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Proceedings of the National Academy of... Sep 2019Dimethylsulfide (DMS), a gas produced by marine microbial food webs, promotes aerosol formation in pristine atmospheres, altering cloud radiative forcing and...
Dimethylsulfide (DMS), a gas produced by marine microbial food webs, promotes aerosol formation in pristine atmospheres, altering cloud radiative forcing and precipitation. Recent studies suggest that DMS controls aerosol formation in the summertime Arctic atmosphere and call for an assessment of pan-Arctic DMS emission (EDMS) in a context of dramatic ecosystem changes. Using a remote sensing algorithm, we show that summertime EDMS from ice-free waters increased at a mean rate of 13.3 ± 6.7 Gg S decade (∼33% decade) north of 70°N between 1998 and 2016. This trend, mostly explained by the reduction in sea-ice extent, is consistent with independent atmospheric measurements showing an increasing trend of methane sulfonic acid, a DMS oxidation product. Extrapolation to an ice-free Arctic summer could imply a 2.4-fold (±1.2) increase in EDMS compared to present emission. However, unexpected regime shifts in Arctic geo- and ecosystems could result in future EDMS departure from the predicted range. Superimposed on the positive trend, EDMS shows substantial interannual changes and nonmonotonic multiyear trends, reflecting the interplay between physical forcing, ice retreat patterns, and phytoplankton productivity. Our results provide key constraints to determine whether increasing marine sulfur emissions, and resulting aerosol-cloud interactions, will moderate or accelerate Arctic warming in the context of sea-ice retreat and increasing low-level cloud cover.
Topics: Aerosols; Arctic Regions; Atmosphere; Climate; Ecosystem; Ice Cover; Mesylates; Oceans and Seas; Phytoplankton; Seasons; Seawater; Sulfides
PubMed: 31501321
DOI: 10.1073/pnas.1904378116 -
Bone Marrow Transplantation Jul 2023Busulfan (Bu) combined with cyclophosphamide (Cy) is commonly used as a myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT)....
Busulfan (Bu) combined with cyclophosphamide (Cy) is commonly used as a myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT). There is inter-individual variability of Bu pharmacokinetics (PK) and hence in toxicity and efficacy. The introduction of therapeutic drug monitoring (TDM) of Bu has decreased toxicity of the regimen. Hepatic metabolism of Bu is mediated through Glutathione-S-Transferases (GSTs), mainly GSTA1. Patients with GSTA1*A variants are considered normal metabolizers and GSTA1*B corresponds to poor metabolism, defined by nucleotide changes at -52 or -69 locus in GSTA1 promoter region. The aim of the study was to explore the correlation between GSTA1 polymorphisms and Bu-PK in 60 adult patients receiving an allo-HCT in the BuCyBu clinical study (ClinicalTrials.gov I, ID NCT01779882) comparing the sequence BuCy to CyBu. DNA samples prior to conditioning were genotyped for candidate variants at -52 (rs3957356) and -69 (rs3957357) loci in the GSTA1 promoter. Thirty-three % of patients were GSTA1*A*A, 49% GSTA1*A*B and 18% GSTA1*B*B. In GSTA1*A*A patients, median Bu-AUC was 3.6 ± 0.7 mg*h/L, in GSTA1*A*B 4.5 ± 1.6 and in GSTA1*B*B 4.9 ± 1.4 (AUC 35% higher than GSTA1*A*A, p = 0.03), with a similar significant correlation with Bu-clearance (p = 0.04). The correlation between GSTA1 polymorphism and AUC remained significant in multivariate linear regression analysis. There was a trend for lower non-relapse mortality (NRM) in patients with low AUC. We could not demonstrate a correlation between GSTA1 polymorphisms and NRM, acute graft-versus-host disease (aGvHD) in this small cohort, but there is a trend of higher aGvHD incidence in GSTA1*B*B patients.
