Theoretical Insights into N-Glycoside Bond Cleavage of 5-Carboxycytosine by Thymine DNA Glycosylase: A QM/MM Study.

Thymine DNA glycosylase (TDG)-mediated excision of 5-formylcytosine and 5-carboxylcytosine (5-caC) is a critical step in active DNA demethylation. Herein, we employed a combined quantum mechanics/molecular mechanics approach to investigate the reaction mechanism of TDG-catalyzed N-glycosidic bond cleavage of 5-caC. The calculated results show that TDG-catalyzed 5-caC excision follows a concerted (SN2) mechanism in which glycosidic bond dissociation is coupled with nucleophile attack. Protonation of the 5-caC anion contributes to the cleavage of the N-glycoside bond, in which the N3-protonated zwitterion and imino tautomers are more favorable than carboxyl-protonated amino tautomers. This is consistent with the experimental data. Furthermore, our results reveal that the configuration rearrangement process of the protonated 5-caC would lower the stability of the N-glycoside bond and substantially reduce the barrier height for the subsequent C1'-N1 bond cleavage. This should be attributed to the smaller electrostatic repulsion between the leaving base and the negative phosphate group as a result of the structural rearrangement.

Performance on adsorption of toluene by ionic liquid-modified AC in high-humidity exhaust gas.

Volatile organic compounds (VOCs) frequently pose a threat to the biosphere, impacting ecosystems, flora, fauna, and the surrounding environment. Industrial emissions of VOCs often include the presence of water vapor, which, in turn, diminishes the adsorption capacity and efficacy of adsorbents. This occurs due to the competitive adsorption of water vapor, which competes with target pollutants for adsorption sites on the adsorbent material. In this study, hydrophobic activated carbons (BMIMPF6-AC (L), BMIMPF6-AC (g), and BMIMPF6-AC-H) were successfully prepared using 1-butyl-3-methylimidazolium hexafluorophosphate (BMIMPF6) to adsorb toluene under humidity environment. The adsorption performance and mechanism of the resulting ionic liquid-modified activated carbon for toluene in a high-humidity environment were evaluated to explore the potential application of ionic liquids as hydrophobic modifiers. The results indicated that BMIMPF6-AC-H exhibited superior hydrophobicity. The toluene adsorption capacity of BMIMPF6-AC-H was 1.53 times higher than that of original activated carbon, while the adsorption capacity for water vapor was only 37.30% of it at 27 °C and 77% RH. The Y-N model well-fitted the dynamic adsorption experiments. To elucidate the microscopic mechanism of hydrophobic modification, the Independent Gradient Model (IGM) method was employed to characterize the intermolecular interactions between BMIMPF6 and toluene. Overall, this study introduces a new modifier for hydrophobic modification of activated carbon, which could enhance the efficiency of activated carbon in treating industrial VOCs.

Mechanistic Investigation on the Regioselectivity of Electrochemical Co(II)-Catalyzed [2 + 2 + 2] Cycloaddition of Terminal Acetylenes.

In this paper, the regioselectivity of electrochemical Co(II)-catalyzed [2 + 2 + 2] cycloaddition of terminal alkynes was investigated using density functional theory. We explored in detail the energy profiles for both 1,2,4- and 1,3,5-regioselectivity pathways and revealed the origin of the regioselectivity. Two kinds of conformational isomers derived from the different coordination modes of alkynes with cobaltacyclopentadiene have been found, which were formed through electrochemically mediated redox processes. The regioselectivity of the reaction depends on the two coordination modes. When the Co(II) center attacks α-C of the third alkyne, while ß2-C in cyclopentadiene bonds to ß-C of the alkyne, the reaction favors the formation of 1,2,4-products. In contrast, when the Co(II) center connects to ß-C of the alkyne, it forms only the 1,3,5-products via [4 + 2] cycloaddition because of the steric repulsion between the bulky ligand on Co(II) and the phenyl group in the alkyne.

Brain functional connectivity alterations in patients with anterior cruciate ligament injury.

