Gut microbiota-bile acid-vitamin D axis plays an important role in determining oocyte quality and embryonic development.

OBJECTIVE: To reveal whether gut microbiota and their metabolites are correlated with oocyte quality decline caused by circadian rhythm disruption, and to search possible approaches for improving oocyte quality. DESIGN: A mouse model exposed to continuous light was established. The oocyte quality, embryonic development, microbial metabolites and gut microbiota were analyzed. Intragastric administration of microbial metabolites was conducted to confirm the relationship between gut microbiota and oocyte quality and embryonic development. RESULTS: Firstly, we found that oocyte quality and embryonic development decreased in mice exposed to continuous light. Through metabolomics profiling and 16S rDNA-seq, we found that the intestinal absorption capacity of vitamin D was decreased due to significant decrease of bile acids such as lithocholic acid (LCA), which was significantly associated with increased abundance of Turicibacter. Subsequently, the concentrations of anti-Mullerian hormone (AMH) hormone in blood and melatonin in follicular fluid were reduced, which is the main reason for the decline of oocyte quality and early embryonic development, and this was rescued by injection of vitamin D3 (VD3). Secondly, melatonin rescued oocyte quality and embryonic development by increasing the concentration of lithocholic acid and reducing the concentration of oxidative stress metabolites in the intestine. Thirdly, we found six metabolites that could rescue oocyte quality and early embryonic development, among which LCA of 30 mg/kg and NorDCA of 15 mg/kg had the best rescue effect. CONCLUSION: These findings confirm the link between ovarian function and gut microbiota regulation by microbial metabolites and have potential value for improving ovary function.

4-vinylcyclohexene diepoxide induces apoptosis by excessive reactive oxygen species and DNA damage in human ovarian granulosa cells.

4-Vinylcyclohexene diepoxide (VCD) is a hazardous industrial material which is widely used in the production of fragrances, rubber tires, antioxidants, pesticides, flame retardants and plasticizers. Previous studies have shown that exposure to VCD damages the female reproductive system, but the effects and mechanisms of VCD exposure on human granulosa cells are not reported. In this study, we used a human granulosa cell line (SVOG) to explore the effects of VCD exposure and found that VCD exposure had toxic effects on SVOG cells in vitro. VCD exposure led to excessive accumulation of intracellular ROS, caused DNA damage in cells, altered the expression of some key genes related with apoptosis and oxidative stress, and ultimately inhibited the proliferative capacity of granulosa cells, resulting in increased apoptosis. Overall, our findings provide solid evidence showing that VCD exposure produces severe damage to human granulosa cells, which is helpful for understanding the reproductive toxicity of VCD and etiology of infertility.

USP7 reduction leads to developmental failure of mouse early embryos.

As a member of Ubiquitin-specific protease subfamily, ubiquitin specific protease 7 (USP7) has been reported to participate in a variety of cellular processes, including cell cycle, apoptosis, DNA damage response, and epigenetic modification. However, its function in preimplantation embryos is still obscure. To investigate the functions of USP7 during preimplantation embryo development, we used siRNA to degrade endogenous USP7 messenger RNA. We found that USP7 knockdown significantly decreased the development rate of mouse early embryos. Moreover, depletion of USP7 induced the accumulation of the DNA lesions and apoptotic blastomeres in early embryos. In addition, USP7 knockdown caused an abnormal H3K27me3 modification in 2-cell embryos. Overall, our results indicate that USP7 maintains genome stability perhaps via regulating H3K27me3 and DNA damage, consequently controlling the embryo quality.

Analysis of Chinese Medical Syndrome Features of Ischemic Stroke Based on Similarity of Symptoms Subgroup.

