Acyl-CoA Dehydrogenase Drives Heat Adaptation by Sequestering Fatty Acids.

Cells adapt to temperature shifts by adjusting levels of lipid desaturation and membrane fluidity. This fundamental process occurs in nearly all forms of life, but its mechanism in eukaryotes is unknown. We discovered that the evolutionarily conserved Caenorhabditis elegans gene acdh-11 (acyl-CoA dehydrogenase [ACDH]) facilitates heat adaptation by regulating the lipid desaturase FAT-7. Human ACDH deficiency causes the most common inherited disorders of fatty acid oxidation, with syndromes that are exacerbated by hyperthermia. Heat upregulates acdh-11 expression to decrease fat-7 expression. We solved the high-resolution crystal structure of ACDH-11 and established the molecular basis of its selective and high-affinity binding to C11/C12-chain fatty acids. ACDH-11 sequesters C11/C12-chain fatty acids and prevents these fatty acids from activating nuclear hormone receptors and driving fat-7 expression. Thus, the ACDH-11 pathway drives heat adaptation by linking temperature shifts to regulation of lipid desaturase levels and membrane fluidity via an unprecedented mode of fatty acid signaling.

Identifying SARS-CoV-2-related coronaviruses in Malayan pangolins.

The ongoing outbreak of viral pneumonia in China and across the world is associated with a new coronavirus, SARS-CoV-21. This outbreak has been tentatively associated with a seafood market in Wuhan, China, where the sale of wild animals may be the source of zoonotic infection2. Although bats are probable reservoir hosts for SARS-CoV-2, the identity of any intermediate host that may have facilitated transfer to humans is unknown. Here we report the identification of SARS-CoV-2-related coronaviruses in Malayan pangolins (Manis javanica) seized in anti-smuggling operations in southern China. Metagenomic sequencing identified pangolin-associated coronaviruses that belong to two sub-lineages of SARS-CoV-2-related coronaviruses, including one that exhibits strong similarity in the receptor-binding domain to SARS-CoV-2. The discovery of multiple lineages of pangolin coronavirus and their similarity to SARS-CoV-2 suggests that pangolins should be considered as possible hosts in the emergence of new coronaviruses and should be removed from wet markets to prevent zoonotic transmission.

Mage transposon: a novel gene delivery system for mammalian cells.

Transposons, as non-viral integration vectors, provide a secure and efficient method for stable gene delivery. In this study, we have discovered Mage (MG), a novel member of the piggyBac(PB) family, which exhibits strong transposability in a variety of mammalian cells and primary T cells. The wild-type MG showed a weaker insertion preference for near genes, transcription start sites (TSS), CpG islands, and DNaseI hypersensitive sites in comparison to PB, approaching the random insertion pattern. Utilizing in silico virtual screening and feasible combinatorial mutagenesis in vitro, we effectively produced the hyperactive MG transposase (hyMagease). This variant boasts a transposition rate 60% greater than its native counterpart without significantly altering its insertion pattern. Furthermore, we applied the hyMagease to efficiently deliver chimeric antigen receptor (CAR) into T cells, leading to stable high-level expression and inducing significant anti-tumor effects both in vitro and in xenograft mice models. These findings provide a compelling tool for gene transfer research, emphasizing its potential and prospects in the domains of genetic engineering and gene therapy.

Identifying suicide attempter in major depressive disorder through machine learning: the importance of pain avoidance, event-related potential features of affective processing.

How to achieve a high-precision suicide attempt classifier based on the three-dimensional psychological pain model is a valuable issue in suicide research. The aim of the present study is to explore the importance of pain avoidance and its related neural features in suicide attempt classification models among patients with major depressive disorder. By recursive feature elimination with cross-validation and support-vector-machine algorithms, scores from the measurements and the task-based EEG signals were chosen to achieve a suicide attempt classification model. In the multimodal suicide attempt classifier with an accuracy of 83.91% and an area under the curve of 0.90, pain avoidance ranked as the top one in the optimal feature set. Theta (reward positive feedback minus neutral positive feedback) was the shared neural representation ranking as the top one of event-related potential features in pain avoidance and suicide attempt classifiers. In conclusion, the suicide attempt classifier based on pain avoidance and its related affective processing neural features has excellent accuracy among patients with major depressive disorder. Pain avoidance is a stable and strong indicator for identifying suicide risks in both traditional analyses and machine-learning approaches. A novel methodology is needed to clarify the relationship between cognitive and affective processing evoked by punishment stimuli and pain avoidance.