Recent advancements in neuroimaging have illustrated that anterior cruciate ligament (ACL) injuries could impact the central nervous system (CNS), causing neuroplastic changes in the brain beyond the traditionally understood biomechanical consequences. While most of previous functional magnetic resonance imaging (fMRI) studies have focused on localized cortical activity changes post-injury, emerging research has suggested disruptions in functional connectivity across the brain. However, these prior investigations, albeit pioneering, have been constrained by two limitations: a reliance on small-sample participant cohorts, often limited to two to three patients, potentially limiting the generalizability of findings, and an adherence to region of interest based analysis, which may overlook broader network interactions. To address these limitations, our study employed resting-state fMRI to assess whole-brain functional connectivity in 15 ACL-injured patients, comparing them to matched controls using two distinct network analysis methods. Using Network-Based Statistics, we identified widespread reductions in connectivity that spanned across multiple brain regions. Further modular connectivity analysis showed significant decreases in inter-modular connectivity between the sensorimotor and cerebellar modules, and intra-modular connectivity within the default-mode network in ACL-injured patients. Our results thus highlight a shift from localized disruptions to network-wide dysfunctions, suggesting that ACL injuries induce widespread CNS changes. This enhanced understanding has the potential to stimulate the development of strategies aiming to restore functional connectivity and improve recovery outcomes.

Nitric oxide mediates red light-induced perylenequinone production in Shiraia mycelium culture.

Perylenequinones (PQs) from bambusicolous Shiraia fungi serve as excellent photosensitizers for photodynamic therapy. However, the lower yield of PQ production in mycelium cultures is an important bottleneck for their clinical application. Light has long been recognized as a pivotal regulatory signal for fungal secondary metabolite biosynthesis. In this study, we explored the role of nitric oxide (NO) in the growth and PQ biosynthesis in mycelium cultures of Shiraia sp. S9 exposed to red light. The continuous irradiation with red light (627 nm, 200 lx) suppressed fungal conidiation, promoted hyphal branching, and elicited a notable increase in PQ accumulation. Red light exposure induced NO generation, peaking to 81.7 µmol/g FW on day 8 of the culture, with the involvement of nitric oxide synthase (NOS)- or nitrate reductase (NR)-dependent pathways. The application of a NO donor sodium nitroprusside (SNP) restored conidiation of Shiraia sp. S9 under red light and stimulated PQ production, which was mitigated upon the introduction of NO scavenger carboxy-PTIO or soluble guanylate cyclase inhibitor NS-2028. These results showed that red light-induced NO, as a signaling molecule, was involved in the regulation of growth and PQ production in Shiraia sp. S9 through the NO-cGMP-PKG signaling pathway. While mycelial H2O2 content exhibited no significant alternations, a transient increase of intracellular Ca2+ and extracellular ATP (eATP) content was detected upon exposure to red light. The generation of NO was found to be interdependent on cytosolic Ca2+ and eATP concentration. These signal molecules cooperated synergistically to enhance membrane permeability and elevate the transcript levels of PQ biosynthetic genes in Shiraia sp. S9. Notably, the combined treatment of red light with 5 µM SNP yielded a synergistic effect, resulting in a substantially higher level of hypocrellin A (HA, 254 mg/L), about 3.0-fold over the dark control. Our findings provide valuable insights into the regulation of NO on fungal secondary metabolite biosynthesis and present a promising strategy involving the combined elicitation with SNP for enhanced production of photoactive PQs and other valuable secondary metabolites in fungi.

[Distribution Characteristics, Source Analysis and Ecological Risk Assessment of Heavy Metals in the Typical Industry Reclaimed Soil].

To further explore the characteristics of heavy metal pollution and the ecological risk of typical industries in reclaimed soil, based on data from 315 different depth profiles of soil samples collected from 49 plots in Jiading District, Shanghai, the geo-accumulation index and potential ecological risk index were used to evaluate the contents and potential ecological risk of seven heavy metals, namely Cd, Pb, Cu, Zn, Ni, Hg, and As. The APCS-MLR receptor model and PMF positive matrix factorization model were employed to analyze the pollution sources. The results showed that:① except for As, the contents of other heavy metals in the soil of the study area exceeded the Shanghai soil background values to varying degrees. The contents of Cd, Pb, Cu, Zn, Ni, and Hg in the surface soil were 3.54, 2.34, 2.91, 1.20, 3.75, and 4.40 times the background values, respectively. The contents of heavy metals in the soil decreased with the increase in depth, and heavy metals were enriched to a certain extent in the surface soil, indicating that human activities had an impact on the distribution of heavy metals in the soil. ② The APCS-MLR and PMF receptor models identified four main sources of soil heavy metals in the study area. Source 1 (Cu, Zn, and Pb) was a mixture of metal products and automobile manufacturing, source 2 (Ni and Cd) was electroplating enterprises, source 3 (Hg) was mainly from chemical enterprises, and source 4 (As) was natural. The combined use of the two receptor models further improved the accuracy and credibility of source identification. ③ The geo-accumulation index in descending order was Hg(1.54)>Ni(1.32)>Cd(1.21)>Cu(0.96)>Pb(0.64)>Zn(-0.33)>As(-1.02). The potential ecological risk index showed that the comprehensive potential ecological risk index RI value in the study area ranged from 32.50 to 4 910.97, with a mean of 321.40, indicating a strong potential ecological risk. The pollution values of heavy metals Hg, Ni, and Cd in industrial site soil deserve further attention for re-development and utilization purposes.

