Identifying the Real Chemistry of the Synthesis and Reversible Transformation of AuCd Bimetallic Clusters.

The capability of precisely constructing bimetallic clusters with atomic accuracy provides exciting opportunities for establishing their structure-property correlations. However, the chemistry (the charge state of precursors, the property of ligands, the amount of dopant, and so forth) dictating the fabrication of clusters with atomic-level control has been a long-standing challenge. Herein, based on the well-defined Au25(SR)18 cluster (SR = thiolates), we have systematically investigated the factors of steric hindrance and electronic effect of ligands, the charge state of Au25(SR)18, and the amount of dopant that may determine the structure of AuCd clusters. It is revealed that [Au19Cd3(SR)18]- can be obtained when a ligand of smaller steric hindrance is used, while Au24Cd(SR)18 is attained when a larger steric hindrance ligand is used. In addition, negatively charged [Au25(SR)18]- is apt to form [Au19Cd3(SR)18]- during Cd doping, while Au24Cd(SR)18 is produced when neutral Au25(SR)18 is used as a precursor. Intriguingly, the reversible transformation between [Au19Cd3(SR)18]- and Au24Cd(SR)18 is feasible by subtly manipulating ligands with different steric hindrances. Most importantly, by introducing the excess amount of dopant, a novel bimetallic cluster, Au4Cd4(SR)12 is successfully fabricated and its total structure is fully determined. The electronic structures and the chirality of Au4Cd4(SR)12 have been elucidated by density functional theory (DFT) calculations. Au4Cd4(SR)12 reported herein represents the smallest AuCd bimetallic cluster with chirality.

The Factors Dictating Properties of Atomically Precise Metal Nanocluster Electrocatalysts.

Metal nanoparticles occupy an important position in electrocatalysis. Unfortunately, by using conventional synthetic methodology, it is a great challenge to realize the monodisperse composition/structure of metal nanoparticles at the atomic level, and to establish correlations between the catalytic properties and the structure of individual catalyst particles. For the study of well-defined nanocatalysts, great advances have been made for the successful synthesis of nanoparticles with atomic precision, notably ligand-passivated metal nanoclusters. Such well-defined metal nanoclusters have become a type of model catalyst and have shown great potential in catalysis research. In this review, the authors summarize the advances in the utilization of atomically precise metal nanoclusters for electrocatalysis. In particular, the factors (e.g., size, metal doping/alloying, ligand engineering, support materials as well as charge state of clusters) affecting selectivity and activity of catalysts are highlighted. The authors aim to provide insightful guidelines for the rational design of electrocatalysts with high performance and perspectives on potential challenges and opportunities in this emerging field.

Sex differences in growth performance are related to cecal microbiota in chicken.

In poultry industry, male chickens have a better growth performance than female ones under the same genetic background and diet. Emerging evidences proposed an important role of intestinal microbiota in chicken's growth performance. This study aimed to determine gut microbiota related gender based differences in the growth performance of chickens. Therefore, male and female chickens (n = 20) at 7-week age were used to carry out histomorphological, molecular, gene expression analysis with their liver, chest and leg muscle, as well as 16S rRNA sequencing analysis for gut microbiota. The results revealed that Bacteroides and Megamonas genera were more prominently colonized in the cecum of male chickens. The male chicken's cecal microbiota indicated a closer relation with glycan metabolism, while in the female chickens it was more related with lipid metabolism. Gene expression levels associated with glycan and lipid metabolism were different between male and female chickens. Further, using Spearman correlation analysis, we found a positive correlation between glycan and lipid metabolism, and the relative abundance of Bacteroides, Megamona and Lactobacillus in male chickens. Similarly, we also found a positive correlation between the lipid metabolism and the relative abundance of Ruminococcaceae and Enterococcus in female chickens. These findings revealed the association of chicken growth performance with cecal microbiota that contributed to the metabolism of glycan and lipid in a sex-dependent manner.

Simultaneous Detection of Mitochondrial Hydrogen Selenide and Superoxide Anion in HepG2 Cells under Hypoxic Conditions.