Integrated Manipulation and Addressing of Spin Defect in Diamond.

Scalable and addressable integrated manipulation of qubits is crucial for practical quantum information applications. Different waveguides have been used to transport the optical and electrical driving pulses, which are usually required for qubit manipulation. However, the separated multifields may limit the compactness and efficiency of manipulation and introduce unwanted perturbation. Here, we develop a tapered fiber-nanowire-electrode hybrid structure to realize integrated optical and microwave manipulation of solid-state spins at nanoscale. Visible light and microwave driving pulses are simultaneously transported and concentrated along an Ag nanowire. Studied with spin defects in diamond, the results show that the different driving fields are aligned with high accuracy. The spatially selective spin manipulation is realized. And the frequency-scanning optically detected magnetic resonance (ODMR) of spin qubits is measured, illustrating the potential for portable quantum sensing. Our work provides a new scheme for developing compact, miniaturized quantum sensors and quantum information processing devices.

Imaging GPCR Dimerization in Living Cells with Cucurbit[7]uril and Hemicyanine as a "Turn-On" Fluorescence Probe.

Although multiple forms of dimers have been described for GPCR, their dynamics and function are still controversially discussed field. Fluorescence microscopy allows GPCR to be imaged within their native context; however, a key challenge is to site-specifically incorporate reporter moieties that can produce high-quality signals upon formation of GPCR dimers. To this end, we propose a supramolecular sensor approach to detect agonist-induced dimer formation of µ-opioid receptors (µORs) at the surface of intact cells. With the macrocyclic host cucurbit[7]uril and its guest hemicyanine dye tethered to aptamer strands directed against the histidine residues, the sensing module is assembled by host-guest complexation once the histidine-tagged µORs dimerize and bring the discrete supramolecular units into close proximity. With the enhanced sensitivity attributed by the "turn-on" fluorescence emission and high specificity afforded by the intermolecular recognition, in situ visualization of dynamic GPCR dimerization was realized with high precision, thereby validating the supramolecular sensing entity as a sophisticated and versatile strategy to investigate GPCR dimers, which represent an obvious therapeutic target.

Oxygen-Vacancy-Reinforced Vanadium Oxide/Graphene Heterojunction for Accelerated Zinc Storage with Long Life Span.

Vanadium trioxide (V6 O13 ) cathode has recently aroused intensive interest for aqueous zinc-ion batteries (AZIBs) due to their structural and electrochemical diversities. However, it undergoes sluggish reaction kinetics and significant capacity decay during prolonged cycling. Herein, an oxygen-vacancy-reinforced heterojunction in V6 O13- x /reduced graphene oxide (rGO) cathode is designed through electrostatic assembly and annealing strategy. The abundant oxygen vacancies existing in V6 O13- x weaken the electrostatic attraction with the inserted Zn2+ ; the external electric field constructed by the heterointerfaces between V6 O13- x and rGO provides additional built-in driving force for Zn2+ migration; the oxygen-vacancy-enriched V6 O13- x highly dispersed on rGO fabricates the interconnected conductive network, which achieves rapid Zn2+ migration from heterointerfaces to lattice. Consequently, the obtained 2D heterostructure exhibits a remarkable capacity of 424.5 mAh g-1 at 0.1 A g-1 , and a stable capacity retention (96% after 5800 cycles) at the fast discharge rate of 10 A g-1 . Besides, a flexible pouch-type AZIB with real-life practicability is fabricated, which can successfully power commercial products, and maintain stable zinc-ion storage performances even under bending, heavy strikes, and pressure condition. A series of quantitative investigation of pouch batteries demonstrates the possibility of pushing pouch-type AZIBs to realistic energy storage market.

Cold-adapted influenza-vectored RSV vaccine protects BALB/c mice and cotton rats from RSV challenge.