Local Renal Treatments for Acute Kidney Injury: A Review of Current Progress and Future Translational Opportunities.

Acute kidney injury (AKI) constitutes a significant public health concern, with limited therapeutic options to mitigate injury or expedite recovery. A novel therapeutic approach, local renal treatment, encompassing pharmacotherapy and surgical interventions, has exhibited positive outcomes in AKI management. Peri-renal administration, employing various delivery routes, such as the renal artery, intrarenal, and subcapsular sites, has demonstrated superiority over peripheral intravenous infusion. This review evaluates different drug delivery methods, analyzing their benefits and limitations, and proposes potential improvements. Renal decapsulation, particularly with the availability of minimally invasive techniques, emerges as an effective procedure warranting renewed consideration for AKI treatment. The potential synergistic effects of combined drug delivery and renal decapsulation could further advance AKI therapies. Clinical studies have already begun to leverage the benefits of local renal treatments, and with ongoing technological advancements, these modalities are expected to increasingly outperform systemic intravenous therapy.

Selective identification of p-nitroaniline by bromine-mediated polarization of carbon dots.

A fluorometric method based on boron, bromide-codoped carbon dots (BBCNs) was developed for the first time for the highly selective detection of p-nitroaniline (PNA) in wastewater samples. It should be noted that the introduction of bromine greatly increases the molecular polarizability of the probe, which can regulate the energy level matching between the probe and PNA, resulting in the interaction between BBCNs and PNA. In the presence of PNA, the fluorescence of BBCNs is obviously quenched and accompanied by a red shift of the fluorescence band, which might be attributed to the formation of aggregates caused by the polar adsorption of BBCNs and PNA. It is beneficial for constructing a highly selective sensing platform for PNA determination compared to its isomers (o-nitroaniline and m-nitroaniline) through atomic bromine-mediated polarization of the BBCNs. With the help of this mechanism, an excellent linear range of 0.5-300 µM with a low detection limit of 0.24 µM toward PNA was obtained. This work further confirms that there is a significant relationship between the nature of doping elements and the optical and physicochemical properties of fluorescent materials.

Primary renal malignant epithelioid angiomyolipoma with distant metastasis: a case report and literature review.

Epithelioid angiomyolipoma (EAML) is a rare type of mesenchymal angiomyolipoma with potential malignancy in the kidney that can cause lymph node metastases, local recurrence, and distant metastases. Herein, we describe a case of EAML in the right kidney of a 51-year-old man who was admitted to the hospital with a right abdominal mass. Computed tomography revealed a heterogeneously enhanced mass with blurred margins, which was considered a malignant tumor. A radical nephrectomy was then performed. Two years later, the patient developed liver metastases from EAML and was administered sintilimab combined with bevacizumab. The patient survived after 6 months of follow-up. Histologically, the tumors showed clear boundaries and no obvious capsules. The tumor tissue mainly consisted of epithelioid tumor cells, thick-walled blood vessels, and a small amount of adipose tissue. Tumor cells with lipid vacuoles and acinar areas were large, round, polygonal, eosinophilic, or transparent in the cytoplasm. The enlarged and hyperchromatic nuclei were accompanied by distinct nucleoli and pathological mitosis. These histopathological findings resembled those of renal cell carcinoma, and immunohistochemical analysis was performed. The tumor cells were diffusely positive for HMB45, Melan-A, CK20, vimentin antibodies, and TFE3, suggesting that the tumor originated from perivascular epithelioid cells, excluding renal cell carcinoma. The Ki-67 index was 10%. These histopathological features were observed in liver mass puncture tissues. We also summarized 46 cases of EAML with distant metastasis and explored the clinicopathological features of EAML to improve the treatment of the disease. EAML is often ignored in the clinical setting, leading to metastasis and recurrence. Therefore, EAMLs require long-term follow-up, and timely detection of recurrent disease can improve the prognosis.