OBJECTIVE: To derive the Chinese medicine (CM) syndrome classification and subgroup syndrome characteristics of ischemic stroke patients. METHODS: By extracting the CM clinical electronic medical records (EMRs) of 7,170 hospitalized patients with ischemic stroke from 2016 to 2018 at Weifang Hospital of Traditional Chinese Medicine, Shandong Province, China, a patient similarity network (PSN) was constructed based on the symptomatic phenotype of the patients. Thereafter the efficient community detection method BGLL was used to identify subgroups of patients. Finally, subgroups with a large number of cases were selected to analyze the specific manifestations of clinical symptoms and CM syndromes in each subgroup. RESULTS: Seven main subgroups of patients with specific symptom characteristics were identified, including M3, M2, M1, M5, M0, M29 and M4. M3 and M0 subgroups had prominent posterior circulatory symptoms, while M3 was associated with autonomic disorders, and M4 manifested as anxiety; M2 and M4 had motor and motor coordination disorders; M1 had sensory disorders; M5 had more obvious lung infections; M29 had a disorder of consciousness. The specificity of CM syndromes of each subgroup was as follows. M3, M2, M1, M0, M29 and M4 all had the same syndrome as wind phlegm pattern; M3 and M0 both showed hyperactivity of Gan (Liver) yang pattern; M2 and M29 had similar syndromes, which corresponded to intertwined phlegm and blood stasis pattern and phlegm-stasis obstructing meridians pattern, respectively. The manifestations of CM syndromes often appeared in a combination of 2 or more syndrome elements. The most common combination of these 7 subgroups was wind-phlegm. The 7 subgroups of CM syndrome elements were specifically manifested as pathogenic wind, pathogenic phlegm, and deficiency pathogens. CONCLUSIONS: There were 7 main symptom similarity-based subgroups in ischemic stroke patients, and their specific characteristics were obvious. The main syndromes were wind phlegm pattern and hyperactivity of Gan yang pattern.

Maternal exposure to 4-vinylcyclohexene diepoxide during pregnancy induces subfertility and birth defects of offspring in mice.

4-vinylcyclohexene diepoxide (VCD), widely used in industry, is a hazardous compound that can cause premature ovarian failure, but whether maternal VCD exposure affects the health and reproduction of offspring is unknown. Here we focused on the effects of VCD on fertility and physical health of F1 and F2 offspring in mice. The pregnant mice were injected intraperitoneally with different dosages of VCD once every day from 6.5 to 18.5 days post-coitus (dpc). We showed that maternal exposure to VCD during pregnancy significantly reduced the litter size and ovarian reserve, while increasing microtia occurrences of F1 mice. The cytospread staining showed a significant inhibition of meiotic prophase I progression from the zygotene stage to the pachytene stage. Mechanistically, the expression level of DNA damage marker (γ-H2AX) and BAX/BCL2 ratios were significantly increased, and RAD51 and DMC1 were extensively recruited to DNA double strand breaks sites in the oocytes of offspring from VCD-exposed mothers. Overall, our results provide solid evidence showing that maternal exposure to VCD during pregnancy has intergenerational deleterious effects on the offspring.

Effects of Photodynamic Therapy on Nav1.7 Expression in Spinal Dorsal Root Ganglion Neurons.

OBJECTIVE: The aim of this study was to examine the effects of photodynamic therapy (PDT) on the expression of Nav1.7 in spinal dorsal root ganglion (DRG) neurons. METHODS: The primary DRG neurons from newborn SD rats were cultured. The cells were identified by neuron-specific enolase immunofluorescence staining. DRG neurons were divided into four groups: control group, photosensitizer group, laser group, and PDT group. The cell viability was detected by a cell counting kit-8 (CCK8) assay. qRT-PCR and Western blotting were used to determine the mRNA and protein expression levels of Nav1.7 in DRG neurons. RESULTS: The purity of the cultured primary DRG neurons was greater than 90%. Compared with the control group, no significant change was found in the cell viability of the photosensitizer group, while the viability in the laser group and the PDT group was significantly reduced. The mRNA and protein expression levels of Nav1.7 were significantly greater in the laser group and the PDT group than in the control group. At the same time, the mRNA and protein expression levels of Nav1.7 were greater in the laser group than in the PDT group. CONCLUSION: Both laser and PDT could upregulate the expression of Nav1.7 in DRG neurons, and the promoting effect might be related to the pain induced by clinical treatment. This study provides a research basis for the use of laser and PDT to treat pain. A better understanding of the relationship between Nav1.7 and PDT can help clinicians better manage PDT-related pain.