Previous studies proposed that sodium selenite (Na2SeO3) was reduced to hydrogen selenide (H2Se) and that H2Se subsequently reacted with oxygen to generate superoxide anion (O2•-), resulting in tumor cell oxidative stress and apoptosis. However, under the hypoxic conditions of a solid tumor, the anticancer mechanism of sodium selenite remains unclear. To reveal the exact anticancer mechanism of selenite in the real tumor microenvironment, we developed a mitochondria-targeting fluorescent nanosensor, Mito-N-D-MSN, which was fabricated from mesoporous silica nanoparticles (MSNs) loaded with two small-molecule fluorescent probes and a triphenylphosphonium ion as a mitochondria-targeting moiety. With Mito-N-D-MSN, the fluctuations in the contents of mitochondrial hydrogen selenide (H2Se) and superoxide anion (O2•-) in HepG2 cells induced by Na2SeO3 were investigated in detail under normoxic and hypoxic conditions. The results showed that the mitochondrial H2Se content increased gradually, while the O2•- content remained unchanged in HepG2 cells under hypoxic conditions, which indicated that the anticancer mechanism of selenite involves nonoxidative stress in the real tumor microenvironment.

APCCdh1 controls cell cycle entry during liver regeneration.

Cdh1 is one of the two adaptor proteins of anaphase-promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase controlling mitosis and DNA replication. To date, the in vivo functions of Cdh1 have not been fully explored. In order to characterize Cdh1 in liver regeneration, we generated a conditional knock-out mouse model. Our data showed that loss of Cdh1 leads to increased and extended S phase progression possibly due to the upregulation of cyclin D1. Moreover, the increased DNA replication resulted in activated DNA damage response. Interestingly, the final liver weight after partial hepatectomy in the Cdh1 depleted mice did not differ from that of the controls, implying that Cdh1 is not required for the competence of hepatocytes to regenerate itself.

Detection of H2O2 and catalase on a paper-based flow sensor constructed with borate cross-linked PVA hydrogel.

The detections of H2O2 and catalase play an important role in daily life. This study introduces a paper-based flow sensor that is specifically designed to detect H2O2 and catalase. The sensor utilizes a hydrogel composed of cross-linked 4-carboxyphenylboronic acid and polyvinyl alcohol. When H2O2 is in contact with the hydrogel, the B-C bonds of the hydrogel undergo a reactive process, causing decomposition of the hydrogel. The pH indicator strip enables the visual monitoring of the viscosity change that occurs during the gel-sol transition. The quantification of H2O2 is accomplished by assessing the proportion of water coverage on the pH indicator strip. The sensor shows a detection limit of 0.077 wt% and is applicable for the quantitative measurement of H2O2 in routinely used disinfectants. Furthermore, the presence of catalase is effectively identified and the detection of catalase in milk is successfully fulfilled. In summary, this work proposes a simple, user-friendly, label-free, and cost-effective method for constructing a paper-based flow sensor using borate cross-linked polyvinyl alcohol hydrogel, showing great potential for detecting H2O2 and catalase in various practical scenarios.

A homologous series of macrocyclic Ni clusters: synthesis, structures, and catalytic properties.

Due to their intriguing ring structures and promising applications, nickel-thiolate clusters, such as [Nin(SR)2n] (n = 4-6), have attracted tremendous interest. However, investigation of the synthesis, structures, and properties of macrocyclic Nin clusters (n > 8) has been seriously impeded. In this work, a homologous series of macrocyclic nickel clusters, Nin(4MPT)2n (n = 9-12), was fabricated by using 4-methylphenthiophenol (4MPT) as the ligand. The structures and compositions of the clusters were determined by single-crystal X-ray diffraction (SXRD) in combination with electrospray ionization mass spectrometry (ESI-MS). Experimental results and theoretical calculations show that the electronic structures of the clusters do not change significantly with the increase of Ni atoms. The coordination interactions between Ni and S atoms in [NiS4] subunits are proved to play a crucial rule in the remarkable stability of Ni clusters. Finally, these clusters display excellent catalytic activity towards the reduction of p-nitrophenol, and a linear correlation between catalytic activity and ring size was revealed. The study provides a facile approach to macrocyclic homoleptic nickel clusters, and contributes to an in-depth understanding of the structure-property correlations of nickel clusters at the atomic level.

