Dissimilatory nitrate reduction to ammonium coupled to Fe(II) oxidation in sediments of a periodically hypoxic estuary

Estuarine sediments are critical for the remediation of large amounts of anthropogenic nitrogen (N) loading via production of N₂ from nitrate by denitrification. However, nitrate is also recycled within sediments by dissimilatory nitrate reduction to ammonium (DNRA). Understanding the factors that influence the balance between denitrification and DNRA is thus crucial to constraining coastal N budgets. A potentially important factor is the availability of different electron donors (organic carbon, reduced iron and sulfur). Both denitrification and DNRA may be linked to ferrous iron oxidation, however the contribution of Fe(II)-fueled nitrate reduction in natural environments is practically unknown. This study investigated how nitrate-dependent Fe²⁺ oxidation affects the partitioning between nitrate reduction pathways using ¹⁵N-tracing methods in sediments along the salinity gradient of the periodically hypoxic Yarra River estuary, Australia. Increased dissolved Fe²⁺ availability resulted in significant enhancement of DNRA rates from around 10–20% total nitrate reduction in control incubations to over 40% in those with additional Fe²⁺, at several sites. Increases in DNRA at some locations were accompanied by reductions in denitrification. Significant correlations were observed between Fe²⁺ oxidation and DNRA rates, with reaction ratios corresponding to the stoichiometry of Fe²⁺-dependent DNRA. Our results provide experimental evidence for a direct coupling of DNRA to Fe²⁺ oxidation across an estuarine gradient, suggesting that Fe²⁺ availability may exert substantial control on the balance between retention and removal of bioavailable N. Thus, DNRA linked to Fe²⁺ oxidation may be of general importance to environments with Fe-rich sediments

Effect of Intralipid infusion on peripheral blood T cells and plasma cytokines in women undergoing assisted reproduction treatment

Objectives: Intravenous infusion of Intralipid is an adjunct therapy in assisted reproduction treatment (ART) when immune-associated infertility is suspected. Here, we evaluated the effect of Intralipid infusion on regulatory T cells (Treg cells), effector T cells and plasma cytokines in peripheral blood of women undertaking IVF. Methods: This prospective, observational pilot study assessed Intralipid infusion in 14 women exhibiting recurrent implantation failure, a clinical sign of immune-associated infertility. Peripheral blood was collected immediately prior to and 7 days after intravenous administration of Intralipid. Plasma cytokines were measured by Luminex, and T-cell subsets were analysed by flow cytometry. Results: A small increase in conventional CD8+ T cells occurred after Intralipid infusion, but no change was seen in CD4+ Treg cells, or naïve, memory or effector memory T cells. Proliferation marker Ki67, transcription factors Tbet and RORγt, and markers of suppressive capacity CTLA4 and HLA-DR were unchanged. Dimensionality-reduction analysis using the tSNE algorithm confirmed no phenotype shift within Treg cells or other T cells. Intralipid infusion increased plasma CCL2, CCL3, CXCL8, GM-CSF, G-CSF, IL-6, IL-21, TNF and VEGF. Conclusion: Intralipid infusion elicited elevated pro-inflammatory cytokines, and a minor increase in CD8+ T cells, but no change in pro-tolerogenic Treg cells. Notwithstanding the limitation of no placebo control, the results do not support Intralipid as a candidate intervention to attenuate the Treg cell response in women undergoing ART. Future placebo-controlled studies are needed to confirm the potential efficacy and clinical significance of Intralipid in attenuating cytokine induction and circulating CD8+ T cells.Kerrie L Foyle, David J Sharkey, Lachlan M Moldenhauer, Ella S Green, Jasmine J Wilson, Cassandra J Roccisano ... et al

