex of K18-hACE2 mice infected with SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected hundreds of millions of people all over the world and thus threatens human life. Clinical evidence shows that SARS-CoV-2 infection can cause several neurological consequences, but the existing antiviral drugs and vaccines have failed to stop its spread. Therefore, an understanding of the response to SARS-CoV-2 infection of hosts is vital to find a resultful therapy. Here, we employed a K18-hACE2 mouse infection model and LC-MS/MS to systematically evaluate the acetylomes of brain cortexes in the presence and absence of SARS-CoV-2 infection. Using a label-free strategy, 3829 lysine acetylation (Kac) sites in 1735 histone and nonhistone proteins were identified. Bioinformatics analyses indicated that SARS-CoV-2 infection might lead to neurological consequences via acetylation or deacetylation of important proteins. According to a previous study, we found 26 SARS-CoV-2 proteins interacted with 61 differentially expressed acetylated proteins with high confidence and identified one acetylated SARS-CoV-2 protein nucleocapsid phosphoprotein. We greatly expanded the known set of acetylated proteins and provide the first report of the brain cortex acetylome in this model and thus a theoretical basis for future research on the pathological mechanisms and therapies of neurological consequences after SARS-CoV-2 infection.

[Role of Eukaryotic Translation Elongation Factor 1 Family Members in the Tumorigenesis and Progression of Lung Adenocarcinoma].

Objective To investigate the role and mechanism of eukaryotic translation elongation factor 1(EEF1) family members (EEF1D,EEF1A1,and EEF1A2) in lung adenocarcinoma (LUAD) based on public databases.Methods We examined EEF1 member expression levels in human LUAD samples via The Cancer Genome Atlas in the UCSC Xena browser and the Clinical Proteomic Tumor Analysis Consortium.We analyzed the mRNA and protein levels of EEF1D,EEF1A1,and EEF1A2 and their correlations with pathological variables via the Mann-Whitney U test.The Kaplan-Meier curves were established to assess the prognostic values of EEF1D,EEF1A1,and EEF1A2.The single-sample gene set enrichment analysis algorithm was employed to explore the relationship between the expression levels of EEF1 members and tumor immune cell infiltration.Spearman and Pearson correlation analyses were performed to examine the relationship between the expression levels of EEF1 members and those of the genes in the phosphatidylinositol 3-kinase/protein kinase B signaling pathway.The immunohistochemical assay was employed to determine the expression levels of EEF1D,EEF1A1,and EEF1A2 in the LUAD tissue (n=75) and paracancer tissue (n=75) samples.Results The mRNA and protein levels of EEF1D,EEF1A1,and EEF1A2 showed significant differences between tumor and paracancer tissues (all P<0.001).The patients with high protein levels of EEF1A1 showed bad prognosis in terms of overall survival (P=0.039),and those with high protein levels of EEF1A2 showed good prognosis in terms of overall survival (P=0.012).The influence of the mRNA level of EEF1D on prognosis was associated with pathological characteristics.The expression levels of EEF1 members were significantly associated with the infiltration of various immune cells and the expression of key molecules in the phosphatidylinositol 3-kinase/protein kinase B signaling pathway.Conclusion EEF1D,EEF1A1,and EEF1A2 are associated with the progression of LUAD,serving as the candidate prognostic markers for LUAD.

Global profiling of lysine succinylation in human lungs.

The lysine succinylation (Ksucc) is involved in many core energy metabolism pathways and affects the metabolic process in mitochondria, making this modification highly valuable for studying diseases related to mitochondrial disorders. In this paper, we used liquid chromatography with tandem mass spectrometry (LC-MS/MS) to perform the first global profiling of succinylation in human lungs under normal physiological conditions. Using an MS-based platform, we identified 1485 Ksucc sites in 568 proteins. We then compared these sites with those previously identified in human succinylome studies to investigate specific succinylated proteins and identify their possible functions in the lung and to explore the substrate preferences of succinylation modifiers in different cell lines and at different subcellular localizations. Our work expands the succinylation database and supplementary materials on the human succinylome and will thus help in further study of the function of Ksucc and regulation under related physiological and pathological conditions.

Seroprevalence and humoral immune durability of anti-SARS-CoV-2 antibodies in Wuhan, China: a longitudinal, population-level, cross-sectional study.

