Adult nephron-specific MR-deficient mice develop a severe renal PHA-1 phenotype

Aldosterone is the main mineralocorticoid hormone controlling sodium balance, fluid homeostasis, and blood pressure by regulating sodium reabsorption in the aldosterone-sensitive distal nephron (ASDN). Germline loss-of-function mutations of the mineralocorticoid receptor (MR) in humans and in mice lead to the "renal" form of type 1 pseudohypoaldosteronism (PHA-1), a case of aldosterone resistance characterized by salt wasting, dehydration, failure to thrive, hyperkalemia, and metabolic acidosis. To investigate the importance of MR in adult epithelial cells, we generated nephron-specific MR knockout mice (MR$^{Pax8/LC1}$) using a doxycycline-inducible system. Under standard diet, MR$^{Pax8/LC1}$ mice exhibit inability to gain weight and significant weight loss compared to control mice. Interestingly, despite failure to thrive, MR$^{Pax8/LC1}$ mice survive but develop a severe PHA-1 phenotype with higher urinary Na^+ levels, decreased plasma Na(+), hyperkalemia, and higher levels of plasma aldosterone. This phenotype further worsens and becomes lethal under a sodium-deficient diet. Na^+/Cl^- co-transporter (NCC) protein expression and its phosphorylated form are downregulated in the MR$^{Pax8/LC1}$ knockouts, as well as the αENaC protein expression level, whereas the expression of glucocorticoid receptor (GR) is increased. A diet rich in Na^+ and low in K^+ does not restore plasma aldosterone to control levels but is sufficient to restore body weight, plasma, and urinary electrolytes. In conclusion, MR deletion along the nephron fully recapitulates the features of severe human PHA-1. ENaC protein expression is dependent on MR activity. Suppression of NCC under hyperkalemia predominates in a hypovolemic state

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Commissural neurons transgress the cns/pns boundary in absence of ventricular zone-derived netrin 1

During the development of the central nervous system (CNS), only motor axons project into peripheral nerves. Little is known about the cellular and molecular mechanisms that control the development of a boundary at the CNS surface and prevent CNS neuron emigration from the neural tube. It has previously been shown that a subset of spinal cord commissural axons abnormally invades sensory nerves in Ntn1 hypomorphic embryos and Dcc knockouts. However, whether netrin 1 also plays a similar role in the brain is unknown. In the hindbrain, precerebellar neurons migrate tangentially under the pial surface, and their ventral migration is guided by netrin 1. Here, we show that pontine neurons and inferior olivary neurons, two types of precerebellar neurons, are not confined to the CNS in Ntn1 and Dcc mutant mice, but that they invade the trigeminal, auditory and vagus nerves. Using a Ntn1 conditional knockout, we show that netrin 1, which is released at the pial surface by ventricular zone progenitors is responsible for the CNS confinement of precerebellar neurons. We propose, that netrin 1 distribution sculpts the CNS boundary by keeping CNS neurons in netrin 1-rich domains.This work was supported by grants from the Agence Nationale de la Recherche (ANR-14-CE13-0004-01) (to A.C.). It was performed in the frame of the Labex Lifesenses (ANR-10-LABX-65) supported by French state funds managed by the Agence Nationale de la Recherche within the Investissements d'Avenir programme under ANR-11-IDEX-0004-02 (to A.C.).Peer reviewe

Influence of grazing on triclosan toxicity to stream periphyton

Interactions between emerging contaminants and other drivers of community structure and function are poorly known. We used laboratory microcosms to investigate the single and combined effects of grazing and triclosan toxicity on the structure and function of stream periphyton. Grazing alone strongly reduced algal biomass, but also reduced oxidative stress and increased periphyton productivity and phosphorus (P) uptake capacity. This suggests that grazed algal communities can compensate for reduced biomass by enhanced growth after being released from grazing. Triclosan exposure (11.6 ± 1.1 μg L−1) reduced the detoxification capacity and P-uptake capacity of periphyton and altered diatom taxonomic composition. This indicates that triclosan at environmentally relevant concentrations affects the capacity of periphyton to remove dissolved nutrients and to cope with toxicant mixtures commonly occurring in streams. Triclosan exposure and grazing pressure had negative synergistic effects on algal size-class distribution and diatom mortality, since the effects of triclosan were higher than expected when periphyton was subject to grazing. Periphyton exposed to toxic substances such as triclosan had a lower capacity to cope with grazing than unexposed communities, because toxicity can limit algal regrowth after release from grazing and promote the loss of less abundant species. This synergism may have important implications because grazing pressure will magnify the negative effects of toxicants on community structure and ecosystem functions such as primary production and nutrient cycling.SCOPUS: cp.jinfo:eu-repo/semantics/publishe