Respiratory syncytial virus (RSV) remains the primary cause of lower respiratory tract infections, particularly in infants and the elderly. In this study, we employed reverse genetics to generate a chimeric influenza virus expressing neuraminidase-3F protein conjugate with three repeats of the RSV F protein protective epitope inserted into the NA gene of A/California/7/2009 ca (CA/AA ca), resulting in rFlu/RSV/NA-3F (hereafter, rFRN3). The expression of NA-3F protein was confirmed by Western blotting. The morphology and temperature-sensitive phenotype of rFRN3 were similar to CA/AA ca. Its immunogenicity and protective efficiency were evaluated in BALB/c mice and cotton rats. Intranasal administration of rFRN3 elicited robust humoral, cellular, and to some extent, mucosal immune responses. Compared to controls, rFRN3 protected animals from RSV infection, attenuated lung injury, and reduced viral titers in the nose and lungs post-RSV challenge. These results demonstrate that rFRN3 can trigger RSV-specific immune responses and thus exhibits potent protective efficacy. The "dual vaccine" approach of a cold-adapted influenza vector RSV vaccine will improve the prophylaxis of influenza and RSV infection. rFRN3 thus warrants further clinical investigations as a candidate RSV vaccine.

Optomechanical Frequency Comb Based on Multiple Nonlinear Dynamics.

Phonon-based frequency combs that can be generated in the optical and microwave frequency domains have attracted much attention due to the small repetition rates and the simple setup. Here, we experimentally demonstrate a new type of phonon-based frequency comb in a silicon optomechanical crystal cavity including both a breathing mechanical mode (∼GHz) and flexural mechanical modes (tens of MHz). We observe strong mode competition between two approximate flexural mechanical modes, i.e., 77.19 and 90.17 MHz, resulting in only one preponderant lasing, while maintaining the lasing of the breathing mechanical mode. These simultaneous observations of two-mode phonon lasing state and significant mode competition are counterintuitive. We have formulated comprehensive theories to elucidate this phenomenon in response to this intriguing outcome. In particular, the self-pulse induced by the free carrier dispersion and thermo-optic effects interacts with two approximate flexural mechanical modes, resulting in the repetition rate of the comb frequency-locked to exact fractions of one of the flexural mechanical modes and the mode hopping between them. This phonon-based frequency comb has at least 260 comblines and a repetition rate as low as a simple fraction of the flexural mechanical frequency. Our demonstration offers an alternative optomechanical frequency comb for sensing, timing, and metrology applications.

Machine Learning-Assisted Analysis of Sublingual Microcirculatory Dysfunction for Early Cardiovascular Risk Evaluation and Cardiovascular-Kidney-Metabolic Syndrome Stage in Patients With Type 2 Diabetes Mellitus.

AIMS: To examine whether sublingual microcirculation can be used as an effective and noninvasive method for assessing cardiovascular, kidney, and metabolic risks in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: This cross-sectional observational study enrolled 186 patients with T2DM. All patients were evaluated using the Framingham General Cardiovascular Risk Score (FGCRS) and cardiovascular-kidney-metabolic (CKM) syndrome stage. Side-stream dark-field microscopy was used for sublingual microcirculation, including total and perfused vessel density (TVD and PVD). Multiple machine-learning prediction models have been developed for CKM risk and stage assessment in T2DM patients. Receiver operating characteristic (ROC) curves were generated to determine cutoff points. RESULTS: Compared to patients with T2DM, diabetic patients with subclinical atherosclerosis (SA) had a greater CV risk, as measured by the FGCRS, accompanied by markedly decreased microcirculation perfusion. Microcirculatory parameters (TVD and PVD), including carotid intima-media thickness (IMT), brachial-ankle pulse wave velocity (ba-PWV), and FGCRS, were closely associated with SA incidence. Microcirculatory parameters, Index (DMSA screen), and cut-off points were used to screen for SA in patients with T2DM. Furthermore, a new set of four factors identified through machine learning showed optimal sensitivity and specificity for detecting CKM risk in patients with T2DM. Decreased microcirculatory perfusion served as a useful early marker for CKM syndrome risk stratification in patients with T2DM without SA. CONCLUSIONS: Sublingual microcirculatory dysfunction is closely correlated with the risk of SA and CKM risk in T2DM patients. Sublingual microcirculation could be a novel tool for assessing the CKM syndrome stage in patients with T2DM.

Changes in thyroid hormones predict weight regain in patients with obesity who undergo metabolic surgery.

