Mutations involving the SRY-related gene SOX8 are associated with a spectrum of human reproductive anomalies.

© The Author(s) 2018. Published by Oxford University Press. All rights reserved. SOX8 is an HMG-box transcription factor closely related to SRY and SOX9. Deletion of the gene encoding Sox8 in mice causes reproductive dysfunction but the role of SOX8 in humans is unknown. Here, we show that SOX8 is expressed in the somatic cells of the early developing gonad in the human and influences human sex determination. We identified two individuals with 46, XY disorders/differences in sex development (DSD) and chromosomal rearrangements encompassing the SOX8 locus and a third individual with 46, XY DSD and a missense mutation in the HMG-box of SOX8. In vitro functional assays indicate that this mutation alters the biological activity of the protein. As an emerging body of evidence suggests that DSDs and infertility can have common etiologies, we also analysed SOX8 in a cohort of infertile men (n=274) and two independent cohorts of women with primary ovarian insufficiency (POI; n=153 and n=104). SOX8 mutations were found at increased frequency in oligozoospermic men (3.5%; P < 0.05) and POI (5.06%; P=4.5×10 -5 ) as compared with fertile/normospermic control populations (0.74%). The mutant proteins identified altered SOX8 biological activity as compared with the wild-type protein. These data demonstrate that SOX8 plays an important role in human reproduction and SOX8 mutations contribute to a spectrum of phenotypes including 46, XY DSD, male infertility and 46, XX POI.Link_to_subscribed_fulltex

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

Visual display of forest landscapes derived from NFI data bases

Les préoccupations des sylviculteurs et des gestionnaires de l'espace rural se tournent de plus en plus vers la perception des paysages par le public et la prédiction de leur évolution en fonction de choix d'aménagement. Mais il n'est pas toujours aisé de communiquer l'impact visuel d'une action d'aménagement future à l'ensemble des acteurs intervenant sur le paysage (décideurs locaux ou régionaux, gestionnaires, paysagistes, promeneurs...). Lecoustre et al. (1997) ont développé une méthode de simulation des paysages forestiers qui relie des données contenues dans un système d'information géographique avec la technique de modélisation architecturale des plantes. Auclair et al. (2000) ont utilisé cette méthode pour simuler des aménagements agroforestiers. Ces recherches ont permis de visualiser des paysages à l'échelle d'une ou de plusieurs parcelles forestières, mais ces méthodes n'avaient pas, jusqu'à présent, été utilisées à des échelles plus vastes. Les bases de données de l'IFN fournissent sur l'ensemble du territoire français une cartographie des types de peuplement, ainsi qu'une évaluation statistique de leurs principales caractéristiques dendrométriques. Les logiciels de la gamme "AMAP" permettent de visualiser des paysages virtuels, construits à partir de maquettes informatiques basées sur les concepts scientifiques de la modélisation architecturale des végétaux (de Reffye et al., 1989, 1996), et de modèles numériques de terrain. Il est donc apparu intéressant d'étudier la faisabilité d'un couplage des données de l'IFN avec les logiciels AMAP en vue d'élaborer une éventuelle "base de données de paysages forestiers"

Expression and DNA-binding activity of C/EBPα and C/EBPβ in human liver and differentiated primary hepatocytes

International audienceBackground/Aims: Limited information is available on the expression and role of C/EBP factors in human liver and hepatocytes. We investigated the expression and DNA-binding activity of C/EBPα and C/EBPβ in human liver needle biopsies, surgical lobectomies and differentiated cultured hepatocytes derived from lobectomies.Methods: RNA and protein extracts were analyzed by RNAse protection, immunoblot and gel shift assays.Results: C/EBP mRNAs, isoforms and DNA-binding activities were low/undetectable in lobectomies. In contrast, several C/EBPα (47, 45, 35 and 33 kDa) and C/EBPβ isoforms (47, 43, 40, 35 and 21 kDa) were observed in needle biopsies. In cultured hepatocytes, the C/EBP expression pattern dramatically changed with time. C/EBPα mRNA and the 45 kDa isoform increased in parallel, reaching a maximum after 3–4 weeks coincident with weak DNA-binding activity. C/EBPβ mRNA and isoform expression increased rapidly reaching a plateau within 1–2 weeks; all C/EBPβ isoforms were phosphorylated. C/EBPβ exhibited greater DNA-binding activity than C/EBPα, and this activity paralleled C/EBPβ isoform expression.Conclusions: C/EBP isoforms exhibit markedly different expression patterns in lobectomies, needle biopsies and cultured hepatocytes. Stress stimuli during and/or after surgery for lobectomy resections may account for this difference. The pattern of C/EBP isoform expression in long-term highly differentiated cultured hepatocytes is close to that observed in needle biopsies