BACKGROUND: Wuhan was the epicentre of the COVID-19 outbreak in China. We aimed to determine the seroprevalence and kinetics of anti-SARS-CoV-2 antibodies at population level in Wuhan to inform the development of vaccination strategies. METHODS: In this longitudinal cross-sectional study, we used a multistage, population-stratified, cluster random sampling method to systematically select 100 communities from the 13 districts of Wuhan. Households were systematically selected from each community and all family members were invited to community health-care centres to participate. Eligible individuals were those who had lived in Wuhan for at least 14 days since Dec 1, 2019. All eligible participants who consented to participate completed a standardised electronic questionnaire of demographic and clinical questions and self-reported any symptoms associated with COVID-19 or previous diagnosis of COVID-19. A venous blood sample was taken for immunological testing on April 14-15, 2020. Blood samples were tested for the presence of pan-immunoglobulins, IgM, IgA, and IgG antibodies against SARS-CoV-2 nucleocapsid protein and neutralising antibodies were assessed. We did two successive follow-ups between June 11 and June 13, and between Oct 9 and Dec 5, 2020, at which blood samples were taken. FINDINGS: Of 4600 households randomly selected, 3599 families (78·2%) with 9702 individuals attended the baseline visit. 9542 individuals from 3556 families had sufficient samples for analyses. 532 (5·6%) of 9542 participants were positive for pan-immunoglobulins against SARS-CoV-2, with a baseline adjusted seroprevalence of 6·92% (95% CI 6·41-7·43) in the population. 437 (82·1%) of 532 participants who were positive for pan-immunoglobulins were asymptomatic. 69 (13·0%) of 532 individuals were positive for IgM antibodies, 84 (15·8%) were positive for IgA antibodies, 532 (100%) were positive for IgG antibodies, and 212 (39·8%) were positive for neutralising antibodies at baseline. The proportion of individuals who were positive for pan-immunoglobulins who had neutralising antibodies in April remained stable for the two follow-up visits (162 [44·6%] of 363 in June, 2020, and 187 [41·2%] of 454 in October-December, 2020). On the basis of data from 335 individuals who attended all three follow-up visits and who were positive for pan-immunoglobulins, neutralising antibody levels did not significantly decrease over the study period (median 1/5·6 [IQR 1/2·0 to 1/14·0] at baseline vs 1/5·6 [1/4·0 to 1/11·2] at first follow-up [p=1·0] and 1/6·3 [1/2·0 to 1/12·6] at second follow-up [p=0·29]). However, neutralising antibody titres were lower in asymptomatic individuals than in confirmed cases and symptomatic individuals. Although titres of IgG decreased over time, the proportion of individuals who had IgG antibodies did not decrease substantially (from 30 [100%] of 30 at baseline to 26 [89·7%] of 29 at second follow-up among confirmed cases, 65 [100%] of 65 at baseline to 58 [92·1%] of 63 at second follow-up among symptomatic individuals, and 437 [100%] of 437 at baseline to 329 [90·9%] of 362 at second follow-up among asymptomatic individuals). INTERPRETATION: 6·92% of a cross-sectional sample of the population of Wuhan developed antibodies against SARS-CoV-2, with 39·8% of this population seroconverting to have neutralising antibodies. Our durability data on humoral responses indicate that mass vaccination is needed to effect herd protection to prevent the resurgence of the epidemic. FUNDING: Chinese Academy of Medical Sciences & Peking Union Medical College, National Natural Science Foundation, and Chinese Ministry of Science and Technology. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

CDK5RAP3, a UFL1 substrate adaptor, is crucial for liver development.

Protein modification by ubiquitin and ubiquitin-like proteins (UBLs) regulates numerous biological functions. The UFM1 system, a novel UBL conjugation system, is implicated in mouse development and hematopoiesis. However, its broad biological functions and working mechanisms remain largely elusive. CDK5RAP3, a possible ufmylation substrate, is essential for epiboly and gastrulation in zebrafish. Herein, we report a crucial role of CDK5RAP3 in liver development and hepatic functions. Cdk5rap3 knockout mice displayed prenatal lethality with severe liver hypoplasia, as characterized by delayed proliferation and compromised differentiation. Hepatocyte-specific Cdk5rap3 knockout mice suffered post-weaning lethality, owing to serious hypoglycemia and impaired lipid metabolism. Depletion of CDK5RAP3 triggered endoplasmic reticulum stress and activated unfolded protein responses in hepatocytes. We detected the in vivo interaction of CDK5RAP3 with UFL1, the defined E3 ligase in ufmylation. Notably, loss of CDK5RAP3 altered the ufmylation profile in liver cells, suggesting that CDK5RAP3 serves as a novel substrate adaptor for this UBL modification. Collectively, our study identifies CDK5RAP3 as an important regulator of ufmylation and suggests the involvement of ufmylation in mammalian development.

Phosphoproteome profiling of mouse liver during normal aging.

BACKGROUND: Aging is a complex biological process accompanied by a time-dependent functional decline that affects most living organisms. Omics studies help to comprehensively understand the mechanism of aging and discover potential intervention methods. Old mice are frequently obese with a fatty liver. METHODS: We applied mass spectrometry-based phosphoproteomics to obtain a global phosphorylation profile of the liver in mice aged 2 or 18 months. MaxQuant was used for quantitative analysis and PCA was used for unsupervised clustering. RESULTS: Through phosphoproteome analysis, a total of 5,685 phosphosites in 2,335 proteins were filtered for quantitative analysis. PCA analysis of both the phosphoproteome and transcriptome data could distinguish young and old mice. However, from kinase prediction, kinase-substrate interaction analysis, and KEGG functional enrichment analysis done with phosphoproteome data, we observed high phosphorylation of fatty acid biosynthesis, ß-oxidation, and potential secretory processes, together with low phosphorylation of the Egfr-Sos1-Araf/Braf-Map2k1-Mapk1 pathway and Ctnnb1 during aging. Proteins with differentially expressed phosphosites seemed more directly related to the aging-associated fatty liver phenotype than the differentially expressed transcripts. The phosphoproteome may reveal distinctive biological functions that are lost in the transcriptome. CONCLUSIONS: In summary, we constructed a phosphorylation-associated network in the mouse liver during normal aging, which may help to discover novel antiaging strategies.