[Moxibustion combined with western medication for rheumatoid arthritis with blood stasis obstruction and its effect on platelet activation].

OBJECTIVE: To investigate the clinical efficacy and action mechanism of moxibustion combined with western medication for rheumatoid arthritis (RA) with blood stasis obstruction. METHODS: Fifty-six patients of RA with blood stasis obstruction were randomly divided into an observation group and a control group, with 28 patients in each group. The patients in the control group were treated with oral administration of leflunomide tablets and celecoxib capsules, while the patients in the observation group were treated with moxibustion in addition to the treatment used in the control group. Moxibustion was performed at bilateral Zusanli (ST 36), Shenshu (BL 23), Xuehai (SP 10), and ashi points, once every other day, three times a week. The treatment duration for both groups was 12 weeks. The TCM syndrome score, disease activity score-28 (DAS-28), rheumatoid factor (RF), hypersensitive C-reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR), hemorheological indexes (whole blood viscosity high shear, whole blood viscosity low shear, plasma viscosity), serum calcium ion (Ca2+) level, and platelet count (PLT) were observed before and after treatment, and the clinical efficacy was evaluated after treatment in the two groups. RESULTS: Compared with those before treatment, the TCM syndrome scores, DAS-28 scores, RF, hs-CRP, ESR, whole blood viscosity high shear, whole blood viscosity low shear, plasma viscosity, and PLT were decreased after treatment in both groups (P<0.01), with the observation group showing lower values compared with those in the control group (P<0.05). Compared with those before treatment, the serum Ca2+ levels were increased after treatment in both groups (P<0.01), and the observation group showed a higher increase than that in the control group (P<0.05). The total effective rate was 85.7% (24/28) in the observation group, which was higher than 67.9% (19/28) in the control group (P<0.05). CONCLUSION: Moxibustion combined with western medication could alleviate clinical symptoms in patients with RA of blood stasis obstruction, and its mechanism may be related to the inhibition of platelet activation.

Comparison of antibody persistency through one year between one-dose and two-dose regimens of Ad5-nCoV vaccine for COVID-19.

This post-hoc analysis compared the receptor-binding domain (RBD)-specific and pseudovirus neutralizing antibodies against the wild-type SARS-CoV-2 strain elicited by one or two doses (56-d interval) of Ad5-nCoV vaccine regimen (NCT04341389 and NCT04566770). Both trials had low-dose and high-dose groups. Propensity score matching was used to adjust the baseline between one- and two-dose regimens. To predict the decrease in antibody titers 1 y after vaccination, half-lives of RBD-binding antibodies and pseudovirus neutralizing antibodies were computed. We obtained 34 and 29 pairs of participants in the low- and high-dose groups based on the propensity score matching. The two-dose regimen of Ad5-nCoV increased the peaking level of neutralizing antibodies compared to the one-dose regimen at day 28, but the responses of the neutralizing antibodies were not consistent with those of the RBD antibodies. Half-lives of the RBD-binding antibodies in the two-dose Ad5-nCoV regimen (202-209 days) were longer than those in the one-dose regimen (136-137 d); half-lives of the pseudovirus neutralizing antibody in the one-dose Ad5-nCoV regimen (177 d) were longer than those in the two-dose regimen (116-131 d). The predicted positive rates of RBD-binding antibodies in the one-dose regimen (34.1%-38.3%) would be lower than those in the two-dose Ad5-nCoV regimen (67.0%-84.0%), while the positive rates of pseudovirus neutralizing antibodies in the one-dose regimen (65.4%-66.7%) would be higher than those in the two-dose regimen (48.3%-58.0%). The two-dose Ad5-nCoV regimen with a 56-d interval had no effect on the persistence of neutralizing antibodies but slowed decay trend of RBD-binding antibodies.

Cord blood fatty acid binding protein 4 and lipids in infants born small- or large-for-gestational-age.