AIM: To investigate the relationship between thyroid function and weight regain in patients with obesity after metabolic surgery. METHODS: This retrospective study enrolled 162 patients who underwent metabolic surgery. Correlations between decreases in thyroid hormone levels and changes in weight, waist circumference (WC) and the Chinese visceral adiposity index (CVAI) were assessed. Binary logistic regression and receiver operating characteristic (ROC) curves were used to identify predictors and clinically useful cut-off values, respectively. RESULTS: The levels of thyroid-stimulating hormone (TSH) and free triiodothyronine (FT3) decreased markedly at 1 year after surgery, as did weight, body mass index (BMI), triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, WC and CVAI. Decreases in TSH and FT3 after metabolic surgery were associated with changes in weight, BMI and CVAI. Binary logistic regression and ROC curve analyses confirmed that decreases in TSH can predict good weight loss after metabolic surgery to some extent. Finally, binary logistic regression and ROC curve analyses confirmed that changes in TSH can predict weight regain after metabolic surgery. CONCLUSIONS: Changes in TSH and FT3 after metabolic surgery were correlated with changes in weight and CVAI. Changes in thyroid hormones can predict weight regain in patients with obesity who underwent metabolic surgery.

Evaluation of models to predict prognosis in patients with advanced hepatocellular carcinoma treated with TACE combined with apatinib.

BACKGROUND: The HAP, Six-and-Twelve, Up to Seven, and ALBI scores have been substantiated as reliable prognostic markers in patients presenting with intermediate and advanced hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE) treatment. Given this premise, our research aims to assess the predictive efficacy of these models in patients with intermediate and advanced HCC receiving a combination of TACE and Apatinib. Additionally, we have conducted a meticulous comparative analysis of these four scoring systems to discern their respective predictive capacities and efficacies in combined therapy. METHODS: Performing a retrospective analysis on the clinical data from 200 patients with intermediate and advanced HCC, we studied those who received TACE combined with Apatinib at the First Affiliated Hospital of the University of Science and Technology of China between June 2018 and December 2022. To identify the factors affecting survival, the study performed univariate and multivariate Cox regression analyses, with calculations of four different scores: HAP, Six-and-Twelve, Up to Seven, and ALBI. Lastly, Harrell's C-index was employed to compare the prognostic abilities of these scores. RESULTS: Cox proportional hazards model results revealed that the ALBI score, presence of portal vein tumor thrombus (PVTT, )and tumor size are independent determinants of prognostic survival. The Kaplan-Meier analyses showed significant differences in survival rates among patients classified by the HAP, Six-and-Twelve, Up to Seven, and ALBI scoring methods. Of the evaluated systems, the HAP scoring demonstrated greater prognostic precision, with a Harrell's C-index of 0.742, surpassing the alternative models (P < 0.05). In addition, an analysis of the area under the AU-ROC curve confirms the remarkable superiority of the HAP score in predicting short-term survival outcomes. CONCLUSION: Our study confirms the predictive value of HAP, Six-and-Twelve, Up to Seven, and ALBI scores in intermediate to advanced Hepatocellular Carcinoma (HCC) patients receiving combined Transarterial Chemoembolization (TACE) and Apatinib therapy. Notably, the HAP model excels in predicting outcomes for this specific HCC subgroup.

Enterotoxin-related genes PPFIA4 and SCN3B promote colorectal cancer development and progression.

To identify the role of enterotoxin-related genes in colorectal cancer (CRC) development and progression. Upregulated differentially expressed genes shared by three out of five Gene Expression Omnibus (GEO) data sets were included to screen the key enterotoxin-induced oncogenes (EIOGs) according to criteria oncogene definition, enrichment, and protein-protein interaction (PPI) network analysis, followed by prognosis survival, immune infiltration, and protential drugs analyses was performed via integration of RNA-sequencing data and The Cancer Genome Atlas-derived clinical profiles. We screened nine common key EIOGs from at least three GEO data sets. A Cox proportional hazards regression models verified that more alive cases, decreased overall survival, and highest 4-year survival prediction in CRC patients with high-risk score. Protein tyrosine phosphatase receptor type F polypeptide-interacting protein alpha-4 (PPFIA4), STY11, SCN3B, and SPTBN5 were shared in the same PPI network. Immune infiltration results showed that SCN3B and synaptotagmin 11 expression were obviously associated with B cell, macrophage, myeloid dendritic cell, neutrophils, and T cell CD4+ and CD8+ in both colon adenocarcinoma and rectal adenocarcinoma. CHIR-99021, MLN4924, and YK4-279 were identified as the potential drugs for treatment. Finally, upregulated EIOGs genes PPFIA4 and SCN3B were found in colon adenocarcinoma and PPFIA4 and SCN3B were proved to promote cell proliferation and migration in vitro. We demonstrated here that EIOGs promoting a malignancy phenotype was related with poor survival and prognosis in CRC, which might be served as novel therapeutic targets in CRC management.

