Search

Maternal prepregnancy obesity is an important risk factor for offspring obesity, which may partially operate through prenatal programming mechanisms.The study aimed to systematically identify prenatal metabolomic profiles mediating the intergenerational transmission of obesity.We included 450 African American mother-child pairs from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood Study (CANDLE) pregnancy cohort. Liquid chromatography-mass spectrometry was used to conduct metabolomic profiling on the maternal plasma samples of the second trimester. The childhood growth outcomes of interest included body mass index (BMI) trajectories from birth to age 4 (rising-high-, moderate-, and low-BMI trajectories) as well as overweight/obesity (OWO) risk at age 4. Mediation analysis was conducted to identify metabolite mediators linking maternal OWO and childhood growth outcomes. The potential causal effects of maternal OWO on metabolite mediators were examined using the Mendelian Randomization (MR) method.Among 880 metabolites detected in the maternal plasma during pregnancy, 14 and 11 metabolites significantly mediated the effects of maternal prepregnancy OWO on childhood BMI trajectories and the OWO risk at age 4, respectively, and five of those mediated both outcomes. The MR analysis suggested six of the 20 prenatal metabolite mediators might be causally influenced by maternal prepregnancy OWO, most of which are from the pathways related to the metabolism of amino acids (hydroxyasparagine, glutamate, and homocitrulline), sterols (campesterol), and nucleotides (N2, N2-dimethylguanosine).Our study provided further evidence that prenatal metabolomic profiles might mediate the effect of maternal OWO on early childhood growth trajectories and OWO risk in offspring. The metabolic pathways including identified metabolite mediators might provide novel intervention targets for preventing the intrauterine development of obesity in offspring of mothers with obesity.

This work vividly demonstrates the rational design of a coblat selenophosphide anode as an effective strategy to accomplish fast and high sodium-ion storage.

SnRK2 protein kinase family plays an important role in plant response to abiotic stress and has been identified in various plants. This study aimed to identify SnRK2 genes in tobacco and systematically analyze their expression under abscisic acid treatment and abiotic stress. We identified 22 NtSnRK2 members, which were divided into three groups and located on 13 chromosomes, mainly at both ends of the chromosomes; additionally, 11 duplicated NtSnRK2 gene pairs were observed. Phylogenetic analysis showed that these SnRK2 members were divided into three groups in tobacco. The motifs of NtSnRK2 proteins in the same group were highly similar. Subcellular localization indicated that NtSnRK2s in Group3 were present in the nucleus, cytomembrane, and cytoplasm. Gene expression pattern analysis revealed that NtSnRK2 genes played a role in the responses to several abiotic stresses (salt, drought, and low-temperature stress), indicating that they are widely involved in the adaptation of tobacco to adverse environmental conditions.

AgPd–Ag2O and AgPd–AgF heterointerfaces are prepared through reconstruction and designed by using “2D materials on metal” heterostructure models to illustrate their impact mechanism on electrocatalytic activity toward the formate oxidation reaction.

The maturity of fresh tobacco leaves affects the browning of leaves to differing degrees during the curing process, thus affecting the quality of cured tobacco leaves. In this study, tobacco leaves of increasing maturity (M1–M4) were selected. Dark-box experiments were performed to investigate the roasting characteristics and relationship between tobacco leaf maturity and browning and to determine their polyphenol oxidase (PPO) activities and qualities. We found that mature tobacco leaves (M3) had high substance accumulation, and the PPO activity decreased throughout the baking process. After 72 h of curing, the PPO activity in the M3 leaves was 81.22 U/g, which was significantly different from that in M1 and M2. On this basis, three different browning inhibitors (control: 10 mL of distilled water; T1:10 mL of 0.5% citric acid+0.5% polyphenol; and T2:10 mL 0.5% citric acid+0.5% salicylic acid) were sprayed onto the surface of M2 leaves before curing to observe their inhibitory effects. The T2-treated leaves showed inhibited PPO activity, and after baking for 72 h, the peroxidase enzyme (POD) content of the T2-treated leaves was higher, which effectively inhibited the enzymatic reaction. In conclusion, to reduce the browning ratio of tobacco leaves during the curing process, the harvested tobacco leaves should be allowed to reach full maturity when the values of Soil Plant Analysis Development (SPAD) chlorophyll meter ranged 9–13, and 0.5% citric acid+0.5% salicylic acid (T2) should be used as a browning inhibitor to produce tobacco with the highest sensory quality. The results of this study can help inhibit browning and maintaining the quality of the tobacco leaves during the curing process.