Effects of dual task on turning ability in stroke survivors and older adults

Background: Turning is an integral component of independent mobility in which stroke survivors frequently fall. Objective: This study sought to measure the effects of competing cognitive demands on the stepping patterns of stroke survivors, compared to healthy age-match adults, during turning as a putative mechanism for falls. Methods: Walking and turning (90º) was assessed under single (walking and turning alone) and dual task (subtracting serial 3s while walking and turning) conditions using an electronic, pressure-sensitive walkway. Dependent measures were time to turn, variability in time to turn, step length, step width and single support time during three steps of the turn. Turning ability in single and dual task conditions was compared between stroke survivors (n= 17, mean ± SD: 59 ± 113 months post-stroke, 64 ± 10 years of age) and age-matched healthy counterparts (n = 15). Results: Both groups took longer, were more variable, tended to widen the second step and, crucially, increased single support time on the inside leg of the turn while turning and distracted. Conclusions. Increased single support time during turning may represent biomechanical mechanism, within stepping patterns of turning under distraction, for increased risk of falls for both stroke survivors and older adults

Phenazine cations as anticancer theranostics

The biological properties of two water-soluble organic cations based on polypyridyl structures commonly used as ligands for photoactive transition metal complexes designed to interact with biomolecules are investigated. A cytotoxicity screen employing a small panel of cell lines reveals that both cations show cytotoxicity toward cancer cells but show reduced cytotoxicity to noncancerous HEK293 cells with the more extended system being notably more active. Although it is not a singlet oxygen sensitizer, the more active cation also displayed enhanced potency on irradiation with visible light, making it active at nanomolar concentrations. Using the intrinsic luminescence of the cations, their cellular uptake was investigated in more detail, revealing that the active compound is more readily internalized than its less lipophilic analogue. Colocalization studies with established cell probes reveal that the active cation predominantly localizes within lysosomes and that irradiation leads to the disruption of mitochondrial structure and function. Stimulated emission depletion (STED) nanoscopy and transmission electron microscopy (TEM) imaging reveal that treatment results in distinct lysosomal swelling and extensive cellular vacuolization. Further imaging-based studies confirm that treatment with the active cation induces lysosomal membrane permeabilization, which triggers lysosome-dependent cell-death due to both necrosis and caspase-dependent apoptosis. A preliminary toxicity screen in the Galleria melonella animal model was carried out on both cations and revealed no detectable toxicity up to concentrations of 80 mg/kg. Taken together, these studies indicate that this class of synthetically easy-to-access photoactive compounds offers potential as novel therapeutic leads

APOL1-Associated glomerular disease among African-American children: A collaboration of the chronic kidney disease in children (CKiD) and nephrotic syndrome study network (NEPTUNE) cohorts

Background: Individuals of African ancestry harboring two variant alleles within apolipoprotein L1 (APOL1) are classified with a high-risk (HR) genotype. Adults with an HR genotype have increased risk of focal segmental glomerulosclerosis and chronic kidney disease compared with those with a low-risk (LR) genotype (0 or 1 variants). The role of APOL1 risk genotypes in children with glomerular disease is less well known. Methods: This study characterized 104 African-American children with a glomerular disease by APOL1 genotype in two cohorts: The Chronic Kidney Disease in Children (CKiD) and Nephrotic Syndrome Study Network (NEPTUNE). Results: Among these subjects, 46% had an HR genotype with a similar age at cohort enrollment. For APOL1 HR children, the median age of disease onset was older (CKiD: 4.5 versus 11.5 years for LR versus HR; NEPTUNE: 11 versus 14 years for LR versus HR, respectively) and preterm birth was more common [CKiD: 27 versus 4%; NEPTUNE: 26 versus 12%; combined odds ratio 4.6 (95% confidence interval: 1.4, 15.5)].Within studies, HR children had lower initial estimated glomerular filtration rate (EGFR) (CKiD: 53 versus 69 mL/min/1.73 m2; NEPTUNE: 74 versus 94 mL/min/1.73 m2). Longitudinal EGFR decline was faster among HR children versus LR (CKiD: -18 versus -8% per year; NEPTUNE: -13 versus-3% per year). Conclusions: Children with an HR genotype in CKiD and NEPTUNE seem to have a more aggressive form of glomerular disease, in part due to a higher prevalence of focal segmental glomerulosclerosis. These consistent findings across independent cohorts suggest a common natural history for children with APOL1-Associated glomerular disease. Further study is needed to determine the generalizability of these findings