Aim: Adverse (poor or excessive) fetal growth "programs" an elevated risk of type 2 diabetes. Fatty acid binding protein 4 (FABP4) has been implicated in regulating insulin sensitivity and lipid metabolism relevant to fetal growth. We sought to determine whether FABP4 is associated with poor or excessive fetal growth and fetal lipids. Methods: In a nested case-control study in the Shanghai Birth Cohort including 60 trios of small-for-gestational-age (SGA, an indicator of poor fetal growth), large-for-gestational-age (LGA, an indicator of excessive fetal growth) and optimal-for-gestational-age (OGA, control) infants, we measured cord blood concentrations of FABP4 and lipids [high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterols, triglycerides (TG)]. Results: Adjusting for maternal and neonatal characteristics, higher cord blood FABP4 concentrations were associated with a lower odds of SGA [OR = 0.29 (0.11-0.77) per log unit increment in FABP4, P = 0.01], but were not associated with LGA (P = 0.46). Cord blood FABP4 was positively correlated with both LDL (r = 0.29, P = 0.025) and HDL (r = 0.33, P = 0.01) in LGA infants only. Conclusion: FABP4 was inversely associated with the risk of SGA. The study is the first to demonstrate LGA-specific positive correlations of cord blood FABP4 with HDL and LDL cholesterols, suggesting a role of FABP4 in fetal lipid metabolism in subjects with excessive fetal growth.

Docosahexaenoic acid supplementation in gestational diabetes mellitus and neonatal metabolic health biomarkers.

Background and objective: Gestational diabetes mellitus (GDM) "programs" an elevated risk of metabolic dysfunctional disorders in the offspring, and has been associated with elevated leptin and decreased adiponectin levels in cord blood. We sought to assess whether docosahexaenoic acid (DHA) supplementation in GDM affects neonatal metabolic health biomarkers especially leptin and adiponectin. Methods: In a randomized controlled trial, singleton pregnant women with de novo diagnosis of GDM at 24-28 weeks of gestation were randomized to dietary supplementation of 500 mg DHA per day (intervention, n = 30) until delivery or standard care (control, n = 38). The primary outcomes were cord blood leptin and total adiponectin concentrations. Secondary outcomes included high-molecular-weight (HMW) adiponectin and insulin-like growth factor-1 (IGF-1) concentrations in cord blood, maternal glycemic control post-intervention and birth weight (z score). In parallel, 38 euglycemic pregnant women were recruited for comparisons of cord blood biomarkers. Results: There were no significant differences in cord serum leptin, total and HMW adiponectin and IGF-1 concentrations between DHA supplementation and control groups (all p > 0.05). Maternal fasting and 2-h postprandial blood glucose levels at 12-16 weeks post-intervention were similar between the two groups. The newborns in the DHA group had higher birth weight z scores (p = 0.02). Cord blood total and HMW adiponectin concentrations were significantly lower in GDM vs. euglycemic pregnancies. Conclusion: Docosahexaenoic acid supplementation at 500 mg/day in GDM women did not affect neonatal metabolic biomarkers including leptin, adiponectin and IGF-1. The results are reassuring in light of the absence of influence on neonatal adipokines (leptin and adiponectin), and potential benefits to fetal growth and development. Clinical Trial Registration: Clinicaltrials.gov, NCT03569501.

[Effects of moxibustion on the ultrastructure of synovial cells of knee joint and serum cytokines in adjuvant arthritis rats].

OBJECTIVE: To observe the effects of moxibustion on the ultrastructure of synovial cells of knee joint and serum cytokines in adjuvant arthritis (AA) rats, and to explore the potential mechanism of moxibustion in treatment of rheumatoid arthritis. METHODS: Forty-five Wistar male rats were randomly divided into a normal group, a model group and a moxibustion group, with 15 rats in each group. In the model group and the moxibustion group, the AA model was replicated under wind, cold and humid environment and by injection with complete freund's adjuvant. In the moxibustion group, moxibustion at "Zusanli" (ST 36) and "Shenshu" (BL 23) was used, 20 min each time, once daily, for consecutive 21 days. In the normal group and the model group, no intervention was processed. The scores of the knee joint swelling degree (JSD) and arthritis index (AI) were compared among groups. The ultrastructure of synovial cells of knee joint were observed under transmission electron microscope (TEM). The levels of serum cytokines such as tumor necrosis factor-α (TNF-α), interieukin (IL)-1ß, IL-6 and IL-10 were detected using ELISA method. RESULTS: Compared with the normal group, JSD and AI scores, the levels of TNF-α, IL-1ß and IL-6 were increased (P<0.01), while IL-10 was reduced (P<0.01) in the model group after intervention. JSD and AI scores, and the levels of TNF-α, IL-1ß and IL-6 were lower (P<0.05, P<0.01), while the level of IL-10 was higher (P<0.01) in the moxibustion group compared with the model group. Compared with the normal group, the ultrastructure of synovial cell was obviously damaged in the model group, and the damage was attenuated in the moxibustion group compared with the model group. CONCLUSION: Moxibustion can reduce the symptoms of arthritis in AA rats, which may be related to the improvement of the ultrastructure of synovial cells and the regulation of cytokines.