In the wake of health disasters associated with the chronic use of cyclooxygenase-2 (COX-2) inhibitor drugs, it has been widely proposed that modulation of downstream prostanoid synthases or receptors might provide more specificity than simply shutting down the entire COX cascade for anti-inflammatory benefits. The pathogenic actions of COX-2 have long been thought attributable to the prostaglandin E2 (PGE(2)) signaling through its Gα(s)-coupled EP2 receptor subtype; however, the truly selective EP2 antagonists did not emerge until 2011. These small molecules provide game-changing tools to better understand the EP2 receptor in inflammation-associated conditions. Their applications in preclinical models also reshape our knowledge of PGE(2)/EP2 signaling as a node of inflammation in health and disease. As we celebrate the 10-year anniversary of this breakthrough, the exploration of their potential as drug candidates for next-generation anti-inflammatory therapies has just begun. The first decade of EP2 antagonists passes, while their future looks brighter than ever.

Purpose A targeted drug delivery system that combines protein-arginine deiminase type-4 (PAD4) inhibitors YW3-56 (356) with PTT of NPs is constructed to both decrease the accumulation of gold in metabolic organs and reduce the dose of chemotherapeutic agents. Patients and Methods In vitro cytotoxicity test and in vivo S180 tumor-bearing mice model were used to compare antitumor activity of 356-modified gold nanospheres and nanorods. The A549 tumor-bearing mice model was also exploited in antitumor assessment. In addition, ICP-MS, blood cell analyzer and blood biochemistry analyzer are applied for assessing the biosafety of NPs. Results Both 356-modified gold nanospheres and nanorods showed antitumor activity. However, 356-loaded gold nanorods are found to have better tumor inhibitory activity than 356-loaded gold nanospheres in the presence of laser and without laser irradiation. Thus, 356-loaded gold nanorods are selected to be applied for chemo-photothermal combined therapy on in vivo. We find that combination therapy could inhibit tumor growth and reduce lung tumor metastasis and inflammatory infiltration compared with individual therapy. It triggers apoptosis in tumor tissue observed by TUNEL assay and TEM pictures. Conclusion Thus, an RGD targeting and PAD4 inhibitor-loaded system are established based on chemo-photothermal combined therapy. It could inhibit tumor growth, prevent lung metastasis and improve biosafety., Graphical Abstract

Objective Prenatal metabolomics profiles, providing measures of in utero nutritional and environmental exposures, may improve the prediction of childhood outcomes. We aimed to identify prenatal plasma metabolites associated with early childhood body mass index (BMI) trajectories and overweight/obesity risk in offspring. Methods This study included 450 African American mother-child pairs from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood Study. An untargeted metabolomics analysis was performed on the mothers' plasma samples collected during the second trimester. The children's BMI-z-score trajectories from birth to age 4 [rising-high- (9.8%), moderate- (68.2%), and low-BMI (22.0%)] and overweight/obesity status at age 4 were the main outcomes. The least absolute shrinkage and selection operator (LASSO) was used to select the prenatal metabolites associated with childhood outcomes. Results The mothers were 24.5 years old on average at recruitment, 76.4% having education less than 12 years and 80.0% with Medicaid or Medicare. In LASSO, seven and five prenatal metabolites were associated with the BMI-z-score trajectories and overweight/obese at age 4, respectively. These metabolites are mainly from/relevant to the pathways of steroid biosynthesis, amino acid metabolism, vitamin B complex, and xenobiotics metabolism (e.g., caffeine and nicotine). The odds ratios (95% CI) associated with a one SD increase in the prenatal metabolite risk scores (MRSs) constructed from the LASSO-selected metabolites were 2.97 (1.95-4.54) and 2.03 (1.54-2.67) for children being in the rising-high-BMI trajectory group and overweight/obesity at age 4, respectively. The MRSs significantly improved the risk prediction for childhood outcomes beyond traditional prenatal risk factors. The increase (95% CI) in the area under the receiver operating characteristic curves were 0.10 (0.03-0.18) and 0.07 (0.02-0.12) for the rising-high-BMI trajectory (P = 0.005) and overweight/obesity at age 4 (P = 0.007), respectively. Conclusions Prenatal metabolomics profiles advanced prediction of early childhood growth trajectories and obesity risk in offspring.