Palaeoenvironment of Eocene prodelta in Spitsbergen recorded by the trace fossil Phycosiphon incertum

Ichnological, sedimentological and geochemical analyses were conducted on the Eocene Frysjaodden Formation in order to interpret palaeoenvironment prodelta sediments in the Central Basin of Spitsbergen. Phycosiphon incertum is the exclusive ichnotaxon showing differences in size, distribution, abundance and density, and relation to laminated/bioturbated intervals. Large P. incertum mainly occur dispersed, isolated and randomly distributed throughout the weakly laminated/non-laminated intervals. Small P. incertum occur occasionally in patches of several burrows within laminated intervals or as densely packed burrows in thin horizons in laminated intervals or constituting fully bioturbated intervals that are several centimetres thick. Ichnological changes are mainly controlled by oxygenation, although the availability of benthic food cannot be discarded. Changes in oxygenation and rate of sedimentation can be correlated with the registered variations in the Bouma sequence of the distal turbiditic beds within prodeltal shelf sediments.Funding for this research was provided by Project CGL2012-33281 (Secretaría de Estado de Investigación, Desarrollo e Innovación, Spain), Project RYC-2009-04316 (Ramón y Cajal Programme) and Projects RNM-3715 and RNM-7408 and Research Group RNM-178 (Junta de Andalucía). The authors benefited from a bilateral agreement between the universities of Granada and Oslo, supported by the University of Granada

Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus

Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights

Allan Sandage and the Cosmic Expansion

This is an account of Allan Sandage's work on (1) The character of the expansion field. For many years he has been the strongest defender of an expanding Universe. He later explained the CMB dipole by a local velocity of 220 +/- 50 km/s toward the Virgo cluster and by a bulk motion of the Local supercluster (extending out to ~3500 km/s) of 450-500 km/s toward an apex at l=275, b=12. Allowing for these streaming velocities he found linear expansion to hold down to local scales (~300 km/s). (2) The calibration of the Hubble constant. Probing different methods he finally adopted - from Cepheid-calibrated SNe Ia and from independent RR Lyr-calibrated TRGBs - H_0 = 62.3 +/- 1.3 +/- 5.0 km/s/Mpc.Comment: 12 pages, 11 figures, 1 table, Submitted to Astrophysics and Space Science, Special Issue on the Fundamental Cosmic Distance Scale in the Gaia Er

Parental origin of sequence variants associated with complex diseases

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldEffects of susceptibility variants may depend on from which parent they are inherited. Although many associations between sequence variants and human traits have been discovered through genome-wide associations, the impact of parental origin has largely been ignored. Here we show that for 38,167 Icelanders genotyped using single nucleotide polymorphism (SNP) chips, the parental origin of most alleles can be determined. For this we used a combination of genealogy and long-range phasing. We then focused on SNPs that associate with diseases and are within 500 kilobases of known imprinted genes. Seven independent SNP associations were examined. Five-one with breast cancer, one with basal-cell carcinoma and three with type 2 diabetes-have parental-origin-specific associations. These variants are located in two genomic regions, 11p15 and 7q32, each harbouring a cluster of imprinted genes. Furthermore, we observed a novel association between the SNP rs2334499 at 11p15 and type 2 diabetes. Here the allele that confers risk when paternally inherited is protective when maternally transmitted. We identified a differentially methylated CTCF-binding site at 11p15 and demonstrated correlation of rs2334499 with decreased methylation of that site.info:eu-repo/grantAgreement/EC/FP7/21807