Reduction of the ATPase inhibitory factor 1 (IF1) leads to visual impairment in vertebrates

In vertebrates, mitochondria are tightly preserved energy producing organelles, which sustain nervous system development and function. The understanding of proteins that regulate their homoeostasis in complex animals is therefore critical and doing so via means of systemic analysis pivotal to inform pathophysiological conditions associated with mitochondrial deficiency. With the goal to decipher the role of the ATPase inhibitory factor 1 (IF1) in brain development, we employed the zebrafish as elected model reporting that the Atpif1a−/− zebrafish mutant, pinotage (pnttq209), which lacks one of the two IF1 paralogous, exhibits visual impairment alongside increased apoptotic bodies and neuroinflammation in both brain and retina. This associates with increased processing of the dynamin-like GTPase optic atrophy 1 (OPA1), whose ablation is a direct cause of inherited optic atrophy. Defects in vision associated with the processing of OPA1 are specular in Atpif1−/− mice thus confirming a regulatory axis, which interlinks IF1 and OPA1 in the definition of mitochondrial fitness and specialised brain functions. This study unveils a functional relay between IF1 and OPA1 in central nervous system besides representing an example of how the zebrafish model could be harnessed to infer the activity of mitochondrial proteins during development

Efecto de dosis elevadas de florfenicol sobre algunos parámetros hematológicos en cabras adultas

The objective of this study was to evaluate the effect of high doses of florfenicol on selectedhematological parameters in adult goats. Six adult Saanen goats were treated intramuscularly with threedoses of florfenicol of 40 mg kg-1, administered at 24-hours intervals. Blood samples with anticoagulantwere collected on day 0 and on days 3, 4, 5, 6, 7, 10 and 12 after treatment initiation. The samples wereanalyzed to determine erythrocytes count, hematocrit, hemoglobin, leukocytes count, neutrophils,lymphocytes, monocytes, and platelets. High doses of florfenicol significantly affect total white blood cellcounts, particularly increasing neutrophils and monocytes. However, these findings contrast with previousstudies reporting negative effects of the same dosage on erythrocyte and leukocyte values in adult goats. Theresults of this study may provide useful information for veterinarians monitoring hematological changes inadult goats undergoing florfenicol treatment.El objetivo del presente estudio fue evaluar el efecto de dosis elevadas de florfenicol sobre algunos parámetros hematológicos en cabras adultas. Seis cabras adultas de raza Saanen fueron tratadas por vía intramuscular con tres dosis de florfenicol de 40 mg kg-1 administradas con intervalos de 24 horas. Se obtuvieron muestras de sangre con anticoagulante al día 0 y a los 3, 4, 5, 6, 7, 10 y 12 días luego de iniciado el tratamiento. Las muestras de sangre fueron analizadas y se determinaron los valores de los siguientes parámetros hematológicos: eritrocitos, hematocrito, hemoglobina, leucocitos, neutrófilos, linfocitos, monocitos y plaquetas. Las dosis elevadas de florfenicol en caprinos adultos afectaron significativamente el conteo total de leucocitos y en particular de neutrófilos y monocitos, incrementando sus valores. Sin embargo, estos resultados son opuestos a los reportados por otros autores quienes hallaron que la misma posología de florfenicol en caprinos adultos afectó negativamente los valores de los eritrocitos y la serie leucocitaria. Los resultados de este estudio pueden ser útiles para los médicos veterinarios al momento de evaluar la evolución de los índices hematológicos en caprinos adultos durante una terapéutica realizada con florfenicol

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined (T1D+T2D) GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 diabetic subjects (and 18,582 DKD cases). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, p=4.5×10-8) associated with 'microalbuminuria' in European T2D cases. However, no replication of this signal was observed in Asian subjects with T2D, or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously-reported DKD signals, except for those at UMOD and PRKAG2, both associated with 'EGFR'. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk-variant discovery for DKD.</p

A rise in NAD precursor nicotinamide mononucleotide (NMN) after injury promotes axon degeneration.

