CTLA-4 blockade drives loss of Treg stability in glycolysis-low tumours.

Limiting metabolic competition in the tumour microenvironment may increase the effectiveness of immunotherapy. Owing to its crucial role in the glucose metabolism of activated T cells, CD28 signalling has been proposed as a metabolic biosensor of T cells1. By contrast, the engagement of CTLA-4 has been shown to downregulate T cell glycolysis1. Here we investigate the effect of CTLA-4 blockade on the metabolic fitness of intra-tumour T cells in relation to the glycolytic capacity of tumour cells. We found that CTLA-4 blockade promotes metabolic fitness and the infiltration of immune cells, especially in glycolysis-low tumours. Accordingly, treatment with anti-CTLA-4 antibodies improved the therapeutic outcomes of mice bearing glycolysis-defective tumours. Notably, tumour-specific CD8+ T cell responses correlated with phenotypic and functional destabilization of tumour-infiltrating regulatory T (Treg) cells towards IFNγ- and TNF-producing cells in glycolysis-defective tumours. By mimicking the highly and poorly glycolytic tumour microenvironments in vitro, we show that the effect of CTLA-4 blockade on the destabilization of Treg cells is dependent on Treg cell glycolysis and CD28 signalling. These findings indicate that decreasing tumour competition for glucose may facilitate the therapeutic activity of CTLA-4 blockade, thus supporting its combination with inhibitors of tumour glycolysis. Moreover, these results reveal a mechanism by which anti-CTLA-4 treatment interferes with Treg cell function in the presence of glucose.

Photoexcited Ru single-atomic sites for efficient biomimetic redox catalysis.

The unsatisfactory catalytic activity of nanozymes owing to their inefficient electron transfer (ET) is the major challenge in biomimetic catalysis-related biomedical applications. Inspired by the photoelectron transfers in natural photoenzymes, we herein report a photonanozyme of single-atom Ru anchored on metal-organic frameworks (UiO-67-Ru) for achieving photoenhanced peroxidase (POD)-like activity. We demonstrate that the atomically dispersed Ru sites can realize high photoelectric conversion efficiency, superior POD-like activity (7.0-fold photoactivity enhancement relative to that of UiO-67), and good catalytic specificity. Both in situ experiments and theoretical calculations reveal that photoelectrons follow the cofactor-mediated ET process of enzymes to promote the production of active intermediates and the release of products, demonstrating more favorable thermodynamics and kinetics in H2O2 reduction. Taking advantage of the unique interaction of the Zr-O-P bond, we establish a UiO-67-Ru-based immunoassay platform for the photoenhanced detection of organophosphorus pesticides.

Clonal Abundance of Tumor-Specific CD4(+) T Cells Potentiates Efficacy and Alters Susceptibility to Exhaustion.

Current approaches to cancer immunotherapy aim to engage the natural T cell response against tumors. One limitation is the elimination of self-antigen-specific T cells from the immune repertoire. Using a system in which precursor frequency can be manipulated in a murine melanoma model, we demonstrated that the clonal abundance of CD4(+) T cells specific for self-tumor antigen positively correlated with antitumor efficacy. At elevated precursor frequencies, intraclonal competition impaired initial activation and overall expansion of the tumor-specific CD4(+) T cell population. However, through clonally derived help, this population acquired a polyfunctional effector phenotype and antitumor immunity was enhanced. Conversely, development of effector function was attenuated at low precursor frequencies due to irreversible T cell exhaustion. Our findings assert that the differential effects of T cell clonal abundance on phenotypic outcome should be considered during the design of adoptive T cell therapies, including use of engineered T cells.

Base-Promoted Nucleophilic Phosphorylation of Benzyl Fluorides via C(sp3)-F Cleavage.

Herein, a transition-metal-free phosphorylation of benzyl fluorides with P(O)-H compounds is disclosed. In the presence of tBuOK, various benzyl fluorides react with P(O)-H compounds to produce the corresponding benzyl phosphine oxides, phosphinates, and phosphonates in good to high yields. This base-promoted phosphorylation reaction offers a facile and general strategy for the construction of a C(sp3)-P bond.