A naturally derived small molecule compound suppresses tumor growth and metastasis in mice by relieving p53-dependent repression of CDK2/Rb signaling and the Snail-driven EMT.

The tumor suppressor protein p53 is central to cancer biology, with its pathway reactivation emerging as a promising therapeutic strategy in oncology. This study introduced LZ22, a novel compound that selectively inhibits the growth, migration, and metastasis of tumor cells expressing wild-type p53, demonstrating ineffectiveness in cells devoid of p53 or those expressing mutant p53. LZ22's mechanism of action involves a high-affinity interaction with the histidine-96 pocket of the MDM2 protein. This interaction disrupted the MDM2-p53 binding, consequently stabilizing p53 by shielding it from proteasomal degradation. LZ22 impeded cell cycle progression and diminished cell proliferation by reinstating the p53-dependent suppression of the CDK2/Rb signaling pathway. Moreover, LZ22 alleviated the p53-dependent repression of Snail transcription factor expression and its consequent EMT, effectively reducing tumor cell migration and distal metastasis. Importantly, LZ22 administration in tumor-bearing mice did not manifest notable side effects. The findings position LZ22 as a structurally unique reactivator of p53, offering therapeutic promise for the management of human cancers with wild-type TP53.

Stability analysis and synchronization in discrete-time complex networks with delayed coupling.

A new network of coupled maps is proposed in which the connections between units involve no delays but the intra-neural communication does, whereas in the work of Atay et al. [Phys. Rev. Lett. 92, 144101 (2004)], the focus is on information processing delayed by the inter-neural communication. We show that the synchronization of the network depends on not only the intrinsic dynamical features and inter-connection topology (characterized by the spectrum of the graph Laplacian) but also the delays and the coupling strength. There are two main findings: (i) the more neighbours, the easier to be synchronized; (ii) odd delays are easier to be synchronized than even ones. In addition, compared with those discussed by Atay et al. [Phys. Rev. Lett. 92, 144101 (2004)], our model has a better synchronizability for regular networks and small-world variants.

Caecal microbiota could effectively increase chicken growth performance by regulating fat metabolism.

It has been established that gut microbiota influences chicken growth performance and fat metabolism. However, whether gut microbiota affects chicken growth performance by regulating fat metabolism remains unclear. Therefore, seven-week-old chickens with high or low body weight were used in the present study. There were significant differences in body weight, breast and leg muscle indices, and cross-sectional area of muscle cells, suggesting different growth performance. The relative abundance of gut microbiota in the caecal contents at the genus level was compared by 16S rRNA gene sequencing. The results of LEfSe indicated that high body weight chickens contained Microbacterium and Sphingomonas more abundantly (P < 0.05). In contrast, low body weight chickens contained Slackia more abundantly (P < 0.05). The results of H & E, qPCR, IHC, WB and blood analysis suggested significantly different fat metabolism level in serum, liver, abdominal adipose, breast and leg muscles between high and low body weight chickens. Spearman correlation analysis revealed that fat metabolism positively correlated with the relative abundance of Microbacterium and Sphingomonas while negatively correlated with the abundance of Slackia. Furthermore, faecal microbiota transplantation was performed, which verified that transferring faecal microbiota from adult chickens with high body weight into one-day-old chickens improved growth performance and fat metabolism in liver by remodelling the gut microbiota. Overall, these results suggested that gut microbiota could affect chicken growth performance by regulating fat metabolism.

Chicken jejunal microbiota improves growth performance by mitigating intestinal inflammation.