Topics: Adult; Humans; Busulfan; Pharmacogenetics; Hematopoietic Stem Cell Transplantation; Cyclophosphamide; Polymorphism, Genetic; Transplantation Conditioning; Graft vs Host Disease
PubMed: 37085674
DOI: 10.1038/s41409-023-01963-z -
Acta Crystallographica. Section E,... Jan 2023The title compound, 2,6-di-amino-5-[(2-cyclo-propyl-7,8-dimeth-oxy--1-benzo-pyran-5-yl)meth-yl]pyrimidin-1-ium methane-sulfonate, CHNO ·CHOS, is a salt made up from a...
The title compound, 2,6-di-amino-5-[(2-cyclo-propyl-7,8-dimeth-oxy--1-benzo-pyran-5-yl)meth-yl]pyrimidin-1-ium methane-sulfonate, CHNO ·CHOS, is a salt made up from a protonated iclaprim mol-ecule and a mesylate anion. The pyrimidine and chromene units of the iclaprim mol-ecule form an orthogonal arrangement [inter-planar angle of 89.67 (6)°], and the 3-nitro-gen position of the pyrimidine ring is protonated. Four distinct N-H⋯O inter-actions and an additional N-H⋯N hydrogen bond connect iclaprim and mesylate mol-ecules to one another, resulting in an infinite hydrogen-bonded mol-ecular tape structure. The central section of the tape is formed by a sequence of fused hydrogen-bonded rings involving four distinct ring types.
PubMed: 36628360
DOI: 10.1107/S2056989022011689 -
Genomics Sep 2022Ralstonia solanacearum severely damages the growth of tobacco (Nicotiana tabacum L.) and causes great economic losses in tobacco production. To investigate the root...
Ralstonia solanacearum severely damages the growth of tobacco (Nicotiana tabacum L.) and causes great economic losses in tobacco production. To investigate the root metabolism and transcriptional characteristics of tobacco bacterial wilt susceptible variety Cuibi-1 (CB-1) and resistant new line KCB-1 (derived from an ethyl methanesulfonate (EMS) mutant of CB-1) after infestation with R. solanacearum, root metabolism and transcriptional characteristics were investigated using RNA-Seq and liquid chromatography-mass spectrometry (LC-MS). Differences in resistance between KCB-1 and CB-1 were observed in several aspects: (1) The phenylpropanoid pathway was the main pathway of resistance to bacterial wilt in KCB-1 compared with CB-1. (2) KCB-1 had more differential metabolic markers of disease resistance than CB-1 after infection with R. solanacearum. Among them, the differential coumarin-like metabolites that affect quorum sensing (QS) and biofilm formation of R. solanacearum differ in KCB-1 and CB-1. (3) KCB-1 inhibited production of the R. solanacearum metabolite putrescine, and the level of putrescine in tobacco was positively correlated with susceptibility. (4) Compared with CB-1, the metabolites of KCB-1 had less differential nitrogen sources during the infestation of R. solanacearum, which was detrimental to the growth and reproduction of R. solanacearum. (5) Both indole-3-acetic acid (IAA) and abscisic acid (ABA) in CB-1 and KCB-1 were involved in the response to R. solanacearum infestation, but the levels of IAA and ABA in KCB-1 were greater than in CB-1 at 24 h post inoculation (hpi). In conclusion, R. solanacearum caused reprogramming of both root metabolism and transcription in KCB-1 and CB-1, and the transcriptional and metabolic characteristics of resistant tobacco were more unfavorable to R. solanacearum.
Topics: Abscisic Acid; Coumarins; Ethyl Methanesulfonate; Nitrogen; Plant Diseases; Putrescine; Nicotiana; Transcriptome
PubMed: 36055574
DOI: 10.1016/j.ygeno.2022.110471 -
Genes Feb 2022The identification of mutants through forward genetic screens is the backbone of genetics research, yet many mutants identified through these screens have yet to be...