Intelligent nanovesicle for remodeling tumor microenvironment and circulating tumor chemoimmunotherapy amplification.

Imperceptible examination and unideal treatment effect are still intractable difficulties for the clinical treatment of pancreatic ductal adenocarcinoma (PDAC). At present, despite 5-fluorouracil (5-FU), as a clinical first-line FOLFIRINOX chemo-drug, has achieved significant therapeutic effects. Nevertheless, these unavoidable factors such as low solubility, lack of biological specificity and easy to induce immunosuppressive surroundings formation, severely limit their treatment in PDAC. As an important source of energy for many tumor cells, tryptophan (Trp), is easily degraded to kynurenine (Kyn) by indolamine 2,3- dioxygenase 1 (IDO1), which activates the axis of Kyn-AHR to form special suppressive immune microenvironment that promotes tumor growth and metastasis. However, our research findings that 5-FU can induce effectively immunogenic cell death (ICD) to further treat tumor by activating immune systems, while the secretion of interferon-γ (IFN-γ) re-induce the Kyn-AHR axis activation, leading to poor treatment efficiency. Therefore, a metal matrix protease-2 (MMP-2) and endogenous GSH dual-responsive liposomal-based nanovesicle, co-loading with 5-FU (anti-cancer drug) and NLG919 (IDO1 inhibitor), was constructed (named as ENP919@5-FU). The multifunctional ENP919@5-FU can effectively reshape the tumor immunosuppression microenvironment to enhance the effect of chemoimmunotherapy, thereby effectively inhibiting cancer growth. Mechanistically, PDAC with high expression of MMP-2 will propel the as-prepared nanovesicle to dwell in tumor region via shedding PEG on the nanovesicle surface, effectively enhancing tumor uptake. Subsequently, the S-S bond containing nanovesicle was cut via high endogenous GSH, leading to the continued release of 5-FU and NLG919, thereby enabling circulating chemoimmunotherapy to effectively cause tumor ablation. Moreover, the combination of ENP919@5-FU and PD-L1 antibody (αPD-L1) showed a synergistic anti-tumor effect on the PDAC model with abdominal cavity metastasis. Collectively, ENP919@5-FU nanovesicle, as a PDAC treatment strategy, showed excellent antitumor efficacy by remodeling tumor microenvironment to circulate tumor chemoimmunotherapy amplification, which has promising potential in a precision medicine approach.

Incidence of renal cell carcinoma after solid organ transplantation: a systematic review and meta-analysis.

BACKGROUND: The incidence rate of malignant tumors after solid organ transplantation is higher than the normal population. The aim of our study is to identify the risk of renal cell carcinoma (RCC) after liver, kidney, heart and lung transplantation, respectively, and suggest that transplant patients can be screened early for tumors to avoid risk. METHODS: PubMed, Embase and the Cochrane Library from their inception until August 16,2023. Retrospective and cohort studies which focus on the statistical data of standardized incidence ratios (SIRs) of RCC after solid organ transplantation (SOT) more than one year have been included and extracted. The study was registered with PROSPERO, CRD4202022343633. RESULTS: Sixteen original studies have been included for meta-analysis. Liver transplantation could increase the risk of RCC (SIR = 0.73, 95%CI: 0.53 to 0.93) with no heterogeneity(P = 0.594, I2 = 0.0%). And kidney transplantation could increase the risk of RCC(8.54, 6.68 to 10.40; 0.000,90.0%). Besides, heart and lung transplantation also could increase the risk of RCC(SIR = 0.73, 95%CI: 0.53 to 0.93; SIR = 1.61, 95%CI:0.50 to 2.71). Moreover, significance could also be found in most subgroups, especially the European group and retrospective study group. What's more, after removing studies which have a greater impact on the overall outcome in RCC rate after kidney transplantation, heterogeneity did not solve and significant different was also observed in the European group (7.15, 5.49 to 8.81; 0.000, 78.6%). CONCLUSION: Liver, kidney, heart and lung transplantation patients have an increased risk of processing RCC compared to the general population and most subgroups, especially in geographic location of European subgroup, which suggested that patients should be screened frequently after transplantation.