BACKGROUND: Intestinal inflammation is prevalent in chicken, which results in decreased growth performance and considerable economic losses. Accumulated findings established the close relationship between gut microbiota and chicken growth performance. However, whether gut microbiota impacts chicken growth performance by lessening intestinal inflammation remains elusive. RESULTS: Seven-weeks-old male and female chickens with the highest or lowest body weights were significantly different in breast and leg muscle indices and average cross-sectional area of muscle cells. 16S rRNA gene sequencing indicated Gram-positive bacteria, such as Lactobacilli, were the predominant species in high body weight chickens. Conversely, Gram-negative bacteria, such as Comamonas, Acinetobacter, Brucella, Escherichia-Shigella, Thermus, Undibacterium, and Allorhizobium-Neorhizobium-Pararhizobium-Rhizobium were significantly abundant in low body weight chickens. Serum lipopolysaccharide (LPS) level was significantly higher in low body weight chickens (101.58 ± 5.78 ng/mL) compared with high body weight chickens (85.12 ± 4.79 ng/mL). The expression of TLR4, NF-κB, MyD88, and related inflammatory cytokines in the jejunum was significantly upregulated in low body weight chickens, which led to the damage of gut barrier integrity. Furthermore, transferring fecal microbiota from adult chickens with high body weight into 1-day-old chicks reshaped the jejunal microbiota, mitigated inflammatory response, and improved chicken growth performance. CONCLUSIONS: Our findings suggested that jejunal microbiota could affect chicken growth performance by mitigating intestinal inflammation. Video Abstract.

RNA-Seq-Based Gene Expression Pattern and Morphological Alterations in Chick Thymus during Postnatal Development.

The thymus is a lobulated unique lymphoid immune organ that plays a critical role in the selection, development, proliferation, and differentiation of T cells. The thymus of developing chickens undergoes continued morphological alterations; however, the biomolecular and transcriptional dynamics of the postnatal thymus in avian species is not clear yet. Therefore, the thymuses from chickens at different stages of development (at weeks 0, 1, 5, 9, 18, and 27) were used in the present study. The RNA-seq method was used to study the gene expression patterns. On average, 24120819 clean reads were mapped, differentially expressed genes (DEGs) were identified on the basis of log values (fold change), including 744 upregulated and 425 downregulated genes. The expression pattern revealed by RNA-seq was validated by quantitative real-time PCR (qPCR) analysis of four important genes, which are PCNA, CCNA2, CCNB2, and CDK1. Thus, the current study revealed that during postnatal development, the thymus undergoes severe atrophy. Thymus structure was damaged and gene expression changed dramatically, especially at the 27th week of age. Moreover, we found significant changes of several signaling pathways such as the cytokine-cytokine receptor interaction and cell cycle signaling pathways. Hence, it may be inferred that those signaling pathways might be closely related to the postnatal chicken thymus development.

Aberrant upregulation of PDK1 in ovarian cancer cells impairs CD8+ T cell function and survival through elevation of PD-L1.

Blockade of the programmed cell death 1(PD-1)/PD-1 ligand-1(PD-L1) pathway has been exploited therapeutically in many cancer types. Upregulation of PD-L1 in tumor cells contributes to malignancy through suppression of the T cell-mediated antitumor response. Pyruvate dehydrogenase kinase 1 (PDK1), a glycolytic gate-keeping enzyme, is also known to promote tumor development. Here, we have uncovered a mechanism of regulation of PD-L1 by PDK1 through activation of c-Jun-NH2-kinase (JNK)-c-Jun in ovarian cancer cells. Elevated PDK1 expression was correlated with that of PD-L1 in the TCGA ovarian cancer dataset and ovarian cancer tissue array. Overexpression of PDK1 in ovarian cancer cells impaired CD8+ T cell function by suppressing IFN-γ secretion through the PD-1/PD-L1 pathway. Conversely, knockdown of PDK1 in ovarian cancer cells relieved suppression of CD8+ T cell function. CD8+ T cell apoptosis induced by binding of PD-1 with PD-L1 was increased after co-culture with ovarian cancer cells overexpressing PDK1, while depletion of PDK1 exerted the opposite effect. In vivo experiments revealed synergistic improved overall survival and enhanced inhibition of tumor growth upon co-treatment with dichloroacetate (DCA), a PDK inhibitor, and PD-L1 antibody, accompanied by increased IFN-γ secretion by monocytes infiltrating tumor islets. Moreover, PDK1 expression and CD8+ T cell infiltration were inversely correlated in the ovarian cancer tissue array. Our collective findings provide a novel explanation of how PDK1 contributes to upregulation of PD-L1 in ovarian cancer and highlight its potential as a target therapeutic molecule that cooperates with the immune checkpoint blockade.