The identification of mutants through forward genetic screens is the backbone of genetics research, yet many mutants identified through these screens have yet to be mapped to the genome. This is especially true of mutants that have been identified as mutagen-sensitive (), but have not yet been mapped to their associated molecular locus. Our study addressed the need for additional gene identification by determining the locus and exploring the function of the -linked mutagen-sensitive gene using three available mutant alleles: , , and . After first confirming that all three alleles were sensitive to methyl methanesulfonate (MMS) using complementation analysis, we used deletion mapping to narrow the candidate genes for Through DNA sequencing, we were able to determine that is the uncharacterized gene which encodes the ortholog of the highly conserved DNA2 protein that is important for DNA replication and repair. We further used the sequence and structure of DNA2 to predict the impact of the allele mutations on the final gene product. Together, these results provide a tool for researchers to further investigate the role of DNA2 in DNA repair processes in
Topics: Animals; DNA Repair; Drosophila; Drosophila melanogaster; Methyl Methanesulfonate; Mutagens
PubMed: 35205357
DOI: 10.3390/genes13020312 -
Pharmaceutical Biology Dec 2023di-(2-Ethylhexyl) phthalate (DEHP) has potential reproductive toxicity. Bu-Shen-Tian-Jing formulations (BSTJFs) are beneficial for female reproductive capacity. However,...
CONTEXT
di-(2-Ethylhexyl) phthalate (DEHP) has potential reproductive toxicity. Bu-Shen-Tian-Jing formulations (BSTJFs) are beneficial for female reproductive capacity. However, BSTJF2 has much lower cytotoxicity than BSTJF1.
OBJECTIVE
To investigate the effects of BSTJFs on ovarian granulosa cells exposed to DEHP and determine the potential molecular mechanisms.
METHODS AND MATERIALS
Human granulosa-like tumor cell line (KGN) cells were divided into control, DEHP, BSTJF1 and BSTJF2 groups. The DEHP group were given 1 μM DEHP for 24 h. They were then given BSTJF1 at 200 μg/mL or BSTJF2 at 100 μg/mL for 24 h. The control group was treated with the same concentration of DMSO (0.1%). Oxidative stress and mitochondrial function were measured. The mRNA and protein expression levels of HDAC3 and HSP90AA were determined. Integrative network pharmacology analysis of BSTJF2 was also performed.
RESULTS
DEHP (1 μM) significantly suppressed the proliferation of KGN cells by 17%, significantly increased ROS levels by 28% and MDA levels by 47%, significantly decreased MMP levels by 22% and mtDNA copy by 30%. DEHP significantly increased protein expression of HDAC3 by 21%and HSP90AA by 64%. All these changes were significantly reversed by BSTJFs. Integrative network pharmacology analysis revealed HSP90AA was a key target (degree = 8). Both RGFP966 and BSTJF2 significantly reversed the increased expression of HDAC3 and HSP90AA, attenuated oxidative stress, and mitochondrial damage which were induced by DEHP.
CONCLUSION
BSTJFs might have therapeutic potential on oxidative stress and mitochondrial damage through the HDAC3/HSP90AA pathway which encourages further clinical trials.
Topics: Humans; Female; Diethylhexyl Phthalate; Oxidative Stress; Granulosa Cells; Busulfan; Cell Line, Tumor
PubMed: 37655754
DOI: 10.1080/13880209.2023.2249193 -
Eye and Vision (London, England) Jun 2022It has been found that the extensive use of anticancer drugs containing DNA-alkylating agents not only target cancer cells but also cause retinal inflammation through...
BACKGROUND
It has been found that the extensive use of anticancer drugs containing DNA-alkylating agents not only target cancer cells but also cause retinal inflammation through toxic intermediates. Complement C3 (C3) is a core component of the complement activation pathway, and dysregulation of the complement pathway is involved in several retinal degenerative diseases. However, whether C3 plays a critical role in alkylation-induced retinal degeneration is unclear.
METHODS
Following treatment with the alkylating agent methyl methane sulfonate (MMS), the C3 mRNA and protein level was measured, DNA damage and photoreceptor cell death were assessed in both wild-type (WT) C57BL/6J and C3 knockout (KO) mice.
RESULTS
We determined that complement pathway is activated following MMS treatment, and C3 knockout (KO) increased the rate of photoreceptor cell survival and preserved visual function. The mRNA levels of nuclear erythroid-related factor 2 (Nrf2) and related genes were higher after MMS application in C3 KO mice.
CONCLUSION
In summary, our study found that C3 KO promotes photoreceptor cell survival and activates the Nrf2 signaling pathway in the context of alkylation-induced retinal degeneration.
