Switch in Selectivities by Dinuclear Nickel Catalysis: 1,4-Hydroarylation of 1,3-Dienes to Z-Olefins.

One of the most challenging tasks in organic synthesis is to control selectivities, especially switching the well-known selectivity to obtain new isomers that were previously inaccessible. Inspired by biological catalysis involving multiple metal centers, catalysis enabled by binuclear metal complexes offers the potential to induce reactivity and selectivity that might not be available to mononuclear catalysts. Herein, we describe that using a macrocyclic bis pyridyl diimine dinickel complex as the catalyst, the commonly observed 4,3-regioselectivity of hydroarylation of 1,3-dienes is switched to 1,4-hydroarylation with thermodynamically less stable Z-stereoselectivity, offering challenging synthetic target Z-olefins. DFT calculations show that the activation of 1,3-diene proceeds through dinuclear Ni-diolefin coordination, and the synergistic effects of two Ni nuclei enable reactivity and selectivity of this binuclear catalysis substantially different from those of mononuclear nickel complexes in the current reaction.

Profiling of exosomal microRNAs expression in umbilical cord blood from normal and preeclampsia patients.

BACKGROUND: Epidemiological and experimental studies suggest that preeclampsia has a negative impact on maternity and offspring health. Previous studies report that dysregulation in utero-environment increases risk for elderly disease such as cardiovascular disease. However, the underlying mechanisms remain elusive. Specific microRNAs (miRNAs) are packaged in exosomes may regulate microvascular dysfunction in offspring of mothers with preeclampsia. The present study aimed to identify the differential expression profiles of microRNAs in the serum exosomes between patients with preeclampsia and normal pregnancies. METHODS: A comprehensive miRNA sequence-based approach was performed to compare exosomes carry miRNAs (Exo-miRNAs) expression levels in umbilical serum between normal and preeclampsia patients. Exosomes were isolated using the ExoQuick precipitation kit. Serum exosomes were then viewed under electron microscopy, and their characteristics determined by western blotting and nanoparticle-tracking analysis. Illumina platform was used to perform sequencing. Bioinformatics analysis was used to explore differentially expressed Exo-miRNAs in umbilical serum. RESULTS: Based on sequence similarity, 1733 known miRNAs were retrieved. Furthermore, 157 mature miRNAs in serum exosomes were significantly differential expressed between PE and those control groups (P<0.05, log2|FC| > 1). Out, of the 157 miRNAs, 96 were upregulated miRNAs whereas 61 miRNAs were downregulated. The 157 differentially expressed miRNAs targeted 51,424 differentially expressed genes. Functional analysis through KEGG pathway and Gene Ontology results uncovered that target genes of miRNAs with differential expression were significantly linked to several pathways and biological processes. CONCLUSION: The findings of this study showed differential expression of umbilical serum Exo-miRNAs in normal compared with PE patients, implying that these Exo-miRNAs may associate with microvascular dysfunction in offspring of mothers with preeclampsia.

iTRAQ-based quantitative proteomic analysis of thoracic aortas from adult rats born to preeclamptic dams.

BACKGROUND: Preeclampsia and gestational hypertension can cause vascular function impairment in offspring. In our previous work, we described the protein expression profiles of umbilical artery tissues from patients with preeclampsia. METHODS: To gain insights into the mechanisms of vascular dysfunction in adult rats born to preeclamptic dams, we analyzed thoracic aorta tissues by using iTRAQ isobaric tags and 2D nano LC-MS/MS. RESULTS: By using the iTRAQ method, we analyzed 1825 proteins, of which 106 showed significantly different expression in the thoracic aortic. Ingenuity pathway analysis (IPA) showed that the majority of differentially expressed proteins (DEPs) were associated with cardiovascular function. Further analysis indicated that glucose-6-phosphate dehydrogenase (G6PD), which is inhibited by miR-423-5p and activated by TP53, had the strongest effect on cardiovascular function. The expression of G6PD was upregulated in thoracic aorta tissues, as confirmed by Western blotting. The expression of two other vascular function-related proteins, cysteine- and glycine-rich protein 2 (CSRP2) and tubulin alpha-4 A (TUBA4A), was upregulated, as demonstrated by mass spectrometry (MS). CONCLUSIONS: Although the results require further functional validation, these data provide novel findings related to vascular function impairment in the adult offspring of preeclamptic mothers.

The formation and evolution of carbonate species in CO oxidation over mono-dispersed Fe on graphene.