One-Pot In Situ Construction of a Highly Stable Acylhydrazone-Derived Dy9 Cluster with Photodynamic Sterilization Property.

The extremely low stability of lanthanide clusters with precise structures and nanometer dimensions in aqueous solutions limits their application in the field of photodynamic sterilization. In this study, an hourglass-shaped nine-nucleated Dy9 cluster (1) with excellent light-driven reactive oxygen species (ROS) generation ability and photodynamic sterilization property was constructed using acylhydrazone multidentate chelating ligands obtained via an in situ reaction. The eight chelating ligands were distributed outside cluster 1, tightly wrapping the cluster core, thus preventing solvent molecules from attacking the cluster nucleus and ensuring the stability of cluster 1 in solution, which was demonstrated via X-ray diffraction and high-resolution electrospray ionization mass spectrometry (HRESI-MS). Time-dependent HRESI-MS monitoring of the self-assembly process of cluster 1 allowed two possible self-assembly mechanisms. The heavy atom effect of multiple Dy(III) ions in the Dy9 cluster enhanced the ISC pathway through spin-orbit coupling, promoting energy transfer from the excited singlet state (S1) to the triplet state (T1), which was stabilized, inducing the generation of more ROS. Cluster 1 showed a remarkable sterilization effect due to the generation of abundant ROS under light irradiation conditions. To our knowledge, this is a rare instance of lanthanide clusters with photodynamic sterilization, providing new horizons for the construction of fast and efficient sterilizers.

Pediatric calcaneal osteomyelitis: an analysis of literature-reported 128 cases.

BACKGROUND: Calcaneal osteomyelitis (CO) poses a formidable challenge in treatment due to the distinct anatomical structure and functional properties of the calcaneus. The present study endeavors to furnish a thorough and comprehensive understanding of the clinical manifestations, therapeutic strategies, and therapeutic outcomes pertaining to pediatric calcaneal osteomyelitis (PCO) by conducting a meticulous synthesis and analysis of cases reported in the literature. METHODS: A systematic search of the PubMed, Embase, and Cochrane Library databases was conducted to identify English-language studies analyzing PCO between 2000 and 2021. The quality of the included studies was assessed using the National Institutes of Health (NIH) assessment scale. Effective data were extracted and analyzed. RESULTS: A total of 42 studies, encompassing 128 patients, fulfilled the established inclusion criteria. The gender distribution revealed a male-to-female ratio of 2:1 (81 boys and 40 girls). The median age at the time of diagnosis was 8 years, while the median duration of symptoms was 0.6 month. Trauma emerged as the primary etiology (41 cases, 54%), and limited activity was the most prevalent symptom (68 cases). The positive rate for pathogen culture was 75.4% (49/65), with Staphylococcus aureus being the most commonly isolated pathogen (28 cases, 57.1%). Surgical intervention was performed in 51% (64/126) of the patients, with debridement serving as the primary surgical strategy. The rate of infection recurrence was 6.8% (8/118), and the risk of below-knee amputation was 0.8% (1/124). CONCLUSIONS: PCO occurred more frequently in male patients, with trauma being the primary underlying cause and Staphylococcus aureus being the most prevalent bacterial pathogen isolated. Over half of the patients underwent surgical intervention. Nonetheless, it is imperative that treatment strategies undergo further refinement, as approximately 7% of patients experienced infection recurrence.

Rosmarinic acid in combination with ginsenoside Rg1 suppresses colon cancer metastasis via co-inhition of COX-2 and PD1/PD-L1 signaling axis.

