Interactions between Exposure to Environmental Polycyclic Aromatic Hydrocarbons and DNA Repair Gene Polymorphisms on Bulky DNA Adducts in Human Sperm

BACKGROUND: Nucleotide excision repair (NER) and base excision repair (BER) are the primary mechanisms for repair of bulky adducts caused by chemical agents, such as PAHs. It is expected that polymorphisms in NER or BER genes may modulate individual susceptibility to PAHs exposure. Here, we evaluate the effects of PAHs exposure and polymorphisms in NER and BER pathway, alone or combined, on polycyclic aromatic hydrocarbon-DNA (PAH-DNA) adducts in human sperm. METHODOLOGY/PRINCIPAL FINDINGS: Sperm PAH-DNA adducts were measured by immunofluorescent assay using flow cytometry in a sample of 465 infertile adults. Polymorphisms of XPA, XPD, ERCC1, XPF, and XRCC1 were determined by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) techniques. The PAHs exposure was detected as urinary 1-hydroxypyrene (1-OHP) levels. In multivariate models adjusted for potential confounders, we observed that XRCC1 5'pUTR -T/C, Arg194Trp, Arg399Gln polymorphisms were associated with increased sperm adduct levels. Furthermore, the stratified analysis indicated that adverse effects of XRCC1 Arg194Trp, Arg399Gln polymorphisms on PAH-DNA adducts were detected only in the high PAHs exposure group. CONCLUSIONS/SIGNIFICANCE: These findings provided the first evidence that polymorphisms of XRCC1 may modify sperm PAH-DNA adduct levels and may be useful biomarkers to identify individuals susceptible to DNA damage resulting from PAHs exposure

Functions of IDH1 in zebrafish hematopoiesis and its relevance to human acute myeloid leukemia

Isocitrate dehydrogenase (IDH) is involved in tricarboxylic acid (TCA) cycle by converting isocitrate to α-ketoglutarate (α-KG) in physiological condition. Recently, recurrent mutations of the IDH1/2 have been identified in a variety of cancers, including up to 30% of cytogenetically normal acute myeloid leukemia (CN-AML). IDH1/2 mutations confer new metabolic function to the mutant enzymes that catalyze conversion of α-KG to 2-hydroxyglutarate (2-HG). The latter was thought to inhibit α-KG-dependent dioxygenases, including ten-eleven translocation 2 (TET2) and disrupt the epigenetic regulatory network that normally keeps leukemia initiation in check. Zebrafish has emerged as a model organism for the study of hematopoiesis and human diseases and zebrafish IDH1/2 (zidh1/2) are true orthologs of mammalian IDH1/2. In the present study, we investigated the role of zidh1 in embryonic and adult hematopoiesis and evaluated its pathogenetic and therapeutic relevance to human AML. In adult zebrafish, zidh1 was preferentially expressed in the kidney, the equivalence of human bone marrow. During early embryogenesis, it was first ubiquitously expressed and later around the regions of ventral wall of dorsal aorta (DA) and the caudal hematopoietic tissue (CHT), the sites of definitive hematopoiesis. Morpholino knock-down of zidh1 induced differentiation block of primitive myelopoiesis, characterized by an increase in gene expression associated with early myeloid progenitor (pu.1) and decrease in those associated with late myelomonocytic differentiation (l-plastin, mpeg1 and mpo). Definitive hematopoiesis was also reduced, as shown by the down-regulation of c-myb and runx1 along the ventral wall of DA and T-cell marker rag1 in the thymus. To validate our observations, we constructed a TALEN pair targeting exon 1 of zidh1 and injected the TALEN mRNAs into zygotic stage embryos. The efficiency of inducing small insertions or deletions (indels) was 98.71.5%. The mutant embryos exhibited defective primitive myelopoiesis and definitive hematopoiesis. Mutant adult fish exhibited an increase in hematopoietic precursor cells in the kidney marrow. Morpholino knock-down of zidh2 also resulted in a blockade of myeloid differentiation as evidenced by increased expression associated with early myeloid progenitor (pu.1) and decreased expression associated with late myelomonocytic differentiation (mpo and l-plastin). Definitive hematopoiesis was not affected. Co-injecting zidh2 mRNA with zidh1 morpholino could not rescue the hematopoietic defects of the latter, indicating non-redundant functions of zidh1 and zidh2. To examine whether the leukemogenic mechanisms of human IDH1-R132H is conserved in zebrafish, we microinjected human IDH1-R132H cDNA into zygotic stage embryos. There was significant increase in 2-HG, associated with increased expression of pu.1, l-plastin, mpeg1 and mpo. The response could be ameliorated by an IDH1-R132H specific inhibitor (AGI-5198). Overexpression of a zebrafish orthologue zidh1-R146H significantly increased 2-HG and primitive myelopoiesis but the responses were not inhibited by AGI-5198. The results provided important insights to the role of zidh in myelopoiesis and definitive hematopoiesis. We also developed a zebrafish model of IDH1-R132H that underscored the conserved leukemogenic mechanisms of IDH1 mutation and provided a platform for high-throughput screening for potential novel and personalized agents.published_or_final_versionMedicineDoctoralDoctor of Philosoph

Aldehyde Complexes with Protonated Peptides in Gas Phase

This Article presents a study of aldehyde complexes with peptide ions formed by bimolecular collisions in the gas phase. Desolvated ions generated by electrospray ionization are stored within a radio frequency (RF) ion trap and exposed to aldehyde vapor. Mass spectrometry measurements were performed on the resulting aldehyde complexes formed with single amino acids (LysH+, HisH+, and ArgH+) and polypeptides [Pr0m-Lys+2H]2+ and [(Gly-Ser)m-Lys+2H]2+. These data identify several interesting and unexpected aspects of the aldehyde complex kinetics. It is observed that the formation of stable complexes requires the presence of water vapor. The formation kinetics of aldehyde–peptide complexes exhibits multiexponential time dependence that is modeled by interactions in the presence of structural heterogeneity. Aldehyde binding appears to involve a competition between conformers with unhindered access to protonation sites and conformers with intramolecular solvation of these sites. Proton transfer to the aldehyde ligand is responsible for the loss of the complexes. This is supported by proton affinity calculations and identified by reaction products exhibiting loss of protonation by the parent ion accompanied by the appearance of aldehyde cations

Confning TiO2 Nanotubes in PECVD‑Enabled Graphene Capsules Toward Ultrafast K‑Ion Storage: In Situ TEM/XRD Study and DFT Analysis

© 2020, © 2020, The Author(s). Titanium dioxide (TiO2) has gained burgeoning attention for potassium-ion storage because of its large theoretical capacity, wide availability, and environmental benignity. Nevertheless, the inherently poor conductivity gives rise to its sluggish reaction kinetics and inferior rate capability. Here, we report the direct graphene growth over TiO2 nanotubes by virtue of chemical vapor deposition. Such conformal graphene coatings effectively enhance the conductive environment and well accommodate the volume change of TiO2 upon potassiation/depotassiation. When paired with an activated carbon cathode, the graphene-armored TiO2 nanotubes allow the potassium-ion hybrid capacitor full cells to harvest an energy/power density of 81.2 Wh kg−1/3746.6 W kg−1. We further employ in situ transmission electron microscopy and operando X-ray diffraction to probe the potassium-ion storage behavior. This work offers a viable and versatile solution to the anode design and in situ probing of potassium storage technologies that is readily promising for practical applications.[Figure not available: see fulltext.]