Targeted Radionuclide Therapy Using Auger Electron Emitters: The Quest for the Right Vector and the Right Radionuclide

Auger electron emitters (AEEs) are attractive tools in targeted radionuclide therapy to specifically irradiate tumour cells while sparing healthy tissues. However, because of their short range, AEEs need to be brought close to sensitive targets, particularly nuclear DNA, and to a lower extent, cell membrane. Therefore, radioimmunoconjugates (RIC) have been developed for specific tumour cell targeting and transportation to the nucleus. Herein, we assessed, in A-431CEA-luc and SK-OV-31B9 cancer cells that express low and high levels of HER2 receptors, two 111In-RIC consisting of the anti-HER2 antibody trastuzumab conjugated to NLS or TAT peptides for nuclear delivery. We found that NLS and TAT peptides improved the nuclear uptake of 111In-trastuzumab conjugates, but this effect was limited and non-specific. Moreover, it did not result in a drastic decrease of clonogenic survival. Indium-111 also contributed to non-specific cytotoxicity in vitro due to conversion electrons (30% of the cell killing). Comparison with [125I]I-UdR showed that the energy released in the cell nucleus by increasing the RIC’s nuclear uptake or by choosing an AEE that releases more energy per decay should be 5 to 10 times higher to observe a significant therapeutic effect. Therefore, new Auger-based radiopharmaceuticals need to be developed

Comparison of four bioelectrical impedance analysis formulas in healthy elderly subjects

Background: Changes of body composition occur with aging and influence health status. Thus accurate methods for measuring fat-free mass (FFM) in the elderly are essential.Objective: The purpose of this study was to compare FFM obtained by three bioelectrical impedance analysis (BIA) published formulas specific for the elderly and one equation intended for all age groups, with FFM derived from dual-energy X-ray absorptiometry (FFM(DXA)), in healthy elderly subjects.Methods: Healthy Caucasian subjects over 65 years (106 women, age 75 +/- 6.2, body mass index 25.2 +/- 4.1 and 100 men, age 74.6 +/- 6.6, body mass index 25.8 +/- 3.0) were measured by DXA (Hologic QDR-4500) and BIA (Xitron, 50 kHz). FFM(BIA) was calculated by the published formulas of Deurenberg, Baumgartner, Roubenoff and Kyle and compared to FFM(DXA) by a Bland-Altman analysis.Results: The Deurenberg and Roubenoff BIA formulas underestimated FFM compared to DXA by -7.1 and -2.9 kg in women and -6.7 and -2.3 kg in men, respectively. The Baumgartner formula overestimated FFM by 4.3 kg in women and 1.4 kg in men. The Kyle formula showed differences of 0.0 kg in women and 0.2 kg in men, and the limits of agreement of FFM(BIA (Kyle)) relative to FFM(DXA) were -3.3 and +3.3 kg for women and -3.8 and +4.3 kg for men.Conclusion: The Kyle BIA formula accurately predicts FFM in elderly Swiss subjects between 65 and 94 years, with a body mass index of 17 to 34.9 kg/m(2). The other BIA formulas developed especially for the elderly are not valid in this population.</p

Rapid communication: insights into the role of extracellular vesicles during Auger radioimmunotherapy