Identification of variants in 94 Chinese patients with hereditary spherocytosis by next-generation sequencing.

Hereditary spherocytosis (HS) is the most common type of hereditary erythrocyte membrane disease and has varied phenotypic features and genetic patterns. We herein performed a retrospective study of 94 patients with HS and aimed to investigate the genetic variations and genotype-phenotype correlations using targeted next-generation sequencing. In 79/94 (84%) patients, 83 HS variants including 67 novel variants were identified. Pathogenic variants of SPTB, ANK1, SLC4A1, SPTA1, and EPB42 were found in 32/79(41%), 22/79(28%), 15/79 (19%), 8/79 (9%), and 3/79 (4%) of the patients respectively, revealing that SPTB is the most frequently mutated HS gene in Eastern China. Most SPTB and ANK1 gene variations were nonsense and frameshift variations. Missense variants were the main variant type of SLC4A1, SPTA1, and EPB42 genes. Interestingly, one SPTA1 variant (p. Arg1757Cys) showed an autosomal dominant inheritance pattern and one EPB42 variant (p. Gln377His) was apparent as a hotspot variation. Furthermore, genotype-phenotype analysis was performed among the five mutated gene groups. Besides the finding that patients with the SLC4A1 variant had the highest mean corpuscular hemoglobin levels, no clear correlations between genotype and phenotype were observed.

[Influence of acupuncture on the clinical manifestations and gastrointestinal symptoms of children with autism spectrum disorder].

OBJECTIVE: To observe the effect of acupuncture therapy based on "gut-brain axis" on clinical manifestations and gastrointestinal symptoms of children with autism spectrum disorder (ASD). METHODS: A total of 66 children with ASD were randomly divided into an observation group and a control group, 33 cases in each group. The control group was treated by routine rehabilitation training. On the basis of the control group, the observation group was treated with acupuncture based on "gut-brain axis", and the acupoints were Touwei (ST 8), Shenting (GV 24), Sishencong (EX-HN 1), Tianshu (ST 25), Zhongwan (CV 12), Zusanli (ST 36), etc. Both treatments were given once every other day, 3 times a week, 4 weeks as a course of treatment, consecutively for 3 courses. The scores of autism behavior checklist (ABC), TCM symptoms of gastrointestinal disease and childhood autism rating scale (CARS) were compared between the two groups before and after treatment, and the clinical efficacy was evaluated. RESULTS: After treatment, the scores of ABC, CARS and TCM symptoms of gastrointestinal disease in the two groups were lower than before treatment (P<0.05), and those in the observation group were lower than the control group (P<0.05). The total effective rate of the observation group was 90.9% (30/33), which was higher than 81.8% (27/33) in the control group (P<0.05). CONCLUSION: On the basis of routine rehabilitation training, acupuncture therapy based on "gut-brain axis" is effective in treating ASD, which can relieve the clinical manifestations and gastrointestinal symptoms.

Genome-wide placental DNA methylations in fetal overgrowth and associations with leptin, adiponectin and fetal growth factors.