Metastasis of colorectal cancer (CRC) is a leading cause of mortality among CRC patients. Elevated COX-2 and PD-L1 expression in colon cancer tissue has been linked to distant metastasis of tumor cells. Although COX-2 inhibitors and immune checkpoint inhibitors demonstrate improved anti-tumor efficacy, their toxicity and variable therapeutic effects in individual patients raise concerns. To address this challenge, it is vital to identify traditional Chinese medicine components that modulate COX-2 and PD-1/PD-L1: rosmarinic acid (RA) exerts striking inhibitory effect on COX-2, while ginsenoside Rg1 (GR) possesses the potential to suppress the binding of PD-1/PD-L1. In this study we investigated whether the combination of RA and GR could exert anti-metastatic effects against CRC. MC38 tumor xenograft mouse model with lung metastasis was established. The mice were administered RA (100 mg·kg-1·d-1, i.g.) alone or in combination with GR (100 mg·kg-1·d-1, i.p.). We showed that RA (50, 100, 150 µM) or a COX-2 inhibitor Celecoxib (1, 3, 9 µM) concentration-dependently inhibited the migration and invasion of MC38 cells in vitro. We further demonstrated that RA and Celecoxib inhibited the metastasis of MC38 tumors in vitro and in vivo via interfering with the COX-2-MYO10 signaling axis and inhibiting the generation of filopodia. In the MC38 tumor xenograft mice, RA administration significantly decreased the number of metastatic foci in the lungs detected by Micro CT scanning; RA in combination with GR that had inhibitory effect on the binding of PD-1 and PD-L1 further suppressed the lung metastasis of colon cancer. Compared to COX-2 inhibitors and immune checkpoint inhibitors, RA and GR displayed better safety profiles without disrupting the tissue structures of the liver, stomach and colon, offering insights into the lower toxic effects of clinical traditional Chinese medicine against tumors while retaining its efficacy.

Perceived control, self-management efficacy, and quality of life in patients treated with radiation therapy for breast cancer: a longitudinal study.

OBJECTIVE: This longitudinal study aims to examine the present state of perceived control, self-management efficacy, and overall quality of life (QoL) in patients with breast cancer undergoing radiotherapy, and gain insight into the dynamic trends and factors that influence the quality of life experienced by patients during the course of radiotherapy. METHODS: Participants completed the Cancer Experience and Efficacy Scale (CEES), Strategies Used by People to Promote Health (SUPPH), and Functional Assessment of Cancer Therapy- Breast (FACT-B). The data was analyzed using the software SPSS26.0. Repeated measures analysis of variance (ANOVA) and mixed-effects linear models were used to analyze trends in perceived control, self-management efficacy, and QoL at three-time points, as well as factors affecting QoL during radiotherapy. RESULTS: Perceived control and self-management efficacy were associated with QoL over the course of the radiotherapy. Self-management efficacy (ß = 0.30, P < 0.001), presence of chemotherapy (ß = 18.33, P = 0.024), and duration of illness (ß = 2.25, P = 0.028) had a positive effect on the change in QoL, while time (ß = - 2.95, P < 0.001), cancer experience (ß = - 0.46, P < 0.001), and type of medical insurance (ß = - 2.77, P = 0.021) had the negative effect on the change in QoL. CONCLUSION: The QoL, perceived control, and self-efficacy of patients with breast cancer show dynamic changes during radiotherapy. The higher the self-efficacy, the better the QoL, and the worse the QoL when the sense of disease control is poor. At the same time, more attention should be paid to the QoL of breast cancer radiotherapy patients with a long course of the disease, receiving chemotherapy, and different medical payment methods.

Impact of butylparaben on growth dynamics and microcystin-LR production in Microcystis aeruginosa.