Fe is not only the most abundant metal on the planet but is also the key component of many enzymes in organisms that are capable of catalyzing many chemical conversions. Mono-dispersed Fe atoms on carbonaceous materials are single atom catalysts (SACs) that function like enzymes. To take advantage of the outstanding catalytic performance of Fe-based SACs, we extended a CO oxidation reaction network over mono-dispersed Fe atoms on graphene (FeGR) by first-principles based calculations. FeGR-catalyzed CO oxidation is initiated with a revised Langmuir-Hinshelwood pathway through a CO-assisted scission of the O-O bond in peroxide species (OCOO). We showed that carbonate species (CO3), which were previously generally considered as a persistent species blocking reaction sites, may form from CO2 and negatively charged O species. This pathway competes with desorption of CO2 and reduction of the Fe center with gaseous CO, and it is exothermic and inevitable, especially at low temperatures and with high CO2 content. Although direct dissociation of CO3 is demanding on FeGR, further adsorption of CO on Fe in CO3 is plausible and takes place spontaneously. We then showed that adsorbed CO may react with CO3, forming a cyclic-carbonate-like species that dissociates easily to CO2. These findings highlight the reaction condition-dependent formation and evolution of CO3 as well as its contribution to CO conversion, and it may extend the understanding of the performance of SACs in low temperature CO oxidation.

Successful management of postpartum venous thrombosis following splenectomy for traumatic splenic rupture: a case report.

Traumatic splenic rupture is rare in pregnant women; and multiple venous thromboses of the portal vein system, inferior vena cava and ovarian vein after caesarean section and splenectomy for splenic rupture has not been previously reported. This case report describes a case of multiple venous thromboses after caesarean section and splenectomy for traumatic splenic rupture in late pregnancy. A 34-year-old G3P1 female presented with abdominal trauma at 33+1 weeks of gestation. After diagnosis of splenic rupture, she underwent an emergency caesarean section and splenectomy. Multiple venous thromboses developed during the recovery period. The patient eventually recovered after anticoagulation therapy with low-molecular-weight heparin and warfarin. These findings suggest that in patients that have had a caesarean section and a splenectomy, which together might further increase the risk of venous thrombosis, any abdominal pain should be thoroughly investigated and thrombosis should be ruled out, including the possibility of multiple venous thromboses. Anticoagulant therapy could be extended after the surgery.

Familial and genetic association with neurodevelopmental disorders caused by a heterozygous variant in the SRRM2 gene.

Background: Neurodevelopmental disorders (NDDs) are a class of disorders affecting brain development and function, characterized by an inability to reach cognitive, emotional, and motor developmental milestones. The pathology of NDDs is complex. A recent study found that variants in the SRRM2 gene cause NDDs. However, genetic conditions play the most important role in the etiology of NDD. The genetic causes of NDD are extremely heterogeneous, leading to certain challenges in clinical diagnosis. Methods: A pregnant woman with congenital intelligence disorder came to our hospital for genetic diagnosis to predict the status of her fetus. Her mother and a brother also suffer from congenital intelligence disorder. She has a daughter with speech delay. Whole exome sequencing was used to identify a mutation (c.1415C>G) in the SRRM2 gene of this family that resulted in a change in the 472nd amino acid residue of the SRRM2 protein from serine to terminated. Conclusion: We report a family with an autosomal dominant genetic disorder caused by variants in the SRRM2 gene causing NDDs. Prenatal diagnosis can help patients with this genetic disorder to have healthy offspring.

Postpartum ovarian vein thrombosis after cesarean section and vaginal delivery: Two case reports.

BACKGROUND: Postpartum ovarian vein thrombosis (POVT) is a rare puerperal complication. It is easily missed or misdiagnosed due to its insidious onset and lack of specific clinical symptoms and signs. This paper reports two patients who developed right ovarian vein thrombosis after cesarean section and vaginal delivery, respectively. CASE SUMMARY: Case 1 was a 32-year-old female who underwent a cesarean section in labor at 40 wk of gestation due to fetal distress. The patient was persistently febrile after the operation and escalated antibiotic treatment was ineffective. POVT was diagnosed by abdominal computed tomography (CT) and was treated by increasing the dose of low molecular weight heparin (LMWH). Case 2 was a 21-year-old female with a spontaneous vaginal delivery at 39 wk of gestation. The patient developed fever and abdominal pain 3 days after delivery. POVT was promptly identified by abdominal CT, and the condition was quickly controlled after treatment with LMWH and antibiotics. CONCLUSION: These two cases occurred after cesarean section and vaginal delivery, respectively. The diagnosis was mainly based on imaging examination due to the unspecific clinical symptoms and signs, the CT scan provided an especially high diagnostic value. Comparing these two cases, escalating antibiotics alone did not provide significant therapeutic benefit, but the early escalation of anticoagulant dosage seemed to shorten the disease course. Therefore, early diagnosis by CT followed by aggressive anticoagulation might have a positive effect on improving the prognosis of the disease.