Targetable Mesoporous Silica Nanoprobes for Mapping the Subcellular Distribution of H2Se in Cancer Cells.

Hydrogen selenide, a highly active reductant, is believed as a key molecule in the cytotoxicity of inorganic selenium compounds. However, the detail mechanism has hardly been studied because the distribution of H2Se in the subcellular organelles remains unclear. Herein, we exploited a series of novel targetable mesoporous silica nanoplatforms to map the distribution of H2Se in cytoplasm, lysosome, and mitochondria of cancer cells. The subcellular targeting moiety-conjugated mesoporous silica nanoparticles were assembled with a near-infrared fluorescent probe (NIR-H2Se) for detecting endogenous H2Se in the corresponding organelles. The confocal fluorescence imaging of cancer cells induced by Na2SeO3 found out a higher concentration of H2Se accumulated only in mitochondria. Consequently, the H2Se burst in mitochondria-triggered mitochondrial collapse that led to cell apoptosis. Hence, the selenite-induced cytotoxicity in cancer cells associates with the alteration in mitochondrial function caused by high level of H2Se. These findings provide a new way to explore the tumor cell apoptosis signaling pathways induced by Na2SeO3, meanwhile, we propose a research strategy for tracking the biomolecules in the subcellular organelles and the correlative cellular function and related disease diagnosis.

MicroRNA-98 inhibits TGF-ß1-induced differentiation and collagen production of cardiac fibroblasts by targeting TGFBR1.

To investigate the effects of miR-98 on TGF-ß1-induced cardiac fibrosis in human cardiac fibroblasts (HCFs), and to establish the mechanism underlying these effects, HCFs were transfected with miR-98 inhibitor or mimic, and then treated with or without TGF-ß1. The level of miR-98 was determined by qRT-PCR in TGF-ß1-induced HCFs. Cell differentiation and collagen accumulation of HCFs were detected by qRT-PCR and Western blot assays, respectively. The mRNA and protein expressions of TGFBR1 were determined by qRT-PCR and Western blotting. In this study, the outcomes showed that TGF-ß1 could dramatically decrease the level of miR-98 in a time- and concentration-dependent manner. Upregulation of miR-98 dramatically improved TGF-ß1-induced increases in cell differentiation and collagen accumulation of HCFs. Moreover, bioinformatics analysis predicted that the TGFBR1 was a potential target gene of miR-98. Luciferase reporter assay demonstrated that miR-98 could directly target TGFBR1. Inhibition of TGFBR1 had the similar effect as miR-98 overexpression. Downregulation of TGFBR1 in HCFs transfected with miR-98 inhibitor partially reversed the protective effect of miR-98 overexpression on TGF-ß1-induced cardiac fibrosis in HCFs. Upregulation of miR-98 ameliorates TGF-ß1-induced differentiation and collagen accumulation of HCFs by downregulation of TGFBR1. These results provide further evidence for protective effect of miR-98 overexpression on TGF-ß1-induced cardiac fibrosis.

Polymer-based precipitation preserves biological activities of extracellular vesicles from an endometrial cell line.