The presence of butylparaben (BP), a prevalent pharmaceutical and personal care product, in surface waters has raised concerns regarding its impact on aquatic ecosystems. Despite its frequent detection, the toxicity of BP to the cyanobacterium Microcystis aeruginosa remains poorly understood. This study investigates the influence of BP on the growth and physiological responses of M. aeruginosa. Results indicate that low concentrations of BP (below 2.5 mg/L) have negligible effects on M. aeruginosa growth, whereas higher concentrations (5 mg/L and 10 mg/L) lead to significant growth inhibition. This inhibition is attributed to the severe disruption of photosynthesis, evidenced by decreased Fv/Fm values and chlorophyll a content. BP exposure also triggers the production of reactive oxygen species (ROS), resulting in elevated activity of antioxidant enzymes. Excessive ROS generation stimulates the production of microcystin-LR (MC-LR). Furthermore, lipid peroxidation and cell membrane damage indicate that high BP concentrations cause cell membrane rupture, facilitating the release of MC-LR into the environment. Transcriptome analysis reveals that BP disrupts energy metabolic processes, particularly affecting genes associated with photosynthesis, carbon fixation, electron transport, glycolysis, and the tricarboxylic acid cycle. These findings underscore the profound physiological impact of BP on M. aeruginosa and highlight its role in stimulating the production and release of MC-LR, thereby amplifying environmental risks in aquatic systems.

The secreted peptide BATSP1 promotes thermogenesis in adipocytes.

Although brown adipose tissue (BAT) has historically been viewed as a major site for energy dissipation through thermogenesis, its endocrine function has been increasingly recognized. However, the circulating factors in BAT that play a key role in controlling systemic energy homeostasis remain largely unexplored. Here, we performed a peptidomic analysis to profile the extracellular peptides released from human brown adipocytes upon exposure to thermogenic stimuli. Specifically, we identified a secreted peptide that modulates adipocyte thermogenesis in a cell-autonomous manner, and we named it BATSP1. BATSP1 promoted BAT thermogenesis and induced browning of white adipose tissue in vivo, leading to increased energy expenditure under cold stress. BATSP1 treatment in mice prevented high-fat diet-induced obesity and improved glucose tolerance and insulin resistance. Mechanistically, BATSP1 facilitated the nucleocytoplasmic shuttling of forkhead transcription factor 1 (FOXO1) and released its transcriptional inhibition of uncoupling protein 1 (UCP1). Overall, we provide a comprehensive analysis of the human brown adipocyte extracellular peptidome following acute forskolin (FSK) stimulation and identify BATSP1 as a novel regulator of thermogenesis that may offer a potential approach for obesity treatment.

Biosynthesis of silver nanoparticles using Burkholderia contaminans ZCC and mechanistic analysis at the proteome level.

The biogenic synthesis of silver nanoparticles (AgNPs) by microorganisms has been a subject of increasing attention. Despite extensive studies on this biosynthetic pathway, the mechanisms underlying the involvement of proteins and enzymes in AgNPs production have not been fully explored. Herein, we reported that Burkholderia contaminans ZCC was able to reduce Ag+ to AgNPs with a diameter of (10±5) nm inside the cell. Exposure of B. contaminans ZCC to Ag+ ions led to significant changes in the functional groups of cellular proteins, with approximately 5.72% of the (C-OH) bonds being converted to (C-C/C-H) (3.61%) and CO (2.11%) bonds, and 4.52% of the CO (carbonyl) bonds being converted to (C-OH) bonds. Furthermore, the presence of Ag+ and AgNPs induced the ability of extracellular electron transfer for ZCC cells via specific membrane proteins, but this did not occur in the absence of Ag+ ions. Proteomic analysis of the proteins and enzymes involved in heavy metal efflux systems, protein secretion system, oxidative phosphorylation, intracellular electron transfer chain, and glutathione metabolism suggests that glutathione S-transferase and ubiquinol-cytochrome c reductase iron-sulfur subunit play importance roles in the biosynthesis of AgNPs. These findings contribute to a deeper understanding of the functions exerted by glutathione S-transferase and ferredoxin-thioredoxin reductase iron-sulfur subunits in the biogenesis of AgNPs, thereby hold immense potential for optimizing biotechnological techniques aimed at enhancing the yield and purity of biosynthetic AgNPs.

Integrated transcriptome and 1H NMR-based metabolome to explore the potential mechanism of Spodoptera litura in response to flupyrimin.