Stereocontrolled Self-Assembly of Ln(III)-Pt(II) Heterometallic Cages with Temperature-Dependent Luminescence.

Structurally well-defined discrete d/f heterometallic complexes show diverse application potential in electrooptic and magnetic materials. However, precise control of the component and topology of such heterometallic compounds with fine-tuned photophysical properties is still challenging. Herein, we report the stereocontrolled syntheses of a series of LnIII-PtII heterometallic cages through coordination-driven self-assembly of enantiopure alkynylplatinum-based metalloligands (L1R/S, L2R/S) with lanthanide ions (Ln = EuIII, YbIII, NdIII, LuIII). Taking advantage of the metal-to-ligand charge transfer (MLCT) excited state on the designed alkynylplatinum ligands, the excitation window for the sensitized near-infrared (NIR) luminescence on the YbIII- and NdIII-containing cages can be extended to the visible region (up to 500 nm). Linear temperature-dependent red and NIR emissions observed on the Ln4(L2R/S)6 (LnIII = EuIII and YbIII, respectively) complexes suggest their potential applications as luminescent temperature sensors, with sensitivities of -0.54% (LnIII = EuIII, 77-250 K) and -0.17% (LnIII = YbIII, 77-300 K) per K achieved. This work not only offers a good strategy to prepare new d/f heterometallic supramolecular cages but also paves the way for the design of stimuli-responsive luminescent materials.

Optimal indicator for changing the filter during the continuous renal replacement therapy in intensive care unit patients with acute kidney injury: A crossover randomized trial.

BACKGROUND: The study aims to investigate an optimal indicator for changing the filter during the continuous renal replacement therapy (CRRT) in intensive care unit (ICU) patients with acute kidney injury (AKI). METHODS: Patients with AKI requiring CRRT in an ICU were randomly divided into two groups for crossover trial, i.e., groups A and B. Patients in the group A were firstly treated with continuous veno-venous hemofiltration (CVVH), followed by continuous veno-venous hemodiafiltration (CVVHDF). Patients in the group B were firstly treated with CVVHDF followed by CVVH. Delivered doses of solutes with different molecular weights at the indicated time points between groups were compared. A correlation analysis between the delivered dose and pre-filter pressure (PPRE) and transmembrane pressure (PTM) was performed. Receiver operating characteristic (ROC) curves were constructed to evaluate the accuracy of PTM as an indicator for filter replacement. RESULTS: A total of 50 cases were analyzed, 27 in the group A and 23 in the group B. Delivered doses of different molecular-weight solutes significantly decreased before changing the filter in both modalities, compared with those at the initiation of treatment (all P<0.05). In the late stage of CRRT, the possible rebound of serum medium-molecular-weight solute concentration was observed. PTM was negatively correlated with the delivered dose of medium-molecular-weight solute in both modalities. The threshold for predicting the rebound of serum concentration of medium-molecular-weight solute by PTM was 146.5 mmHg (1 mmHg=0.133 kPa). CONCLUSIONS: The filter can be used as long as possible within the manufacturer's safe use time limits to remove small-molecular-weight solutes. PTM of 146.5 mmHg may be an optimal indicator for changing the filter in CRRT therapies to remove medium-molecular-weight solutes.

Coordination-Directed Self-Assembly of Functional Polynuclear Lanthanide Supramolecular Architectures.