Extracellular vesicles (EVs) are membrane-bound vesicles released by cells and act as media for transfer of proteins, small RNAs and mRNAs to distant sites. They can be isolated by different methods. However, the biological activities of the purified EVs have seldom been studied. In this study, we compared the use of ultracentrifugation (UC), ultra-filtration (UF), polymer-based precipitation (PBP), and PBP with size-based purification (PBP+SP) for isolation of EVs from human endometrial cells and mouse uterine luminal fluid (ULF). Electron microscopy revealed that the diameters of the isolated EVs were similar among the tested methods. UF recovered the highest number of EVs followed by PBP, while UC and PBP+SP were significantly less efficient (P<0.05). Based on the number of EVs-to-protein ratios, PBP had the least protein contamination, significantly better than the other methods (P<0.05). All the isolated EVs expressed exosome-enriched proteins CD63, TSG101 and HSP70. Incubation of the trophoblast JEG-3 cells with an equal amount of the fluorescence-labelled EVs isolated by the studied methods showed that many of the PBP-EVs treated cells were fluorescence positive but only a few cells were labelled in the UC- and UF-EVs treated groups. Moreover, the PBP-EVs could transfer significantly more miRNA to the recipient cells than the other 3 methods (P<0.05). The PBP method could isolate EVs from mouse ULF; the diameter of the isolated EVs was 62±19 nm and expressed CD63, TSG101 and HSP70 proteins. In conclusion, PBP could best preserve the activities of the isolated EVs among the 4 methods studied and was able to isolate EVs from a small volume of sample. The simple setup and low equipment demands makes PBP the most suitable method for rapid EV assessment and isolation of EVs in clinical and basic research settings.

A nanosensor for in vivo selenol imaging based on the formation of Au-Se bonds.

Selenol is a key metabolite of Na2SeO3 and plays an important role in many physiological and pathological processes. The real-time monitoring of selenol is of scientific interest for understanding the anti-cancer mechanism of Na2SeO3. Based on selenol's ability to specifically break AuS bonds and form more stable AuSe bonds on the surfaces of gold nanoparticles (AuNPs), we developed a novel near-infrared fluorescent nanosensor (Cy5.5-peptide-AuNPs) for detecting selenol. The nanosensor exhibited rapid response to selenol with high selectivity and sensitivity, and it was successfully used to image changes in the selenol level in HepG2 cells during Na2SeO3-induced apoptosis. Moreover, in vivo fluorescence imaging of selenol was obtained from H22 tumor-bearing mice injected with both the nanosensor and sodium selenite. The results showed that the tumor cell apoptosis induced by Na2SeO3 is correlated with high-level of selenol under hypoxic conditions. We believe that this nanosensor could serve as a powerful tool for monitoring selenol and exploring the physiological function of selenol in a variety of physiological and pathological contexts and that the probe-designed strategy will provide a new platform for research on relevant selenium chemistry.

Simultaneous fluorescence imaging of selenol and hydrogen peroxide under normoxia and hypoxia in HepG2 cells and in vivo.

Based on the rapid substitution reaction of the Au-S bond by selenol, we designed and synthesized a nanoprobe 5-FAM-peptide-AuNPs for selenol. Real-time imaging shows that this probe together with the molecular probe QCy7-H2O2 is able to simultaneously and differentially monitor the concentrations of selenol and H2O2 in living cells and in vivo.

Cdc14A and Cdc14B Redundantly Regulate DNA Double-Strand Break Repair.

Cdc14 is a phosphatase that controls mitotic exit and cytokinesis in budding yeast. In mammals, the two Cdc14 homologues, Cdc14A and Cdc14B, have been proposed to regulate DNA damage repair, whereas the mitotic exit and cytokinesis rely on another phosphatase, PP2A-B55α. It is unclear if the two Cdc14s work redundantly in DNA repair and which repair pathways they participate in. More importantly, their target(s) in DNA repair remains elusive. Here we report that Cdc14B knockout (Cdc14B(-/-)) mouse embryonic fibroblasts (MEFs) showed defects in repairing ionizing radiation (IR)-induced DNA double-strand breaks (DSBs), which occurred only at late passages when Cdc14A levels were low. This repair defect could occur at early passages if Cdc14A levels were also compromised. These results indicate redundancy between Cdc14B and Cdc14A in DSB repair. Further, we found that Cdc14B deficiency impaired both homologous recombination (HR) and nonhomologous end joining (NHEJ), the two major DSB repair pathways. We also provide evidence that Cdh1 is a downstream target of Cdc14B in DSB repair.