Flupyrimin (FLP) is a novel class of insecticide acting on insect nicotinic acetylcholine receptor (nAChR) and shows robust insecticidal activity. However, the toxicological effects of FLP on Spodoptera litura have not been revealed. In this study, the results showed that the larval survival rate decreased significantly with increasing concentration of FLP. The hematoxylin-eosin (HE) staining showed that FLP exposure damages the structure of the larval midgut. Additionally, FLP treatments significantly increased the activities of detoxification (GST and CarE) and digestive (α-Amylase and Trypsin) enzymes and reduced lipase activity. Transcriptome sequencing identified 855, 1493 and 735 differentially expressed genes (DEGs) at 12 h, 24 h and 48 h after exposure to 3 mM FLP, respectively. Gene function enrichment analysis revealed that DEGs were mainly related to fatty acid metabolic, protein processing in the endoplasmic reticulum and drug metabolism-cytochrome P450. The DEGs associated with food digestion and detoxification was validated by reverse-transcription quantitative PCR (RT-qPCR). Furthermore, a total of fifteen energy-related metabolites were identified, among which thirteen metabolisms were significantly influenced after FLP treatment based on 1H NMR-based metabolome analysis, including tyrosine, glucose, trehalose, malate, threonine, proline, glycine, lysine, citrate, alanine, lactate, valine, and leucine. Taken together, these results provide useful information for revealing the toxicological effect of FLP against S. litura.

Comparison of prognosis between extracorporeal CPR and conventional CPR for patients in cardiac arrest: a systematic review and meta-analysis.

AIM: Compared to the conventional cardiopulmonary resuscitation (CCPR), potential benefits of extracorporeal cardiopulmonary resuscitation (ECPR) for patients with cardiac arrest (CA) are still controversial. We aimed to determine whether ECPR can improve the prognosis of CA patients compared with CCPR. METHODS: We systematically searched PubMed, EMBASE, and Cochrane Library from database's inception to July 2023 to identify randomized controlled trials (RCTs) or cohort studies that compared ECPR with CCPR in adults (aged ≥ 16 years) with out-of-hospital cardiac arrest (OHCA) and in-hospital cardiac arrest (IHCA). This meta-analysis was performed using a random-effects model. Two researchers independently reviewed the relevance of the study, extracted data, and evaluated the quality of the included literature. The primary outcome was short-term (from hospital discharge to one month after cardiac arrest) and long-term (≥ 90 days after cardiac arrest) survival with favorable neurological status (defined as cerebral performance category scores 1 or 2). Secondary outcomes included survival at 1 months, 3-6 months, and 1 year after cardiac arrest. RESULTS: The meta-analysis included 3 RCTs and 14 cohort studies involving 167,728 patients. We found that ECPR can significantly improve good neurological prognosis (RR 1.82, 95%CI 1.42-2.34, I2 = 41%) and survival rate (RR 1.51, 95%CI 1.20-1.89, I2 = 62%). In addition, the results showed that ECPR had different effects on favorable neurological status in patients with OHCA (short-term: RR 1.50, 95%CI 0.98- 2.29, I2 = 55%; long-term: RR 1.95, 95% CI 1.06-3.59, I2 = 11%). However, ECPR had significantly better effects on neurological status than CCPR in patients with IHCA (short-term: RR 2.18, 95%CI 1.24- 3.81, I2 = 9%; long-term: RR 2.17, 95% CI 1.19-3.94, I2 = 0%). CONCLUSIONS: This meta-analysis indicated that ECPR had significantly better effects on good neurological prognosis and survival rate than CCPR, especially in patients with IHCA. However, more high-quality studies are needed to explore the role of ECPR in patients with OHCA.

Improved Alkaline Hydrogen Evolution Performance of Dealloying Fe75-xCoxSi12.5B12.5 Electrocatalyst.