Lanthanide supramolecular chemistry is a fast growing and intriguing research field due to the unique photophysical, magnetic, and coordination properties of lanthanide ions (LnIII). Compared with the intensively investigated mononuclear Ln-complexes, polymetallic lanthanide supramolecular assemblies offer more structural superiority and functional advantages. In recent decades, significant progress has been made in polynuclear lanthanide supramolecules, varying from structural evolution to luminescent and magnetic functional materials. This review summarizes the design principles in ligand-induced coordination-driven self-assembly of polynuclear Ln-structures and intends to offer guidance for the construction of more elegant Ln-based architectures and optimization of their functional performances. Design principles concerning the water solubility and chirality of the lanthanide-organic assemblies that are vital in extending their applications are emphasized. The strategies for improving the luminescent properties and the applications in up-conversion, host-guest chemistry, luminescent sensing, and catalysis have been summarized. Magnetic materials based on supramolecular assembled lanthanide architectures are given in an individual section and are classified based on their structural features. Challenges remaining and perspective directions in this field are also briefly discussed.

Guest-Driven Self-Assembly and Chiral Induction of Photofunctional Lanthanide Tetrahedral Cages.

Chiral luminescent lanthanide-organic cages have many potential applications in enantioselective recognition, sensing, and asymmetric catalysis. However, due to the paucity of structures and their limited cavities, host-guest chemistry with lanthanide-organic cages has remained elusive so far. Herein, we report a guest-driven self-assembly and chiral induction approach for the construction of otherwise inaccessible Ln4L4-type (Ln = lanthanide ions, i.e., EuIII, TbIII; L = ligand) tetrahedral hosts. Single crystal analyses on a series of host-guest complexes reveal remarkable guest-adaptive cavity breathing on the tetrahedral cages, reflecting the advantage of the variation tolerance on coordination geometry of the f-elements. Meanwhile, noncovalent confinement of pyrene within the lanthanide cage not only leads to diminishment of its excimer emission but also facilitates guest to host energy transfer, opening up a new sensitization window for the lanthanide luminescence on the cage. Moreover, stereoselective self-assembly of either Λ4- or Δ4- type Eu4L4 cages has been realized via chiral induction with R/S-BINOL or R/S-SPOL templates, as confirmed by NMR, circular dichroism (CD), and circularly polarized luminescence (CPL) with high dissymmetry factors (glum) up to ±0.125.

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To study the feasibility of simulating the spatial distribution of hydrogen and oxygen stable isotopes composition (δ2H and δ18O) in the surface soil based on the machine learning method and to investigate large-scale distribution of δ2H and δ18O in the upper reaches of Minjiang River, 183 soil samples were collected from the 0-10 cm soil layer. After variable selection, back propagation (BP) neural network, random forests (RF) and support vector machine (SVM) were used to model the δ2H and δ18O of the study area, with the accuracies being evaluated. The structural equation model (SEM) was used to reveal the mechanism between the auxiliary variables and the δ2H and δ18O of soil water. The results showed that the RF model had the highest prediction accuracy, and could explain 75.0% and 64.0% of the variations of δ2H and δ18O in the surface soil, respectively. In this model, soil water content was the most important auxiliary variable, contributing 48.9% and 37.4% to δ2H and δ18O. Vegetation factors had stronger influence on δ2H and δ18O in the surface soil than climate factors, and the influence of climate factors on δ2H and δ18O was media-ted by vegetation factors. Among all the auxiliary variables, hydrogen/oxygen isotope of precipitation had the lowest effect on δ2H and δ18O due to the fractionation. The δ2H and δ18O in the surface soil of the upper reaches of the Minjiang River changed significantly across different months during the growing season. The increases of δ2H and δ18O in the early growing season and the decreases in the late growing season were mainly affected by vegetation, while climate change led to a small fluctuation in the middle growing season.

Coordination-Assembly of Lanthanide Supramolecular Hydrogels with Luminescent Multi-stimulus Response.