Fluvial biofilms: a pertinent tool to assess β-blockers toxicity

Among increasingly used pharmaceutical products, β-blockers have been commonly reported at low concentrations in rivers and littoral waters of Europe and North America. Little is known about the toxicity of these chemicals in freshwater ecosystems while their presence may lead to chronic pollution. Hence, in this study the acute toxicity of 3 β-blockers: metoprolol, propranolol and atenolol on fluvial biofilms was assessed by using several biomarkers. Some were indicative of potential alterations in biofilm algae (photosynthetic efficiency), and others in biofilm bacteria (peptidase activity, bacterial mortality). Propranolol was the most toxic β-blocker, mostly affecting the algal photosynthetic process. The exposure to 531 μg/L of propranolol caused 85% of inhibition of photosynthesis after 24 h. Metoprolol was particularly toxic for bacteria. Though estimated No-Effect Concentrations (NEC) were similar to environmental concentrations, higher concentrations of the toxic (503 μg/L metoprolol) caused an increase of 50% in bacterial mortality. Atenolol was the least toxic of the three tested β-blockers. Effects superior to 50% were only observed at very high concentration (707 mg/L). Higher toxicity of metoprolol and propranolol might be due to better absorption within biofilms of these two chemicals. Since β-blockers are mainly found in mixtures in rivers, their differential toxicity could have potential relevant consequences on the interactions between algae and bacteria within river biofilm

Mutual recognition of parental and F1 lymphocytes. Selective abrogation of eytotoxic potential of FI lymphoeytes by parental lymphocytes.J. Exp. Med

The injection of F1 hybrid animals with parental spleen or lymph node cells leads to the activation of specific parental lymphocytes which recognize major histocompatibility complex (MHC) 1-coded antigens of the other parental haplotype expressed by the F1 host (1). Such recognition can result in graft-vs.-host (GVH) reactions which are frequently associated with depressed in vivo cell-mediated immune functions, such as resistance to bacterial infection (2), skin graft rejection (2, 3), T-helper cell dysfunction (4), as well as antibody responses to thymic-dependent and-independent antigens (5-8). The depression of T-cell-mediated lympholysis (CML) responses by cells from F1 hybrid mice injected with parental lymphocytes has not been reported but could provide a useful approach for investigating T-cell receptors because self MHC-restricted as well as allogeneic CML responses can be analyzed. This report describes an experimental system in which intravenous injection of F1 hybrid mice with parental T-splenic lymphocytes can result in the abrogation or severe depression of CML potential. This loss of CML activity did not appear to be specific for self determinants because responses to alloantigens, trinitrophenyl (TNP)modified F1 cells (TNP-self), and TNP-modified parental cells were all affected. However, an unexpected finding was the observation that the parental-induced CML depression was dependent upon the H-2 type of the injected parental lymphocytes. Thus, the injection of H-2 a, H-2 k, or H-2 a, but not H-2 6, parental lymphocytes resulted in depressed CML potential. These findings are discussed with respect to (a) the selective resistance of F1 mice to H-2 b parental lymphocytes, and (b) the possibility that Fa lymphocytes recognize idiotypic determinants specific for non-H-2 b antigens on H-2 b lymphocytes, but not those for H-2 b antigens on non-H-2 b lymphocytes

Triclosan persistence through wastewater treatment plants and its potential toxic effects on river biofilms

Triclosan is a commonly used bactericide that survives several degradation steps in WWTP (wastewater treatment plants) and potentially reaches fluvial ecosystems. In Mediterranean areas, where water scarcity results in low dilution capacity, the potential environmental risk of triclosan is high. A set of experimental channels was used to examine the short-term effects of triclosan (from 0.05 to 500 μg L−1) on biofilm algae and bacteria. Environmentally relevant concentrations of triclosan caused an increase of bacterial mortality with a no effect concentration (NEC) of 0.21 μg L−1. Dead bacteria accounted for up to 85% of the total bacterial population at the highest concentration tested. The toxicity of triclosan was higher for bacteria than algae. Photosynthetic efficiency was inhibited with increasing triclosan concentrations (NEC = 0.42 μg L−1), and non-photochemical quenching mechanisms decreased. Diatom cell viability was also affected with increasing concentrations of triclosan. Algal toxicity may be a result of indirect effects on the biofilm toxicity, but the clear and progressive reduction observed in all the algal-related endpoints suggest the existence of direct effects of the bactericide. The toxicity detected on the co-occurring non-target components of the biofilm community, the capacity of triclosan to survive through WWTP processes and the low dilution capacity that characterizes Mediterranean systems extend the relevance of triclosan toxicity beyond bacteria in aquatic habitats.This study was supported by the European Commission project Modelkey (Project 511237-2 GOCE). Additional funds were provided by the European Project Keybioeffects (MRTN-CT-2006-035695), the Spanish projects Fluvialfitomarc (GCL 2006-12785/HID), VIECO (009/RN08/011), SCARCE (Consolider-Ingenio 2010, CSD2009-00065) and Fluvialmultiestres (CTM2009-14111-CO2-01), as well as by Consorci de la Costa Brava and Empresa Mixta d’Aigües de la Costa Brava, S.A.Peer reviewe

Deletion of the serine protease CAP2/Tmprss4 leads to dysregulated renal water handling upon dietary potassium depletion

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