The electrocatalytic performance of a Fe65Co10Si12.5B12.5 Fe-based compounds toward alkaline hydrogen evolution reaction (HER) is enhanced by dealloying. The dealloying process produced a large number of nanosheets on the surface of NS-Fe65Co10Si12.5B12.5, which greatly increased the specific surface area of the electrode. When the dealloying time is 3 h, the overpotential of NS-Fe65Co10Si12.5B12.5 is only 175.1 mV at 1.0 M KOH and 10 mA cm-2, while under the same conditions, the overpotential of Fe65Co10Si12.5B12.5 is 215 mV, which is reduced. In addition, dealloying treated electrodes also show better HER performance than un-dealloying treated electrodes. With the increase in Co doping amount, the overpotential of the hydrogen evolution reaction decreases, and the hydrogen evolution activity is the best when the addition amount of Co is 10%. This work not only provides a basic understanding of the relationship between surface activity and the dealloying of HER catalysts, but also paves a new way for doping transition metal elements in Fe-based electrocatalysts working in alkaline media.

Harmonizing Enzyme-like Cofactors to Boost Nanozyme Catalysis.

Engineering isolated metal sites resembling the primary coordination sphere of metallocofactors enables atomically dispersed materials as promising nanozymes. However, most existing nanozymes primarily focus on replicating specific metallocofactors while neglecting other supporting cofactors within active pockets, leading to reduced electron transfer (ET) efficiency and thus inferior catalytic performances. Herein, we report a metal-organic framework UiO-67 nanozyme with atomically dispersed iron sites, which involves multiple tailored enzyme-like nanocofactors that synergistically drive the ET process for enhanced peroxidase-like catalysis. Among them, the linker-coupled atomic iron site plays a critical role in substrate activation, while bare linkers and zirconia nodes facilitate the ET efficiency of intermediates. The synergy of three nanocofactors results in a 4.29-fold enhancement compared with the single effort of isolated metal site-based nanocofactor, holding promise in immunoassay for sensitive detection of chlorpyrifos. This finding opens a new way for designing high-performance nanozymes by harmonizing various nanocofactors at the atomic and molecular scale.

Quantitative Label-Free SERS Detection of Trace Fentanyl in Biofluids with a Freestanding Hydrophobic Plasmonic Paper Biosensor.

The prevalence of fentanyl abuse raises global public health concerns with an unprecedented surge in overdose deaths. Rapid identification and quantification of fentanyl in biofluids is of paramount importance to combat fentanyl abuse for law enforcement agencies and promptly treat patients for medical professionals. Herein, a freestanding surface-enhanced Raman spectroscopy (SERS) biosensor with excellent condensing enrichment capability, termed FrEnSERS biosensor, is reported for quantitative label-free detection of trace fentanyl in biofluids. This biosensor comprises a reduced graphene oxide membrane decorated with high-density hydrophobic Au nanostars. A combination of the high SERS enhancement and the focusing effect for analyte enrichment of the hydrophobic surface accounts for the remarkable SERS performance of the FrEnSERS biosensor. We demonstrate that the FrEnSERS biosensor achieves the sensitive and quantitative detection of fentanyl in both serum and urine over a wide dynamic range spanning more than 4 orders of magnitude, with a limit of detection of 0.47 ng/mL for serum samples and 0.73 ng/mL for urine samples. Our biosensor is sensitive, cost-effective, and reliable for rapid quantitative analysis of fentanyl in biofluids with great promise for forensic analysis and clinical diagnosis.

"One-Pot" In Situ Tandem Reaction─Dy(III) Coordination-Catalyzed Multicomponent Condensation of Salicylaldehyde Derivatives to Obtain Ketals.