PubMed: 35676725
DOI: 10.1186/s40662-022-00292-4 -
Blood Advances May 2020Reduced-intensity/reduced-toxicity conditioning and allogeneic T-cell replete hematopoietic stem cell transplantation are curative in patients with hemophagocytic...
Reduced-intensity/reduced-toxicity conditioning and allogeneic T-cell replete hematopoietic stem cell transplantation are curative in patients with hemophagocytic lymphohistiocytosis (HLH). Unstable donor chimerism (DC) and relapses are clinical challenges . We examined the effect of a reduced-intensity conditioning regimen based on targeted busulfan to enhance myeloid DC in HLH. The European Society for Bone and Marrow Transplantation-approved reduced-intensity conditioning protocol comprised targeted submyeloablative IV busulfan, IV fludarabine, and serotherapy comprising IV alemtuzumab (0.5-0.8 mg/kg) for unrelated-donor and IV rabbit anti-T-cell globulin for related-donor transplants. We assessed toxicity, engraftment, graft-versus-host disease (GHVD), DC in blood cell subtypes, and overall survival/event-free survival. Twenty-five patients from 7 centers were treated (median age, 0.68 year). The median total dose and cumulative area under the curve of busulfan was 13.1 mg/kg (6.4-26.4) and 63.1 mg/L × h (48-77), respectively. Bone marrow, peripheral blood stem cell, or cord blood transplants from HLA-matched related (n = 7) or unrelated (n = 18) donors were administered. Donor cells engrafted in all patients (median: neutrophils d+20/platelets d+28). At last follow-up (median, 36 months; range, 8-111 months), the median DC of CD15+ neutrophils, CD3+ T cells, and CD16+56+ natural killer cells was 99.5% (10-100), 97% (30-100), and 97.5% (30-100), respectively. Eight patients (32%) developed sinusoidal obstruction syndrome, resolving after defibrotide treatment. The 3-year overall survival and event-free survival rates were both 100%. None of the patients developed acute grade III to IV GHVD. Limited chronic GVHD was encountered in 4%. This regimen achieves excellent results with stable DC in patients with HLH.
Topics: Animals; Busulfan; Hematopoietic Stem Cell Transplantation; Humans; Lymphohistiocytosis, Hemophagocytic; Neoplasm Recurrence, Local; Rabbits; Transplantation Conditioning
PubMed: 32384542
DOI: 10.1182/bloodadvances.2020001748 -
Frontiers in Plant Science 2022Unique variants are desired in the development of genetically improved crops to meet farmer and market needs hence ethyl methane sulfonate (EMS) was used to induce...
Unique variants are desired in the development of genetically improved crops to meet farmer and market needs hence ethyl methane sulfonate (EMS) was used to induce genetic variability in cowpea ( cv. ). The main objective of this research was to characterize induced variations in EMS chemically mutagenized population of cowpea ( L. Walp Var. Asontem) in the M and M generations. The optimum concentration (LD50) of EMS for generating the mutagenized population was determined by treating seeds with different concentrations of EMS (0.0, 0.2, 0.4, 0.6, and 0.8% v/v) and observing the germination count after 5 days of planting the seeds in Petri dishes. Three thousand cowpea seeds were treated with the 0.4% EMS to generate the M and M populations that were evaluated for agronomic and morphological traits with untreated seeds serving as control. Data analysis involved distribution of qualitative and quantitative traits. Germination was significantly reduced in the mutagenized population (17.8%) and compared with that of the wild type (61.6%). Percentage survival was significantly higher in wild type (98.38%) as compared with the M population (78.46%). Percentage germination in the M population (74.03%) was lower than the wild type (80%). A wide spectrum of agro-morphological abnormalities was observed in the M population. Wide variations and uniquely different phenotypic classes were observed in leaf color, leaf shape, growth habit, plant pigmentation, twining tendency, pod curvature, seed shape, and seed coat color. M individuals were widely distributed for days to flowering, number of pods per plant, number of seeds per pod, number of locules per pods, percentage seed set, pod length and number of seeds per plant. In conclusion, the EMS mutagenesis was effective in inducing the unique variations that will be useful for breeding and development of new farmer preferred varieties.