The dicarbonylation of 1,3‐butadiene to adipic acid derivatives offers the potential for a more cost‐efficient and environmentally benign industrial process. However, the complex reaction network of regioisomeric carbonylation and isomerization pathways, make a selective and direct transformation particularly difficult. Here, we report surprising solvent effects on this palladium‐catalysed process in the presence of 1,2‐bis‐di‐tert‐butylphosphin‐oxylene (dtbpx) ligands, which allow adipate diester formation from 1,3‐butadiene, carbon monoxide, and methanol with 97 % selectivity and 100 % atom‐economy under scalable conditions. Under optimal conditions a variety of di‐ and triesters from 1,2‐ and 1,3‐dienes can be obtained in good to excellent yields., High value‐added conversion: From gas to nylon precursor. This 100 % atom economic and industrially relevant process is strongly influenced by the system polarity.

BH3120 is a heterodimeric bispecific antibody, designed to target 4-1BB and PD-L1 simultaneously with Pentambody™ platform, to stimulate anti-tumor immune response in a tumor microenvironment (TME) specific manner. BH3120 showed strong antitumor efficacy in multiple tumor models, and combination of BH3120 with a PD-1 antagonist showed synergic effects eradicating tumor. While BH3120 consistently activates T cells, both as a monotherapy and in combination with a PD-1 antagonist, modulation of immune system in the tumor tissue is clearly de-coupled from that in peripheral blood, suggesting reduced risks of immune related adverse events (irAEs) with BH3120. To verify this hypothesis, BH3120 was compared with reference bispecific antibodies. Combination of BH3120 with a PD-1 antogonist does not result in elevation of transaminase enzymes, while the reference bispecific antibodies, when combined with the same PD-1 antagonist, show significant increase of the enzymes and macrophage in liver. In the toxicology studies conducted so far with cynomolgus monkeys, NOAEL of BH3120 was determined to be 200 mg/kg (QW X 5). Citation Format: Jing Wang, Jun Wang, Yang Liu, Yan Pang, Aihong Zhang, Jie Feng, Aibo Sun, Xiao Ma, Jingmei Cai, Jiangcheng Xu, Jiawang Liu, Kyoungwoo Lee. BH3120, a bispecific antibody targeting 4-1BB and PD-L1 simultaneously, stimulates T cells in tumor tissue preferred manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1799.

Covering: up to August 2020The dramatic increase in the identification of dimeric natural products generated by microorganisms and plants has played a significant role in drug discovery. The biosynthetic pathways of these products feature inherent dimerization reactions, which are valuable for biosynthetic applications and chemical transformations. The extraordinary mechanisms of the dimerization of secondary metabolites should advance our understanding of the uncommon chemical rules for natural product biosynthesis, which will, in turn, accelerate the discovery of dimeric reactions and molecules in nature and provide promising strategies for the total synthesis of natural products through dimerization. This review focuses on the enzymes involved in the dimerization in the biosynthetic pathway of microbial natural products, with an emphasis on cytochrome P450s, laccases, and intermolecular [4 + 2] cyclases, along with other atypical enzymes. The identification, characterization, and catalytic landscapes of these enzymes are also introduced.

Objective Peptidyl alkaloids, a series of important natural products can be assembled by fungal non-ribosomal peptide synthetases (NRPSs). However, many of the NRPSs associated gene clusters are silent under laboratory conditions, and the traditional chemical separation yields are low. In this study, we aim to discovery and efficiently prepare fungal peptidyl alkaloids assembled by fungal NRPSs. Methods Bioinformatics analysis of gene cluster containing NRPSs from the genome of Penicillium thymicola, and heterologous expression of the putative gene cluster in Aspergillus nidulans were performed. Isolation, structural identification, and biological evaluation of the product from heterologous expression were carried out. Results The putative tri-modular NRPS AncA was heterologous-expressed in A. nidulans to give anacine (1) with high yield, which showed moderate and selective cytotoxic activity against A549 cell line. Conclusion Heterologous expression in A. nidulans is an efficient strategy for mining fungal peptidyl alkaloids.