It is difficult to subject simple reaction starting materials to a "one-pot" in situ tandem reaction without post-treatment under mild reaction conditions to obtain multimers with complex structural linkages. In organic synthesis, acetal reactions are often used to protect derivatives containing carbonyl functional groups. Therefore, acetal products tend to have very low stability, and performing multi-step condensation to obtain complex multimeric products is difficult. Herein, we achieved the first efficient multiple condensation of o-vanillin derivatives using Dy(OAc)3·6H2O undergoing a "one-pot" in situ tandem reaction under mild solvothermal conditions to obtain a series of dimers (I and II, clusters 1 and 2) and trimers (I and II, clusters 3 and 4). When methanol or ethanol is used as the solvent, the alcoholic solvent participates in acetal and dehydration reactions to obtain dimers (I and II). Surprisingly, when using acetonitrile as the reaction solvent, the o-vanillin derivatives undergo acetal and dehydration reactions to obtain trimers (I and II). In addition, clusters 1-4 all showed distinct single-molecule magnetic behaviors under zero-field conditions. To the best of our knowledge, this is the first time that multiple acetal reactions catalyzed by coordination-directed catalysis under "one-pot" conditions have been realized, opening a new horizon for the development of fast, facile, green, and efficient synthetic methods for complex compounds.

Aggregation-Induced Emission via the Restriction of the Intramolecular Vibration Mechanism of Pinacol Lanthanide Complexes.

Pinacol lanthanide complexes PyraLn (Ln = Dy and Tb) with the restriction of intramolecular vibration were obtained for the first time via an in situ solvothermal coordination-catalyzed tandem reaction using cheap and simple starting materials, thereby avoiding complex, time-consuming, and expensive conventional organic synthesis strategies. A high-resolution electrospray ionization mass spectrometry (HRESI-MS) analysis confirmed the stability of PyraLn in an organic solution. The formation process of PyraLn was monitored in detail using time-dependent HRESI-MS, which allowed for proposing a mechanism for the formation of pinacol complexes via in situ tandem reactions under one-pot coordination-catalyzed conditions. The PyraLn complexes constructed using a pinacol ligand with a butterfly configuration exhibited distinct aggregation-induced emission (AIE) behavior, with the αAIE value as high as 60.42 according to the AIE titration curve. In addition, the PyraLn complexes in the aggregated state exhibit a rapid photoresponse to various 3d metal ions with low detection limits. These findings provide fast, facile, and high-yield access to dynamic, smart lanthanide complex emissions with bright emission and facilitate the rational construction of molecular machines for artificial intelligence.

Ni-catalyzed C-F activation to construct C-P bond with P-P(O) and P(O)OR mediation.

Here we developed an efficient Ni-catalyzed C-F bond phosphorylation of aryl fluorides via the crucial intermediates of P-P(O) and P(O)OR. P-P(O) mediated organophosphorus generation is observed for active aryl fluorides, whereas inactive aryl fluorides can also be activated and phosphorylated via a P(O)OR-mediated pathway, which is barely reported yet. Facile scale-up to the gram level and the upgrading of the bioactive molecule make this protocol to have promising applications in synthetic chemistry.

Human milk-derived extracellular vesicles alleviate high fat diet-induced non-alcoholic fatty liver disease in mice.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD), characterized by excessive hepatic lipid accumulation, imposes serious challenges on public health worldwide. Breastfeeding has been reported to reduce the risk of NAFLD. Extracellular vesicles (EVs) are bilayer membrane vesicles released from various cells into the extracellular space, participating in multiple life processes. Whether EVs from human milk exert metabolic benefits against NAFLD is worth investigating. METHODS AND RESULTS: In this study, the EVs were isolated from human milk collected from healthy mothers and quantified. Functional analyses were performed using the NAFLD mouse model and free fatty acid (FFA)-stimulated mouse primary hepatocytes. The results showed that human milk-derived EVs could effectively alleviate high fat diet-induced hepatic steatosis and insulin resistance in mice with NAFLD via inhibiting lipogenesis and increasing lipolysis. The FFA-induced lipid accumulation was also inhibited in hepatocytes after treatment with human milk-derived EVs. Mechanistically, the human milk derived-EVs cargo (proteins and miRNAs), which linked to lipid metabolism, may be responsible for these beneficial effects. CONCLUSION: The findings of this study highlighted the therapeutic benefits of human milk-derived EVs and provided a new strategy for NAFLD treatment.