PubMed: 36003816
DOI: 10.3389/fpls.2022.952247 -
Transplantation and Cellular Therapy Apr 2022The use of haploidentical related donors (HRDs) is a common alternative donor strategy used when matched sibling or unrelated donors are not available for hematopoietic...
Post-Transplantation Cyclophosphamide-Based Haploidentical versus Matched Unrelated Donor Peripheral Blood Hematopoietic Stem Cell Transplantation Using Myeloablative Targeted Busulfan-Based Conditioning for Pediatric Acute Leukemia.
The use of haploidentical related donors (HRDs) is a common alternative donor strategy used when matched sibling or unrelated donors are not available for hematopoietic stem cell transplantation (HSCT). However, there have been no studies comparing HRD HSCT with post-transplantation cyclophosphamide (PTCy) and matched unrelated donor (MUD) HSCT with antithymocyte globulin using similar busulfan-based myeloablative conditioning regimens in pediatric acute leukemia. Here we compared the outcomes in children and adolescents with high-risk acute leukemia who underwent HRD HSCT with PTCy (n = 35) or MUD HSCT (n = 45) after targeted busulfan-based myeloablative conditioning using intensive pharmacokinetic monitoring. The median duration of follow-up was 3.7 years in the HRD group and 4.6 years in the MUD group. No engraftment failure was observed in either group. There were no significant between-group differences in the cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) (34.3% versus 48.9%; P = .142), grade III-IV acute GVHD (2.9% versus 8.9%; P = .272), moderate to severe chronic GVHD (11.4% versus 18.3%; P = .417), relapse (25.6% versus 28.0%; P = .832), and nonrelapse mortality (0% versus 2.2%; P = .420). The 3-year severe chronic GVHD-free/relapse-free survival (GRFS), leukemia-free survival (LFS), and overall survival (OS) rates in the HRD and MUD groups were 62.9% (95% confidence interval [CI], 45.8% to 80.0%) versus 49.8% (95% CI, 34.9% to 64.7%; P = .318), 74.4% (95% CI, 58.7% to 90.1%) versus 67.5% (95% CI, 53.4% to 81.6%; P = .585), and 88.6% (95% CI, 78.0% to 99.2%) versus 83.7% (95% CI, 72.5% to 94.9%; P = .968), respectively. In a subgroup analysis of patients with acute lymphoblastic leukemia (HRD, n = 17; MUD, n = 26), the 3-year GRFS, LFS, and OS rates in the HRD and MUD groups were 49.4% (95% CI, 24.3% to 74.5%) versus 39.5% (95% CI, 19.7% to 59.3%; P = .601), 61.8% (95% CI, 37.5% to 86.1%) versus 63.6% (95% CI, 44.4% to 82.8%; P = .872), and 82.4% (95% CI, 64.4%, 100%) versus 84.2% (95% CI, 70.1% to 98.3%; P = .445), respectively. In patients with acute myelogenous leukemia (AML) (HRD, n = 16; MUD, n = 16), the 3-year GRFS, LFS, and OS rates in the HRD and MUD groups were 80.8% (95% CI, 61.2% to 100%) versus 61.9% (95% CI, 37.8% to 86.0%; P = .326), 87.1% (95% CI, 70.2% to 100%) versus 73.9% (95% CI, 51.8% to 96.0%; P = .478), and 93.8% (95% CI, 81.8% to 100%) versus 85.6% (95% CI, 67.0% to 100%; P = .628), respectively. Although the difference was not statistically significant and the number of patients was small, the promising outcomes of HRD HSCT in AML patients were encouraging. Our results demonstrate that HRD HSCT with PTCy using a targeted busulfan-based myeloablative conditioning regimen has outcomes similar to those of MUD HSCT with antithymocyte globulin. HRD HSCT with PTCy could be a feasible option for pediatric high-risk acute leukemia patients who lack an HLA-matched related or unrelated donor.
Topics: Adolescent; Busulfan; Child; Cyclophosphamide; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Retrospective Studies; Unrelated Donors
PubMed: 35021131
DOI: 10.1016/j.jtct.2022.01.002