Role of organic matter chemistry in iron redox transformations, sorption to iron oxides, and wetland carbon storage, The

2018 Summer.Includes bibliographical references.Organic carbon comprises a versatile and complex class of compounds that influence water quality, soil health, fate and transport of environmental contaminants, biogeochemical cycles, and climate change. Key to predicting the responses of these systems and processes to environmental change is a molecular-level understanding of how organic carbon reacts with other components of soil and water. Yet due to its complexity and that of the systems in which it is found, organic carbon dynamics remain poorly understood. In both terrestrial and aquatic environments, the reactivity and biological necessity of iron and carbon link the biogeochemical cycling of these elements. Complexation of iron by dissolved organic carbon molecules alters its solubility and oxidation-reduction behavior and may explain the persistence of reduced iron (Fe(II)) in oxic aquatic environments. By examining the coordination environment of Fe(II) complexed by dissolved organic matter (DOM) and evaluating the effects of complexation on Fe(II) oxidation, I determined that the majority of Fe(II)–DOM complexes were characterized by coordination with citrate-like ligands, which were unlikely to inhibit oxidation by molecular oxygen. Nonetheless, association with reduced organic matter could extend the lifetime of Fe(II) in oxic environments by several hours. In soils and sediments, iron minerals act as effective sorbents of organic matter, preserving substantial amounts of carbon from microbial decomposition. These interactions have increasingly been recognized as important components of carbon sequestration, yet the effects of temperature on sorption behavior remain unknown. Through several batch and continuous flow experiments, I demonstrated a positive relationship between temperature and sorption of DOM on iron oxide surfaces. The temperature sensitivity of sorption behavior varied among riverine, peat, and soil DOM types, with riverine natural organic matter sorbing and desorbing the most at all temperatures. Analyses of effluents also revealed preferential sorption of aromatic compounds during the initial stages of sorption. In soils, organic matter quantity and composition are determined primarily by the balance between plant productivity and microbial decomposition, which are in turn dependent upon climate, temperature, hydrology, nutrient availability, and soil composition. Wetlands store disproportionately large amounts of carbon, yet the processes controlling storage are poorly understood. I investigated how different environments created by the hydrology and geomorphic setting of two wetland types, depressional and slope, impacted soil organic carbon storage and composition. Results showed a prevalence of aliphatic structures in depressional wetlands, especially in deeper soils, suggestive of anaerobic decomposition processes. By comparison, carbon in slope wetlands was dominated by labile plant carbohydrates in surface soils and aromatic compounds at depth, a likely indication of less anaerobic conditions. These results demonstrate divergent pathways of organic matter processing in different hydrogeomorphic environments. In total, this work contributes to more mechanistic understandings of important carbon dynamics that influence carbon and iron cycling, climate change, and environmental health

The Vehicle, 1961, Vol. 3 no. 2

Vol. 3, No. 2 Table of Contents The Voting CattleLinda Kay Campbellpage 5 But For the Passage of TimeDon Shepardsonpage 14 LoveJon Woodspage 16 Infinite JourneyJames E. Martinpage 19 The Clover ChainRichard W. Blairpage 20 SnowballSusan Daughertypage 24 Sureness Is NeverDon Shepardsonpage 26 ConceptionChristine McCollpage 34 Comedy: Relief and GriefTom McPeakpage 35 The Unspoken WordChristine McCollpage 35 CharmBenjamin Polkpage 36 Screaming SpiderTom McPeakpage 39 Just Once in an Early SpringE.J.B.page 39 HummingbirdPauline B. Smithpage 40 Willow TreesPauline B. Smithpage 40 MaturityChristine McCollpage 41 The New YearLinda Campbellpage 41 The StormMary-Jean Pitratpage 42 Ebony IvoryJean Danenbargerpage 42 The Fireball MailAllen Engelbrightpage 43 ExpectationChristine McCollpage 44 CatastropheChristine McCollpage 44 SophisticationBenjamin Polkpage 45 On Playing BridgeMyrna Jo Handleypage 46 SonnetMignon Stricklandpage 48https://thekeep.eiu.edu/vehicle/1009/thumbnail.jp

The Vehicle, 1961, Vol. 3 no. 2

Vol. 3, No. 2 Table of Contents The Voting CattleLinda Kay Campbellpage 5 But For the Passage of TimeDon Shepardsonpage 14 LoveJon Woodspage 16 Infinite JourneyJames E. Martinpage 19 The Clover ChainRichard W. Blairpage 20 SnowballSusan Daughertypage 24 Sureness Is NeverDon Shepardsonpage 26 ConceptionChristine McCollpage 34 Comedy: Relief and GriefTom McPeakpage 35 The Unspoken WordChristine McCollpage 35 CharmBenjamin Polkpage 36 Screaming SpiderTom McPeakpage 39 Just Once in an Early SpringE.J.B.page 39 HummingbirdPauline B. Smithpage 40 Willow TreesPauline B. Smithpage 40 MaturityChristine McCollpage 41 The New YearLinda Campbellpage 41 The StormMary-Jean Pitratpage 42 Ebony IvoryJean Danenbargerpage 42 The Fireball MailAllen Engelbrightpage 43 ExpectationChristine McCollpage 44 CatastropheChristine McCollpage 44 SophisticationBenjamin Polkpage 45 On Playing BridgeMyrna Jo Handleypage 46 SonnetMignon Stricklandpage 48https://thekeep.eiu.edu/vehicle/1009/thumbnail.jp