International audiencePurpose: Non-targeted effects, including bystander and systemic effects, play a crucial role during Auger targeted radionuclide therapy. Here, we investigated whether small extracellular vesicles (sEVs) produced by irradiated cells could contribute to the bystander cytotoxic effects in vitro and also to therapeutic efficacy in vivo, after their injection in tumor xenografts.Materials and methods: B16F10 melanoma donor cells were exposed to radiolabeled antibodies (Auger radioimmunotherapy, RIT) for 48 h or to X-rays (donor cells). Then, donor cells were incubated with fresh medium for 2 h to prepare conditioned medium (CM) that was transferred onto recipient cells for bystander effect assessment, or used for sEVs enrichment. Resulting sEVs were incubated in vitro with recipient cells for determining bystander cytotoxicity, or injected in B16F10 melanoma tumors harbored by athymic and C57BL/6 mice.Results: In vitro analysis of bystander cytotoxic effects showed that CM killed about 30-40% of melanoma cells. SEVs isolated from CM contributed to this effect. Moreover, the double-stranded DNA (dsDNA) content was increased in sEVs isolated from CM of exposed cells compared to control (not exposed), but the difference was significant only for the X-ray condition. These results were supported by immunodetection of cytosolic dsDNA in donor cells, a phenomenon that should precede dsDNA enrichment in sEVs. However, sEVs cytotoxicity could not be detected in vivo. Indeed, in athymic and in immunocompetent mice that received four intratumoral injections of sEVs (1/day), tumor growth was not delayed compared with untreated controls. Tumor growth was slightly (not significantly) delayed in immunocompetent mice treated with sEVs from X-ray-exposed cells, and significantly with sEVs purified from CM collected after 48 h of incubation. These results highlight the need to determine the optimal conditions, including radiation absorbed dose and sEVs collection time, to obtain the strongest cytotoxic effects.Conclusions: This study demonstrates that sEVs could play a role during Auger RIT through bystander effects in vitro. No systemic effects were observed in vivo, under our experimental conditions. However, X-rays experiments showed that sEVs collection time might be influencing the nature of sEVs, a parameter that should also be investigated during Auger RIT

Total body mass, fat mass, fat-free mass, and skeletal muscle in older people: cross-sectional differences in 60-year-old persons

Objectives: To evaluate body composition parameters, including fat-free mass (FFM), appendicular skeletal muscle mass (ASMM), relative skeletal muscle mass (RSM) index, body cell mass (BCM), BCM index, total body potassium (TBK), fat mass, percentage fat mass (FM), and their differences between age groups and to evaluate the frequency of sarcopenia in healthy older subjects Design: Cross-sectional, nonrandomized study. Setting: Outpatient clinic. Participants: Ninety-one healthy men and 100 healthy women age 60 and older. Measurements: FFM, ASMM, FM, and percentage fat mass by whole-body dual-energy x-ray absorptiometry; TBK, BCM, and TBK/FFM ratio by whole body potassium-40 counter. Results: All lean body mass parameters were significantly (P &lt;.05) lower in subjects age 80 and older than in those age 70 to 79, except ASMM in women. Mean FFM was 4.2 kg (7.3%) lower in men age 80 and older than in those younger than 70 and 2.9 kg (6.8%) lower in women age 80 and older than in those younger than 70. The skeletal muscle mass, reflected by ASMM, decreased more than FFM. This suggests that nonskeletal muscle mass is proportionally preserved during aging. Forty-five percent of men and 30% of women were sarcopenic by definition of BCM index and 11.0% of men and women by definition of RSM index. Conclusions: Significant age-related differences exist in body composition of older men and women between age 60 and 95. The greater decrease in TBK and BCM than the decrease in FFM and skeletal muscle mass suggests changing composition of FFM with age. Lack of agreement between two independent sarcopenia indexes suggests that further refinement in the definition of a sarcopenia index is necessary.</p

Bronchopneumopathie chronique obstructive: risques et bénéfices d’un traitement de testostérone

Muscular wasting is frequently encountered in COPD patients and is related to a decrease in exercise tolerance, a higher morbidity and mortality. One of the potential causes isa low serum testosterone, which is frequent in COPD. Various studies have explored the effect of testosterone administration alone or as part of combined pulmonary rehabilitation and nutrition protocols. Testosterone had a positive impact on muscle mass and force, and to a lesser extent on physical endurance and respiratory parameters. Future studies should better define appropriate dosage and treatment duration. In the meantime, testosterone should be administered to COPD patients with overt hypogonadism, or in multidisciplinary specialized programmes