Circ-Luc7l Absence Attenuates Diabetic Nephropathy Progression by Reducing Mesangial Cell Excessive Proliferation, Inflammation, and Extracellular Matrix Accumulation via Mediating the miR-205-5p/Tgfbr1 Pathway.

Diabetic nephropathy (DN) threatens the survival quality of patients, with complex pathogenesis. Circular RNA (circRNA) dysregulation occurs in DN development. This work aimed to investigate the role of circ-Luc7l in DN cell models and related molecular mechanisms. The expression of circ-Luc7l, microRNA (miR)-205-5p, and transforming growth factor-beta receptor 1 (Tgfbr1) was examined by real-time quantitative PCR (RT-qPCR). Cell viability and proliferation were detected by Cell Counting Kit-8 (CCK-8) assay and EdU assay. The expression of extracellular matrix (ECM)-related markers and Tgrbr1 protein was measured by Western blot. The binding between miR-205-5p and circ-Luc7l or Tgfbr1 was validated by dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay, or RNA pull-down assay. Experimental animal models were established to elucidate the function of circ-Luc7l in vivo. Circ-Luc7l expression was notably enhanced in high glucose (HG)-treated mesangial cells. Knockdown of circ-Luc7l attenuated HG-induced cell proliferation, inflammation, and ECM accumulation in vitro and relieved inflammation and ECM accumulation of kidneys of diabetic mice in vivo. Circ-Luc7l targeted miR-205-5p, and miR-205-5p inhibition rescued the depletion effects of circ-Luc7l knockdown on cell proliferation, inflammation, and ECM accumulation. MiR-205-5p bound to Tgfbr1 whose expression was negatively regulated by circ-Luc7l. Tgfbr1 overexpression also rescued the depletion effects of circ-Luc7l knockdown on cell proliferation, inflammation, and ECM accumulation. In HG conditions, increased circ-Luc7l upregulated Tgfbr1 expression via targeting miR-205-5p to induce DN progression.

Vibration-Dependent Dual-Phosphorescent Cu4 Nanocluster with Remarkable Piezochromic Behavior.

The dual emission (DE) characteristics of atomically precise copper nanoclusters (Cu NCs) are of significant theoretical and practical interest. Despite this, the underlying mechanism driving DE in Cu NCs remains elusive, primarily due to the complexities of excited state processes. Herein, a novel [Cu4(PPh3)4(C≡C-p-NH2C6H4)3]PF6 (Cu4) NC, shielded by alkynyl and exhibiting DE, was synthesized. Hydrostatic pressure was applied to Cu4, for the first time, to investigate the mechanism of DE. With increasing pressure, the higher-energy emission peak of Cu4 gradually disappeared, leaving the lower-energy emission peak as the dominant emission. Additionally, the Cu4 crystal exhibited notable piezochromism transitioning from cyan to orange. Angle-dispersive synchrotron X-ray diffraction results revealed that the reduced inter-cluster distances under pressure brought the peripheral ligands closer, leading to the formation of new C-H⋅⋅⋅N and N-H⋅⋅⋅N hydrogen bonds in Cu4. It is proposed that these strengthened hydrogen bond interactions limit the ligands' vibration, resulting in the vanishing of the higher-energy peak. In situ high-pressure Raman and vibrationally resolved emission spectra demonstrated that the benzene ring C=C stretching vibration is the structural source of the DE in Cu4.

Salt-Induced Hepatic Inflammatory Memory Contributes to Cardiovascular Damage Through Epigenetic Modulation of SIRT3.