Impaired Vascular Contractility and Aortic Wall Degeneration in Fibulin-4 Deficient Mice: Effect of Angiotensin II Type 1 (AT1) Receptor Blockade

Medial degeneration is a key feature of aneurysm disease and aortic dissection. In a murine aneurysm model we investigated the structural and functional characteristics of aortic wall degeneration in adult fibulin-4 deficient mice and the potential therapeutic role of the angiotensin (Ang) II type 1 (AT1) receptor antagonist losartan in preventing aortic media degeneration. Adult mice with 2-fold (heterozygous Fibulin-4+/R) and 4-fold (homozygous Fibulin-4R/R) reduced expression of fibulin-4 displayed the histological features of cystic media degeneration as found in patients with aneurysm or dissection, including elastin fiber fragmentation, loss of smooth muscle cells, and deposition of ground substance in the extracellular matrix of the aortic media. The aortic contractile capacity, determined by isometric force measurements, was diminished, and was associated with dysregulation of contractile genes as shown by aortic transcriptome analysis. These structural and functional alterations were accompanied by upregulation of TGF-β signaling in aortas from fibulin-4 deficient mice, as identified by genome-scaled network analysis as well as by immunohistochemical staining for phosphorylated Smad2, an intracellular mediator of TGF-β. Tissue levels of Ang II, a regulator of TGF-β signaling, were increased. Prenatal treatment with the AT1 receptor antagonist losartan, which blunts TGF-β signaling, prevented elastic fiber fragmentation in the aortic media of newborn Fibulin-4R/R mice. Postnatal losartan treatment reduced haemodynamic stress and improved lifespan of homozygous knockdown fibulin-4 animals, but did not affect aortic vessel wall structure. In conclusion, the AT1 receptor blocker losartan can prevent aortic media degeneration in a non-Marfan syndrome aneurysm mouse model. In established aortic aneurysms, losartan does not affect aortic architecture, but does improve survival. These findings may extend the potential therapeutic application of inhibitors of the renin-angiotensin system to the preventive treatment of aneurysm disease

Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in $\textit{CHM}$ in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.This work was supported by The National Institute for Health Research England (NIHR) for the NIHR BioResource – Rare Diseases project (grant number RG65966). The Moorfields Eye Hospital cohort of patients and clinical and imaging data were ascertained and collected with the support of grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital, National Health Service Foundation Trust, and UCL Institute of Ophthalmology, Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, the Foundation Fighting Blindness (USA), and Retinitis Pigmentosa Fighting Blindness. M.M. is a recipient of an FFB Career Development Award. E.M. is supported by UCLH/UCL NIHR Biomedical Research Centre. F.L.R. and D.G. are supported by Cambridge NIHR Biomedical Research Centre

Spectrum of mutational signatures in T-cell lymphoma reveals a key role for UV radiation in cutaneous T-cell lymphoma

Funder: Galderma; doi: http://dx.doi.org/10.13039/501100009754Funder: NIHR-BRC Cambridge core grantFunder: National Institute for Health Research; doi: http://dx.doi.org/10.13039/501100000272Funder: NHS EnglandAbstract: T-cell non-Hodgkin’s lymphomas develop following transformation of tissue resident T-cells. We performed a meta-analysis of whole exome sequencing data from 403 patients with eight subtypes of T-cell non-Hodgkin’s lymphoma to identify mutational signatures and associated recurrent gene mutations. Signature 1, indicative of age-related deamination, was prevalent across all T-cell lymphomas, reflecting the derivation of these malignancies from memory T-cells. Adult T-cell leukemia-lymphoma was specifically associated with signature 17, which was found to correlate with the IRF4 K59R mutation that is exclusive to Adult T-cell leukemia-lymphoma. Signature 7, implicating UV exposure was uniquely identified in cutaneous T-cell lymphoma (CTCL), contributing 52% of the mutational burden in mycosis fungoides and 23% in Sezary syndrome. Importantly this UV signature was observed in CD4 + T-cells isolated from the blood of Sezary syndrome patients suggesting extensive re-circulation of these T-cells through skin and blood. Analysis of non-Hodgkin’s T-cell lymphoma cases submitted to the national 100,000 WGS project confirmed that signature 7 was only identified in CTCL strongly implicating UV radiation in the pathogenesis of cutaneous T-cell lymphoma

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Complexation and Redox Buffering of Iron(II) by Dissolved Organic Matter

Iron (Fe) bioavailability depends upon its solubility and oxidation state, which are strongly influenced by complexation with natural organic matter (NOM). Despite observations of Fe­(II)–NOM associations under conditions favorable for Fe oxidation, the molecular mechanisms by which NOM influences Fe­(II) oxidation remain poorly understood. In this study, we used X-ray absorption spectroscopy to determine the coordination environment of Fe­(II) associated with NOM (as-received and chemically reduced) at pH 7, and investigated the effect of NOM complexation on Fe­(II) redox stability. Linear combination fitting of extended X-ray absorption fine structure (EXAFS) data using reference organic ligands demonstrated that Fe­(II) was complexed primarily by carboxyl functional groups in reduced NOM. Functional groups more likely to preserve Fe­(II) represent much smaller fractions of NOM-bound Fe­(II). Fe­(II) added to anoxic solutions of as-received NOM oxidized to Fe­(III) and remained organically complexed. Iron oxidation experiments revealed that the presence of reduced NOM limited Fe­(II) oxidation, with over 50% of initial Fe­(II) remaining after 4 h. These results suggest reduced NOM may preserve Fe­(II) by functioning both as redox buffer and complexant, which may help explain the presence of Fe­(II) in oxic circumneutral waters