NAD metabolism regulates diverse biological processes, including ageing, circadian rhythm and axon survival. Axons depend on the activity of the central enzyme in NAD biosynthesis, nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2), for their maintenance and degenerate rapidly when this activity is lost. However, whether axon survival is regulated by the supply of NAD or by another action of this enzyme remains unclear. Here we show that the nucleotide precursor of NAD, nicotinamide mononucleotide (NMN), accumulates after nerve injury and promotes axon degeneration. Inhibitors of NMN-synthesising enzyme NAMPT confer robust morphological and functional protection of injured axons and synapses despite lowering NAD. Exogenous NMN abolishes this protection, suggesting that NMN accumulation within axons after NMNAT2 degradation could promote degeneration. Ectopic expression of NMN deamidase, a bacterial NMN-scavenging enzyme, prolongs survival of injured axons, providing genetic evidence to support such a mechanism. NMN rises prior to degeneration and both the NAMPT inhibitor FK866 and the axon protective protein Wld(S) prevent this rise. These data indicate that the mechanism by which NMNAT and the related Wld(S) protein promote axon survival is by limiting NMN accumulation. They indicate a novel physiological function for NMN in mammals and reveal an unexpected link between new strategies for cancer chemotherapy and the treatment of axonopathies

New application of density fractionation: assessing trace element/soil matrix associations within organic waste-amended agricultural soils

International audienceinc (Zn) is a trace element (TE) that occurs naturally in soils, however spreading Zn-rich organic waste (OW) on farmlands may lead to hazardous Zn levels. Common problems arerelated to phytotoxicity, introduction into the food chain and groundwater contamination. Assessing the associations between OW-borne Zn and the soil matrix is paramount to predict its short- and long-term behavior in the environment. This is usually pursued by using either single/sequential extractions (SSE) or spectroscopic methods such as XAS. Nevertheless, SSE reflects element extractability rather than the nature of its interactions with bearing phases, while XAS requires synchrotron radiation sources that are not available in certain regions of the world. We applied a third approach in this study – namely soil density fractionation – to isolate and characterize the constituents of the soil matrix (i.e. potential Zn bearing phases) and thereafter identify their associations with natural and OW-borne Zn. The target density fractionswere the following: 2.7 g cm-3, plus an extractable fraction. The soil analyzed was a clayey Hapludox soil that received controlled pig slurry applications over 11 years, causing a 2-fold increase in Zn concentration within the surface layer: from 105.8 mg kg-1 of Zn (control soil) to 206.6 mg kg-1 of Zn (amended soil). Among the six selected density fractions, two of them were the most contrasting and representative. (I) The light fraction (<1.9 g cm-3) contained high OM concentration but accounted for only ~5% of the bulk soil mass. (II) The mineral-rich fraction (2.5–2.7 g cm-3) contained mainly quartz, kaolinite, vermiculite, a small amount of hematite and accounted for ~80% of the soil mass. In the control soil (no pig slurry application), 79.7% of the Zn was found in the mineral-rich 2.5–2.7 g cm-3 fraction. In the soil amended with pig slurry, the proportion of Zn found in the 2.5–2.7 g cm-3 fraction decreased to 57.3%, as Zn was also found in the OMrich <1.9 g cm-3 fraction (13.2%) and in the extractable fraction (16.6%). Other fractions were less representative in both soils (control and amended). The extractable, <1.9 g cm-3 and 2.5– 2.7 g cm-3 fractions accounted for roughly 1/3 each of the OW-borne Zn fate in the amended soil. Finally, these results were compared with data we previously reported for the same field experiment using well-stablished SSE and XAS techniques. Density fractionation not onlyagreed but also complemented the understanding of previous observations. This work demonstrates that density fractionation may be used as either main or complementary approach for assessing the biogeochemistry of TE such as Zn in the context of OW recycling in agricultural soils