Integrase inhibitors in late pregnancy and rapid HIV viral load reduction

Minimizing time to Human Immunodeficiency Virus (HIV) viral suppression is critical in pregnancy. Integrase strand transfer inhibitors (INSTIs), like raltegravir, are known to rapidly suppress plasma HIV ribonucleic acid (RNA) in nonpregnant adults. There is limited data in pregnant women

A revised evolutionary history of the CYP1A subfamily : gene duplication, gene conversion, and positive selection

Author Posting. © The Authors, 2005. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Journal of Molecular Evolution 62 (2006): 708-717, doi:10.1007/s00239-005-0134-z.Members of cytochrome P450 subfamily 1A (CYP1As) are involved in detoxification and bioactivation of common environmental pollutants. Understanding the functional evolution of these genes is essential to predicting and interpreting species differences in sensitivity to toxicity by such chemicals. The CYP1A gene subfamily comprises a single ancestral representative in most fish species and two paralogs in higher vertebrates, including birds and mammals. Phylogenetic analysis of complete coding sequences suggests that mammalian and bird paralog pairs (CYP1A1/2 and CYP1A4/5, respectively) are the result of independent gene duplication events. However, comparison of vertebrate genome sequences revealed that CYP1A genes lie within an extended region of conserved fine-scale synteny, suggesting that avian and mammalian CYP1A paralogs share a common genomic history. Algorithms designed to detect recombination between nucleotide sequences indicate that gene conversion has homogenized most of the length of the chicken CYP1A genes, as well as the 5’ end of mammalian CYP1As. Together, these data indicate that avian and mammalian CYP1A paralog pairs resulted from a single gene duplication event and that extensive gene conversion is responsible for the exceptionally high degree of sequence similarity between CYP1A4 and CYP1A5. Elevated non-synonymous/synonymous substitution ratios within a putatively unconverted stretch of ~250 bp suggests that positive selection may have reduced the effective rate of gene conversion in this region, which contains two substrate recognition sites. This work significantly alters our understanding of functional evolution in the CYP1A subfamily, suggesting that gene conversion and positive selection have been the dominant processes of sequence evolution.Funding for this work was provided by the NIH Superfund Basic Research Program at Boston University (5-P42-ES-07381) and by the Woods Hole Oceanographic Institution

Akutna oralna toksičnost organofosfornih insekticida i inhibicija kolinesteraza u pilića

Acute toxic effects of three commonly used insecticidal preparations of the organophosphates chlorpyrifos, diazinon, and dichlorvos were examined in mixed breed broiler chicks, and cholinesterase activity in plasma and brain were measured. The acute (24 h) oral median lethal doses (LD50) of chlorpyrifos, diazinon, and dichlorvos were 10.79 mg kg-1, 6.32 mg kg-1, and 6.30 mg kg-1, respectively, as determined by the up-and-down method in chicks. Signs of cholinergic toxicosis in the chicks appeared within two hours after dosing, and they included salivation, lacrimation, gasping, frequent defecation, drooping of wings, tremors, convulsions, and recumbency before death. Halving the oral LD50 of chlorpyrifos (5 mg kg-1), diazinon (3 mg kg-1), and dichlorvos (3 mg kg-1) caused immobility and wing drooping, but not the clinical signs of cholinergic toxicity. However, at full LD50 doses of these insecticides, chicks showed clinical signs of cholinergic toxicity similar to those seen in the LD50 experiments. Two out of six chicks died within two hours after treatment with LD50 doses of chlorpyrifos and dichlorvos, whereas LD50 dosing with diazinon caused death in three out of six chicks. Compared to control values, the insecticides reduced plasma and whole brain cholinesterase activities by 29 % to 84 % and 18 % to 77 %, respectively, depending on the dose. The decrease in plasma cholinesterase correlated well (r = 0.82) with that of the brain. These data suggest that organophosphate insecticides administered orally at LD50 doses induce clinical signs of cholinergic poisoning and concurrently reduce brain and plasma cholinesterase activities in chicks.Ispitano je akutno toksično djelovanje triju često rabljenih organofosfornih insekticida klorpirifosa, diazinona i diklorvosa u brojlera te je izmjerena aktivnost kolinesteraza u njihovoj plazmi i mozgu. Srednja letalna doza LD50 klorpirifosa iznosila je 10,79 mg kg-1, diazinona 6,32 mg kg-1 te diklorvosa 6,30 mg kg-1. Prvi su se znakovi kolinergičkoga sindroma u pilića javili unutar dva sata od oralne primjene, a obuhvaćali su slinjenje, suženje, teško disanje, učestalu defekaciju, obješena krila, drhtavicu, grčenje i nesposobnost stajanja uoči smrti. Oralna primjena polovice srednje letalne doze insekticida klorpirifosa (5 mg kg-1), diazinona (3 mg kg-1) i diklorvosa (3 mg kg-1) dovela je do nepokretnosti i obješenih krila, ali bez kliničkih znakova kolinergičke toksičnosti koji su uočeni kod pokusa radi utvrđivanja srednje letalne doze (LD50). Međutim, doze ovih insekticida koje su odgovarale LD50, dovele su do kliničkih znakova kolinergičke toksičnosti sličnih onima zamijećenim kod utvrđivanja LD50. Dva od šest pilića uginula su unutar dva sata od primjene bilo klorpirifosa bilo diklorvosa u dozama koje su odgovarale LD50, dok je diazinon u odgovarajućoj srednjoj letalnoj dozi uzrokovao smrt triju od šest pilića. U odnosu na kontrolne vrijednosti, insekticidi su doveli do smanjenja aktivnosti kolinesteraze koja je ovisila o dozi, a kretala se od 29 % do 84 % u plazmi te od 18 % do 77 % u mozgu. Pad aktivnosti kolinesteraze u plazmi dobro je korelirao s njezinim padom u mozgu (r=0,82). Ovi podaci upućuju na to da oralna primjena organofosfornih insekticida u dozama koje odgovaraju srednjoj letalnoj dozi dovode do znakova kolinergičkoga trovanja u pilića te do istodobnoga pada aktivnosti kolinesteraza u mozgu i plazmi