Luminescent supramolecular hydrogels have shown extensive potential for a variety of applications due to their unique optical properties and biocompatibility. Coordination self-assembly provides a promising strategy for the preparation of supramolecular hydrogels. In this contribution, a series of luminescent lanthanide (Ln) supramolecular hydrogels HG-Ln2nL3n1/2 are synthesized by coordination self-assembly of Ln ions and V shaped bis-tetradentate ligands (H4L1 and H4L2) with different bent angles (∠B). Two rigid conjugated ligands H4L1 and H4L2 with bent angles (∠B ≈ 150°) featuring a 2,6-pyridine bitetrazolate chelating moiety were designed and synthesized, which generated hydrogels via the deprotonation self-assembly with lanthanide ions. Characteristic Eu3+ and Yb3+ emissions were realized in the corresponding hydrogels, with intriguing multi-stimulus response behaviors. The luminescence of the HG-Eu2nL3n1 hydrogel can be enhanced or quenched when stimulated by diverse metal ions, attributed to the replacement of the coordinated lanthanide ions and changes in the intersystem crossing efficiency of the ligand. Furthermore, pH-responsive emission of the HG-Eu2nL3n1 hydrogel has also been observed. Our work provides potential strategies for the design of next-generation smart responsive hydrogel materials with variable structures.

Base- and Metal-Dependent Self-Assembly of Lathanide-Organic Coordination Polymers or Macrocycles with Tetradentate Acylhydrazone-based Ditopic Ligands.

Herein, we report a comprehensive study on the lanthanide-directed coordination self-assembly with two bis-tetradentate acylhydrazone ligands H4 L1 and H4 L2 . Multifarious outcomes, which are base- and metal-dependent, were revealed by NMR, ESI-TOF-MS and X-ray crystallography. In the absence of base, bent H4 L1 was assembled into dinuclear double-strand helicate Ln2 (H2 L1 )2 by partially-deprotonated assembly with La, Sm or Eu, while trinuclear Ln3 (H2 L1 )3 with Yb or Lu. For linear H4 L2 , infinite 1D zig-zag metal-organic polymeric chain (Ln2 H2 L2 )n was obtained. However, complete deprotonated L1 and L2 assembled into discrete trinuclear Ln3 (L1 /2 )3 and tetranuclear Ln4 (L1 /2 )4 macrocyclic structures under the basic condition. For these, there are multiple possible isomers coexisting in the solution which were enumerated and simulated with molecular mechanic modeling. Visible-light sensitized NIR emissions on the Yb complexes have been observed, endowing them potential application in photofunctional materials.

Coordination-Assembled Water-Soluble Anionic Lanthanide Organic Polyhedra for Luminescent Labeling and Magnetic Resonance Imaging.

Lanthanide-containing functional complexes have found a variety of applications in materials science and biomedicine because of their unique electroptical and magnetic properties. However, the poor stability and solubility in water of multicomponent lanthanide organic assemblies significantly limit their practical applications. We report here a series of water-stable anionic Ln2nL3n-type (n = 2, 3, 4, and 5) lanthanide organic polyhedra (LOPs) constructed by deprotonation self-assembly of three fully conjugated ligands (H4L1 and H4L2a/b) featuring a 2,6-pyridine bitetrazolate chelating moiety. The outcomes of the LOPs formation reactions were found to be very sensitive toward the reaction conditions including base, metal source, solvents, and concentrations as characterized by a combination of NMR, high-resolution ESI-MS and X-ray crystallography. Ligands H4L2a/b manifested an excellent sensitization toward lanthanide ions (Ln = EuIII and TbIII), with high luminescent quantum yields for Tb8L2a12 (Φ = 11.2% in water) and Eu8L2b12 (Φ = 76.8% in DMSO) measured in polar solvents. Furthermore, due to the giant molecular weight and rigidity of the polyhedral skeleton, Gd8L2b12 showed a very high longitudinal relaxivity (r1) of 400.53 mM-1S-1. The performance of Gd8L2b12 as potential magnetic resonance imaging contrast agents (CAs) in vivo was evaluated with much longer retention time in the tumor sites compared with the commercial GdIII-based CAs. Dual-modal imaging potential has also been demonstrated with the mixed Eu/Gd LOPs. Our results not only provide a new design route toward water-stable multinuclear lanthanide organic assemblies but also offer potential candidates of supramolecular-edifices for bioimaging and drug delivery.