BACKGROUND: Fetal overgrowth "programs" an elevated risk of type 2 diabetes in adulthood. Epigenetic alterations may be a mechanism in programming the vulnerability. We sought to characterize genome-wide alterations in placental gene methylations in fetal overgrowth and the associations with metabolic health biomarkers including leptin, adiponectin and fetal growth factors. RESULTS: Comparing genome-wide placental gene DNA methylations in large-for-gestational-age (LGA, an indicator of fetal overgrowth, n = 30) versus optimal-for-gestational-age (OGA, control, n = 30) infants using the Illumina Infinium Human Methylation-EPIC BeadChip, we identified 543 differential methylation positions (DMPs; 397 hypermethylated, 146 hypomethylated) at false discovery rate < 5% and absolute methylation difference > 0.05 after adjusting for placental cell-type heterogeneity, maternal age, pre-pregnancy BMI and HbA1c levels during pregnancy. Twenty-five DMPs annotated to 20 genes (QSOX1, FCHSD2, LOC101928162, ADGRB3, GCNT1, TAP1, MYO16, NAV1, ATP8A2, LBXCOR1, EN2, INCA1, CAMTA2, SORCS2, SLC4A4, RPA3, UMAD1,USP53, OR2L13 and NR3C2) could explain 80% of the birth weight variations. Pathway analyses did not detect any statistically significant pathways after correcting for multiple tests. We validated a newly discovered differentially (hyper-)methylated gene-visual system homeobox 1 (VSX1) in an independent pyrosequencing study sample (LGA 47, OGA 47). Our data confirmed a hypermethylated gene-cadherin 13 (CDH13) reported in a previous epigenome-wide association study. Adiponectin in cord blood was correlated with its gene methylation in the placenta, while leptin and fetal growth factors (insulin, IGF-1, IGF-2) were not. CONCLUSIONS: Fetal overgrowth may be associated with a large number of altered placental gene methylations. Placental VSX1 and CDH13 genes are hypermethylated in fetal overgrowth. Placental ADIPOQ gene methylations and fetal circulating adiponectin levels were correlated, suggesting the contribution of placenta-originated adiponectin to cord blood adiponectin.

Origins of Stereospecificity and Divergent Reactivity of Pd-Catalyzed Cross Coupling with α,α-Disubstituted Alkenyl Hydrazones.

This article presents an exploration of stereospecificity and divergent reactivity of Pd-catalyzed α,α-disubstituted alkenyl hydrazones to synthesize 1,4-dienes in the Z configuration and vinylcyclopropane. We calculated the energy profiles of four α,α-disubstituted alkenyl hydrazones. The results show that the energy profiles of the whole catalytic cycle are basically the same before the syn-carbopalladation step. Subsequent syn-ß-C elimination yields skipping dienes, or direct ß-H elimination yields vinylcyclopropane. Current theoretical calculations reveal that the stereospecificity and the divergent reactivity of reactions result from the competition between syn-ß-C elimination and ß-H elimination. The C-C bond rotation and subsequent syn-ß-C elimination step control the stereospecificity of the reaction by changing the olefin stereostructure from E to Z configuration. The steric factor of α-substituted groups mediates the transformation between syn-ß-C elimination and ß-H elimination. The results are of great significance for the scientific design of substrates to achieve accurate synthesis of target products.

Associations of executive function and age of first use of methamphetamine with methamphetamine relapse.

Background and aims: Methamphetamine (MA) is a psychostimulant associated with a high relapse rate among patients with MA use disorder (MUD). Long-term use of MA is associated with mental disorders, executive dysfunction, aggressive behaviors, and impulsivity among patients with MUD. However, identifying which factors may be more closely associated with relapse has not been investigated. Thus, we aimed to investigate the psychological factors and the history of MA use that may influence MA relapse. Methods: This cross-sectional study included 168 male MUD patients (MUD group) and 65 healthy male residents (control group). Each patient was evaluated with self-report measures of executive dysfunction, psychopathological symptoms, impulsiveness, aggressiveness, and history of MA use. Data were analyzed with t-tests, analyses of variance, and correlation and regression analyses. Results: The MUD group reported greater executive dysfunction, psychopathological symptoms, impulsivity, and aggression than the control group. Lower age of first MA use was associated both with having relapsed one or more times and with having relapsed two or more times; greater executive dysfunction was associated only with having relapsed two or more times. Conclusion: Patients with MUD reported worse executive function and mental health. Current results also suggest that lower age of first MA use may influence relapse rate in general, while executive dysfunction may influence repeated relapse in particular. The present results add to the literature concerning factors that may increase the risk of relapse in individuals with MUD.

Catalytic Enantioselective Desymmetrization of Prochiral Triacylamines via Pseudopeptidic Guanidine-Guanidinium Catalysis.

Triacylamines with Cs symmetry have been explored in asymmetric organocatalysis, leading to the development of a novel catalytic enantioselective desymmetrization of prochiral triacylamines by methanolysis under the catalysis of chiral pseudopeptidic guanidine-guanidinium salt having a weakly coordinating anion. This organocatalytic methodology provides an effective approach to the synthetically useful chiral imide-esters with a 1,5-dicarbonyl moiety, and its synthetic potential has been manifested in the asymmetric synthesis of two GABA analogue drugs, (R)-Baclofen·HCl and (S)-Pregabalin.