A novel PHKA2 variant in a Chinese boy with glycogen storage diseases type IXa.

Background: Glycogen storage diseases (GSDs) are a group of heterogeneous inherited metabolic disorders with an incidence of 4%-5%. There are 19 types of GSDs, making diagnosis one of the greatest challenges. Methods: The proband and his parents were referred to our hospital for genetic diagnosis. Ultrasound screening suggested hepatomegaly. A novel insertion variant NM_000292 c.1155_1156insT (p. 386N>*) in PHKA2 gene was identified using trio whole exome sequencing (Trio-WES), which resulted in the codon of amino acid 386 from asparagine to termination (p. 386N>*). The 3D mutant protein structure was predicted using AlphaFold, and the results showed that the truncated PHKA2 protein contained 385 of the 1,235 amino acids of the mature protein. Conclusion: We describe a previously unreported case of a GSDs IXa type Chinese boy caused by a novel PHKA2 variant. This clinical case contributes to the understanding of the characteristics of GSDs type IXa and expands the variants spectrum of genes related to GSDs type IXa. Our findings demonstrated the significance of genetic testing in the diagnosis of GSDs.

The m6A methyltransferase METTL3 promotes trophoblast cell invasion by regulating MYLK expression.

INTRODUCTION: The progression of placental diseases such as preeclampsia is closely related to trophoblast dysfunction. Recent studies indicated the dysregulation of N6-methyladenosine (m6A) RNA modification in trophoblast disorders, while the function of METTL3, a methyltransferase of m6A, in trophoblasts remains to be studied. METHODS: The expression of METTL3 was determined by real-time PCR and immunoblotting. METTL3 expression in trophoblast cell lines HTR-8/SVneo and JEG-3 was knocked down using shRNA. The invasion of trophoblast cells in Matrigel was determined using xCELLigence. The m6A-containing transcripts was determined by m6A-sequencing in HTR-8/SVneo cells. The myosin light chain kinase (MYLK) gene was transfected into HTR-8/SVneo cells. RESULTS: The expression of METTL3 was downregulated in preeclamptic placentae compared to normal placentae. Knockdown of METTL3 repressed the invasion of extravillous trophoblast cells. Mechanistically, METTL3 promoted the stability of MYLK mRNA through m6A modification. Overexpression of MYLK rescued retarded cell invasion by METTL3 depletion. DISCUSSION: Collectively, our results highlight an essential role of METTL3-MYLK axis in trophoblast invasion.

Proteomics and bioinformatics analysis of cardiovascular related proteins in offspring exposed to gestational diabetes mellitus.

Introduction: Previous studies have demonstrated that exposed to the initial suboptimal intrauterine environment of gestational diabetes mellitus (GDM) may increase risk of cardiovascular disease in adulthood. Methods: In order to investigate the underlying mechanisms involved in the increased risk of cardiovascular diseases (CVDs) in the offspring of GDM, we applied a high-throughput proteomics approach to compare the proteomic expression profile of human umbilical vessels of normal and GDM offspring. Results: A total of significantly different 100 proteins were identified in umbilical vessels from GDM group compared with normal controls, among which 31 proteins were up-regulated, while 69 proteins were down-regulated. Differentially expressed proteins (DEPs) are validated using Western blotting analysis. The analysis of these differently expressed proteins (DEPs) related diseases and functions results, performed by Ingenuity Pathway Analysis (IPA) software. Based on "Diseases and Disorders" analysis, 17 proteins (ACTA2, ADAR, CBFB, DDAH1, FBN1, FGA, FGB, FGG, GLS, GSTM1, HBB, PGM3, PPP1R13L, S100A8, SLC12A4, TPP2, VCAN) were described to be associated with CVD, especially in Anemia, Thrombus and Myocardial infarction. Functional analysis indicated that DEPs involved in many cardiovascular functions, especially in "vasoconstriction of blood vessel" (related DEPs: ACTA2, DDAH1, FBN1, FGA, FGB, and FGG). Upstream regulator analyses of DEPs identifies STAT3 as inhibitor of ACTA2, FGA, FGB, and FGG. Conclusion: The results of this study indicate that intrauterine hyperglycemia is associated with an elevated risk of cardiovascular risk in the offspring.