Polychlorinated Biphenyls and Biotransformation Enzymes in Three Species of Sea Turtles from the Baja California Peninsula of Mexico

Concentrations of polychlorinated biphenyls (PCBs) as well as the expression patterns of cytochrome P450 (CYP) enzymes and glutathione-S-transferase (GST) activities were measured in livers of loggerhead (Caretta caretta), green (Chelonia mydas), and olive ridley (Lepidocheyls olivacea) sea turtles from the Baja California peninsula of Mexico. The mean concentrations of total PCBs were 18.1, 10.5, and 15.2 ng/g wet weight (ww) respectively for the three species and PCB 153 was the dominant congener in all samples. Total PCB concentrations were dominated by penta- and hexa-chlorinated biphenyls. The mean estimated TEQs were 42.8, 22.9, and 10.4 pg/g (ww) for loggerhead, green, and olive ridley, respectively, and more than 70% was accounted for by non-ortho PCBs. Western blots revealed the presence of hepatic microsomal proteins that cross-reacted with anti-CYP2K1 and anti-CYP3A27 antibodies but not with anti-CYP1A antibody. There were no significant differences in GST activities between species. Grouping congeners based on structure–activity relationships for CYP isoenzymes suggested limited activity of CYP1A contribution to PCB biotransformation in sea turtles. These results suggest potential accumulation of PCBs that are CYP1A substrates and provide evidence for biotransformation capacity, which differs from known animal models, highlighting the need for further studies in reptiles, particularly those threatened with extinction

Transcriptional Changes during Naturally Acquired Zika Virus Infection Render Dendritic Cells Highly Conducive to Viral Replication

Summary: Although dendritic cells are among the human cell population best equipped for cell-intrinsic antiviral immune defense, they seem highly susceptible to infection with the Zika virus (ZIKV). Using highly purified myeloid dendritic cells isolated from individuals with naturally acquired acute infection, we here show that ZIKV induces profound perturbations of transcriptional signatures relative to healthy donors. Interestingly, we noted a remarkable downregulation of antiviral interferon-stimulated genes and innate immune sensors, suggesting that ZIKV can actively suppress interferon-dependent immune responses. In contrast, several host factors known to support ZIKV infection were strongly upregulated during natural ZIKV infection; these transcripts included AXL, the main entry receptor for ZIKV; SOCS3, a negative regulator of ISG expression; and IDO-1, a recognized inducer of regulatory T cell responses. Thus, during in vivo infection, ZIKV can transform the transcriptome of dendritic cells in favor of the virus to render these cells highly conducive to ZIKV infection. : Sun et al. find distinct transcriptional signatures in myeloid dendritic cells isolated from individuals with naturally acquired Zika Virus infection. These data indicate that Zika virus can reprogram dendritic cells to increase their susceptibility to further ZIKV infection. Keywords: Zika virus, flavivirus, interferon stimulated genes, dendritic cells, acute infection, RNA-seq, SOCS3, IDO-1, AX