Primary effusion lymphoma (PEL) is an aggressive malignancy with poor prognosis even under chemotherapy. Kaposi sarcoma–associated herpesvirus (KSHV), one of the human oncogenic viruses, is the principal causative agent. Currently, there is no specific treatment for PEL; therefore, developing new therapies is of great importance. Sphingolipid metabolism plays an important role in determining the fate of tumor cells. Our previous studies have demonstrated that there is a correlation between sphingolipid metabolism and KSHV+ tumor cell survival. To further develop sphingolipid metabolism-targeted therapy, after screening a series of newly synthesized ceramide analogs, here, we have identified compounds with effective anti-PEL activity. These compounds induce significant PEL apoptosis, cell-cycle arrest, and intracellular ceramide production through regulation of ceramide synthesizing or ceramide metabolizing enzymes and dramatically suppress tumor progression without visible toxicity in vivo. These new compounds also increase viral lytic gene expression in PEL cells. Our comparative transcriptomic analysis revealed their mechanisms of action for inducing PEL cell death and identified a subset of novel cellular genes, including AURKA and CDCA3, controlled by sphingolipid metabolism, and required for PEL survival with functional validation. These data provide the framework for the development of promising sphingolipid-based therapies against this virus-associated malignancy.

A chemo‐, regio‐, and stereoselective mono‐hydroamidation of (un)symmetrical 1,3‐diynes is described. Key for the success of this novel transformation is the utilization of an advanced palladium catalyst system with the specific ligand Neolephos. The synthetic value of this general approach to synthetically useful α‐alkynyl‐α, β‐unsaturated amides is showcased by diversification of several structurally complex molecules and marketed drugs. Control experiments and density‐functional theory (M06L‐SMD) computations also suggest the crucial role of the substrate in controlling the regioselectivity of unsymmetrical 1,3‐diynes., The advanced Pd catalyst system with Neolephos as a ligand enables highly selective hydroamidation of unbiased (un)symmetrical 1,3‐diynes. In this way, a wide range of synthetically useful α‐alkynyl‐α,β‐unsaturated amides are afforded in good to high yields with excellent chemo‐, regio‐, and stereoselectivities.

To achieve the well-dispersed Ni–NiS dual-cocatalysts anchored CdS, the samples have been successfully constructed by a cheap and convenient method of hydroxy acid assisted hydrothermal method. Based on the coordination and reduction effects of hydroxy acids, Ni2+ can be facilely transformed into the high dispersed dual-function sites of Ni0 electrons trap and NiS holes reservoir. The highly dispersed Ni–NiS dual-cocatalysts not only provide more dual-function active sites but also present distinctly enhanced visible light absorption, effectively separated electron hole pairs and quickly migrated charge carriers. The optimized Ni–NiS/CdS–CA presented an excellent photocatalytic H2 generation rate of 57.88 mmol·h−1·g−1, which is about 15.35 times higher than that of NiS/CdS. Moreover, the stability can be distinctly increased by modulating the surface cover of Ni–NiS with a suitable Ni/(Ni + Cd) atomic ratio. This work would provide a unique strategy to design the high effective photocatalysts with high dispersed bi-function dual cocatalysts. The well-dispersed Ni-NiS dual-cocatalysts anchored CdS in situ have been successfully constructed via the coordination and reduction effects of hydroxy acid assisted hydrothermal method. Ni-NiS/CdS-CA not only presents dual-function active sites but also exhibits distinctly enhanced visible light absorption, effectively separated electron hole pairs and quickly migrated charge carriers, resulting in a remarkable enhancement in photocatalytic H2 evolution activity.

Here, we describe a selective palladium catalyst system for chemodivergent functionalization of alkynes with syngas. In the presence of the advanced ligand L2 bearing 2-pyridyl substituent as a bui...

A carbonylation path to a nylon precursor Adipic acid and its esters are manufactured on a massive scale, primarily to produce nylon. However, the standard route requires large quantities of corrosive nitric acid. J. Yang et al. present an efficient alternative route whereby a palladium catalyst adds carbon monoxide to each end of butadiene (see the Perspective by Schaub). Both reactants are available at commodity scale, and the reaction produces no by-products. An optimized bidentate phosphine ligand bearing a pyridine substituent for proton shuttling proved key to attaining the necessary selectivity. Science , this issue p. 1514 ; see also p. 1447