BACKGROUND: High salt intake is the leading dietary risk factor for cardiovascular diseases. Although clinical evidence suggests that high salt intake is associated with nonalcoholic fatty liver disease, which is an independent risk factor for cardiovascular diseases, it remains elusive whether salt-induced hepatic damage leads to the development of cardiovascular diseases. METHODS: Mice were fed with normal or high-salt diet for 8 weeks to determine the effect of salt loading on liver histological changes and blood pressure, and salt withdrawal and metformin treatment were also conducted on some high-salt diet-fed mice. Adeno-associated virus 8, global knockout, or tissue-specific knockout mice were used to manipulate the expression of some target genes in vivo, including SIRT3 (sirtuin 3), NRF2 (NF-E2-related factor 2), and AMPK (AMP-activated protein kinase). RESULTS: Mice fed with a high-salt diet displayed obvious hepatic steatosis and inflammation, accompanied with hypertension and cardiac dysfunction. All these pathological changes persisted after salt withdrawal, displaying a memory phenomenon. Gene expression analysis and phenotypes of SIRT3 knockout mice revealed that reduced expression of SIRT3 was a chief culprit responsible for the persistent inflammation in the liver, and recovering SIRT3 expression in the liver effectively inhibits the sustained hepatic inflammation and cardiovascular damage. Mechanistical studies reveal that high salt increases acetylated histone 3 lysine 27 (H3K27ac) on SIRT3 promoter in hepatocytes, thus inhibiting the binding of NRF2, and results in the sustained inhibition of SIRT3 expression. Treatment with metformin activated AMPK, which inhibited salt-induced hepatic inflammatory memory and cardiovascular damage by lowering the H3K27ac level on SIRT3 promoter, and increased NRF2 binding ability to activate SIRT3 expression. CONCLUSIONS: This study demonstrates that SIRT3 inhibition caused by histone modification is the key factor for the persistent hepatic steatosis and inflammation that contributes to cardiovascular damage under high salt loading. Avoidance of excessive salt intake and active intervention of epigenetic modification may help to stave off the persistent inflammatory status that underlies high-salt-induced cardiovascular damage in clinical practice.

Body-Centered-Cubic-Kernelled Ag15Cu6 Nanocluster with Alkynyl Protection: Synthesis, Total Structure, and CO2 Electroreduction.

While atomically monodisperse nanostructured materials are highly desirable to unravel the size- and structure-catalysis relationships, their controlled synthesis and the atomic-level structure determination pose challenges. Particularly, copper-containing atomically precise alloy nanoclusters are potential catalyst candidates for the electrochemical CO2 reduction reaction (eCO2RR) due to high abundance and tunable catalytic activity of copper. Herein, we report the synthesis and total structure of an alkynyl-protected 21-atom AgCu alloy nanocluster [Ag15Cu6(C≡CR)18(DPPE)2]-, denoted as Ag15Cu6 (HC≡CR: 3,5-bis(trifluoromethyl)phenylacetylene; DPPE: 1,2-bis(diphenylphosphino)ethane). The single-crystal X-ray diffraction reveals that Ag15Cu6 consists of an Ag11Cu4 metal core exhibiting a body-centered cubic (bcc) structure, which is capped by 2 Cu atoms, 2 Ag2DPPE motifs, and 18 alkynyl ligands. Interestingly, the Ag15Cu6 cluster exhibits excellent catalytic activity for eCO2RR with a CO faradaic efficiency (FECO) of 91.3% at -0.81 V (vs the reversible hydrogen electrode, RHE), which is much higher than that (FECO: 48.5% at -0.89 V vs RHE) of Ag9Cu6 with bcc structure. Furthermore, Ag15Cu6 shows superior stability with no significant decay in the current density and FECO during a long-term operation of 145 h. Density functional theory calculations reveal that the de-ligated Ag15Cu6 cluster can expose more space at the pair of AgCu dual metals as the efficient active sites for CO formation.

Coexistent, Competing Tunnelling, and Hopping Charge Transport in Compressed Metal Nanocluster Crystals.

Understanding charge transport among metal particles with sizes of approximately 1 nm poses a great challenge due to the ultrasmall nanosize, yet it holds great significance in the development of innovative materials as substitutes for traditional semiconductors, which are insulative and unstable in less than ∼10 nm thickness. Herein, atomically precise gold nanoclusters with well-defined compositions and structures were investigated to establish a mathematical relation between conductivity and interparticle distance. This was accomplished using high-pressure in situ resistance characterizations, synchrotron X-ray diffraction (XRD), and the Murnaghan equation of state. Based on this precise correlation, it was predicted that the conductivity of Au25(SNap)18 (SNap: 1-naphthalenethiolate) solid is comparable to that of bulk silver when the interparticle distance is reduced to approximately 3.6 Å. Furthermore, the study revealed the coexisting, competing tunneling, and incoherent hopping charge transport mechanisms, which differed from those previously reported. The introduction of conjugation-structured ligands, tuning of the structures of metal nanoclusters, and use of high-pressure techniques contributed to enhanced conductivity, and thus, the charge carrier types were determined using Hall measurements. Overall, this study provides valuable insight into the charge transport in gold nanocluster solids and represents an important advancement in metal nanocluster semiconductor research.