Self-Assembly of Lanthanide-Covalent Organic Polyhedra: Chameleonic Luminescence and Efficient Catalysis.

A series of multinuclear lanthanide-covalent organic polyhedra (LnCOPs), including pillar-typed triangular prisms 1-Ln3 and tetrahedra 2-Ln4 (Ln = LaIII, SmIII, EuIII), have been constructed for the first time, through either one-pot subcomponent self-assembly or postassembly metalation. In contrast to the known tetrahedral cages based on transition metals, the pillar-typed polyhedra were favored from the same organic components in the presence of lanthanides. Besides this, facile transmetalations between the 1-Ln3 polyhedra endow cascade chameleonic luminescence. Meanwhile, the open metal sites and pendent amine groups on 1-Ln3 enable these polyhedra to catalyze the Henry reaction efficiently.

Metal ion adaptive self-assembly of photoactive lanthanide-based supramolecular hosts.

A post-synthetic transmetallation self-assembly strategy was developed for the preparation of near infrared (NIR) emitting Yb8L6 cubes, which could not be synthesized through direct metal-ligand assembly procedures. Metal-adaptive critical structural transformations from La6L3 triangular prism to Ln8L6 cubes were observed along the lanthanide series, the latter of which showed size-selective guest binding behaviour toward poly-aromatic hydrocarbon (PAH) molecules.

Chiral auxiliary and induced chiroptical sensing with 5d/4f lanthanide-organic macrocycles.

A stereocontrolled self-assembly of 5d/4f heterometal-organic macrocycles has been realized by a post-assembly chiral auxiliary approach. Interligand π-π stacking interactions promoted chiral transfer from point-chirality of the auxiliary ligand to metal centers and then the helicates to produced CD and CPL active europium assemblies, facilitating a feasible enantiomeric excess determination by induced chiroptical signals.

SIRT1 inhibitory compounds from the roots of Codonopsis pilosula.

Three new compounds, pilosulinene A (1), pilosulinols A (2), and B (3), along with seven known compounds, were isolated from the roots of Codonopsis pilosula cultivated in Xundian County of Yunnan Province. The structures of new compounds were established by spectroscopic methods. In particular, the presence of an aromatic ring in the structure of 1 makes it intriguing. The inhibitory activity of compounds against SIRT1 was evaluated. The results showed that 8 could inhibit Sirt1 in a dose-dependent manner.

A supramolecular lanthanide separation approach based on multivalent cooperative enhancement of metal ion selectivity.

Multivalent cooperativity plays an important role in the supramolecular self-assembly process. Herein, we report a remarkable cooperative enhancement of both structural integrity and metal ion selectivity on metal-organic M4L4 tetrahedral cages self-assembled from a tris-tridentate ligand (L1) with a variety of metal ions spanning across the periodic table, including alkaline earth (CaII), transition (CdII), and all the lanthanide (LnIII) metal ions. All these M4L14 cages are stable to excess metal ions and ligands, which is in sharp contrast with the tridentate (L2) ligand and bis-tridentate (L3) ligand bearing the same coordination motif as L1. Moreover, high-precision metal ion self-sorting is observed during the mixed-metal self-assembly of tetrahedral M4L4 cages, but not on the M2L3 counterparts. Based on the strong cooperative metal ion self-recognition behavior of M4L4 cages, a supramolecular approach to lanthanide separation is demonstrated, offering a new design principle of next-generation extractants for highly efficient lanthanide separation.