Isolating Contiguous Ir Atoms and Forming Ir-W Intermetallics with Negatively Charged Ir for Efficient NO Reduction by CO.

The lack of efficient catalysts with a wide working temperature window and vital O2 and SO2 resistance for selective catalytic reduction of NO by CO (CO-SCR) largely hinders its implementation. Here, a novel Ir-based catalyst with only 1 wt% Ir loading is reported for efficient CO-SCR. In this catalyst, contiguous Ir atoms are isolated into single atoms, and Ir-W intermetallic nanoparticles are formed, which are supported on ordered mesoporous SiO2 (KIT-6). Notably, this catalyst enables complete NO conversion to N2 at 250 °C in the presence of 1% O2 and has a wide temperature window (250-400 °C), outperforming the comparison samples with Ir isolated-single-atomic-sites and Ir nanoparticles, respectively. Also, it possesses a high SO2 tolerance. Both experimental results and theoretical calculations reveal that single Ir atoms are negatively charged, dramatically enhancing the NO dissociation, while the Ir-W intermetallic nanoparticles accelerate the reduction of the N2 O and NO2 intermediates by CO.

Fetal Congenital Heart Disease Caused by Compound Heterozygous Mutations in the DNAH9 Gene: A Case Report.

Background: Fetal congenital heart disease (CHD) is the most common congenital defect, with an incidence of 0.6-0.8%, accounting for 30-50% of infant congenital disease deaths. The pathogenesis of CHD is still unclear, so an active and effective prenatal diagnosis is very important for the prevention and control of CHD. Herein, a Chinese CHD patient with rare compound heterozygous mutations in the DNAH9 gene was reported, and the 3D structure and functional changes of DNAH9 protein were predicted. Case presentation: A 23-year-old pregnant woman came to our hospital for prenatal diagnosis at 27 weeks of gestation. Both she and her partner were unaffected. Fetal CHD was detected by ultrasound screening. Copy number variation sequencing (CNV-seq) revealed an 81 kb deletion at chr17p12 (11,486,795-11,568,385), including exons 1-15 of DNAH9 gene, which plays a key role in cardiac development. Then, whole exome sequencing (WES) was used and identified a nonsense mutation (c.10975C>T) in DNAH9, which resulted in the mutation of amino acid 3,659 from glutamine to termination. The 3D mutant protein structures were predicted using SWISS-MODEL and showed structural changes from functional ß-sheet and α-helix to termination, respectively. Conclusion: We describe a case of fetal CHD caused by DNAH9 mutations and provide an effective diagnostic technique for identifying intragenic deletions. This diagnostic process can be implicated in prenatal diagnosis of CHD.

Characterization of the intestinal absorption of morroniside from Cornus officinalis Sieb. et Zucc via a Caco-2 cell monolayer model.

Morroniside is a biologically active polyphenol found in Cornus officinalis Sieb. et Zucc (CO) that exhibits a broad spectrum of pharmacological activities, such as protecting nerves, and preventing diabetic liver damage and renal damage. However, little data are available regarding the mechanism of its intestinal absorption. Here, an in vitro human intestinal epithelial cell model of cultured Caco-2 cells was applied to study the absorption and transport of morroniside. The effects of donor concentration, pH and inhibitors were investigated. The bidirectional permeability of morroniside from the apical (AP) to the basolateral (BL) side and in the reverse direction was studied. When administered at three tested concentrations (5, 25 and 100 µM), the apparent permeability coefficient (Papp) values in the AP-to-BL direction ranged from 1.59 × 10-6 to 2.66 × 10-6 cm/s. In the reverse direction, BL-to-AP, the value was ranged from 2.67 × 10-6 to 4.10 × 10-6 cm/s. The data indicated that morroniside transport was pH-dependent. The permeability of morroniside was affected by treatment with various inhibitors, such as multidrug resistance protein inhibitors MK571 and indomethacin, as well as the breast cancer resistance protein inhibitor apigenin. The mechanisms of the intestinal absorption of morroniside may involve multiple transport pathways, such as the passive diffusion and efflux protein-mediated active transport especially involving multidrug resistance protein 2 and breast cancer resistance protein. After the addition of CO, the Papp values in the AP-to-BL direction increased significantly, therefore, it can be assumed that some ingredients in the CO promote morroniside absorption in the small intestine.