Adsorption Behavior of TEMPO-Based Organic Friction Modifiers during Sliding between Iron Oxide Surfaces: A Molecular Dynamics Study.

Organic friction modifiers (OFMs) added to lubricating oils to reduce friction and wear are crucial for reducing energy loss and CO2 emissions. In our previous studies, we have developed N-(2,2,6,6-tetramethyl-1-oxyl-4-piperidinyl)dodecaneamide, referred to as C12TEMPO, as a new type of OFM and experimentally demonstrated its superior performance to conventional OFMs of stearic acid and glycerol monooleate. However, the behavior of C12TEMPO adsorbing onto solid surfaces from base oil during sliding, which largely dictates the lubrication performance, is yet to be elucidated. Here, we performed molecular dynamics simulations for confined shear of a C12TEMPO solution in poly-α-olefin between hematite surfaces. Unlike conventional OFMs, which typically have one functional group or multiple functional groups of the same type, C12TEMPO features two functional groups of different types: one amide and one terminal free oxygen radical. The results showed that adsorbed boundary films with a double-layer structure form stably during sliding, owing to double- or single-site surface adsorption and interlayer hydrogen bonding via the two functional groups. Additionally, some molecules in each of the first and second layers also form intralayer hydrogen bonding. Such multitype adsorption is unique and favorable for enhancing the strength of boundary films to withstand heavily loaded and prolonged sliding. The velocity distribution indicates that the first and second layers are solid- and liquid-like, respectively. The second layer could act as a buffer for the first layer, which is the last barrier to prevent solid-solid contact, against shear. We also found that the second layer can act as a reservoir to rapidly repair the once depleted region in the first layer because of the interlayer hydrogen bonding. The combination of the high strength and self-repair ability of the C12TEMPO boundary films can rationally explain the experimentally observed properties of high load-carrying capacity, excellent antiwear effect, and high stability of friction over time.

Phase transitions induced by exchange coupling, magnetic field, and temperature in a strongly correlated molecular trimer with a triangular topology.

Regulating the physical properties such as the quantum phase and the Kondo effect of molecular electronic devices near critical points may play a key role in increasing the robustness of quantum memory, which is a crucial component in quantum information processing. Molecules with a triangular topology are ideal prototypes to reveal the competition among magnetic frustration, Kondo screening, and local inter-molecule exchange interactions. Herein, motivated by a recent work investigating the single-electron tunneling through a redox-active edge-fused porphyrin trimer by using a Hubbard dimer model [J. O. Thomas, J. K. Sowa, B. Limburg, X. Bian, C. Evangeli, J. L. Swett, S. Tewari, J. Baugh, G. C. Schatz, G. A. D. Briggs, H. L. Anderson and J. A. Mol, Chem. Sci., 2021, 12, 11121], we studied the phase transition, the electronic transport, and the thermodynamical properties of a real molecular trimer structure organized in a triangular topology, with and without an external magnetic field, and at zero and non-zero temperatures. Both the Hubbard electron-electron interaction and the Heisenberg exchange interaction are fully taken into account, with the aid of the state-of-the-art numerical renormalization group method. Various kinds of Kondo behaviors and quantum phase transitions are demonstrated, due to the competition among the Ruderman-Kittel-Kasuya-Yosida interaction, the direct exchange coupling, and the Zeeman effect. Our findings may offer deep insights into the manipulation of the quantum phase and the Kondo behavior in a molecular trimer with a triangular topology.

Modifying the Electrocatalytic Selectivity of Oxidation Reactions with Ionic Liquids.

The "solid catalyst with ionic liquid layer" (SCILL) is an extremely successful new concept in heterogeneous catalysis. The idea is to boost the selectivity of a catalyst by its modification with an ionic liquid (IL). Here, we show that it is possible to use the same concept in electrocatalysis for the selective transformation of organic compounds. We scrutinize the electrooxidation of 2,3-butanediol, a reaction which yields two products, singly oxidized acetoin and doubly oxidized diacetyl. When adding the IL (1-ethyl-3-methyl-imidazolium trifluormethanesulfonate, [C2 C1 Im][OTf]), the selectivity for acetoin increases drastically. By in situ spectroscopy, we analyze the underlying mechanism: Specific adsorption of the IL anions suppresses the activation of water for the second oxidation step and, thus, enhances the selectivity for acetoin. Our study demonstrates the great potential of this approach for selective transformation of organic compounds.