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Approximately 30% of alleles causing genetic disorders generate premature termination codons (PTCs), which are usually associated with severe phenotypes. However, bypassing the deleterious stop codon can lead to a mild disease outcome. Splicing at NAGNAG tandem splice sites has been reported to result in insertion or deletion (indel) of three nucleotides. We identified such a mechanism as the origin of the mild to asymptomatic phenotype observed in cystic fibrosis patients homozygous for the E831X mutation (2623G>T) in the CFTR gene. Analyses performed on nasal epithelial cell mRNA detected three distinct isoforms, a considerably more complex situation than expected for a single nucleotide substitution. Structure-function studies and in silico analyses provided the first experimental evidence of an indel of a stop codon by alternative splicing at a NAGNAG acceptor site. In addition to contributing to proteome plasticity, alternative splicing at a NAGNAG tandem site can thus remove a disease-causing UAG stop codon. This molecular study reveals a naturally occurring mechanism where the effect of either modifier genes or epigenetic factors could be suspected. This finding is of importance for genetic counseling as well as for deciding appropriate therapeutic strategies.

Key Clinical Message In vitro functional tests aimed to investigate CFTR dysfunction appear critical to help elucidate the functional impact of new variants of uncertain clinical significance and solve inconclusive cases, especially in early deceased newborns. In vitro functional tests aimed to investigate CFTR dysfunction appear critical to help elucidate the functional impact of new variants of uncertain clinical significance and solve inconclusive cases, especially in early deceased newborns.

Low copy numbers (CNs) of C4 genes are associated with systemic autoimmune disorders and affects autoantibody diversity and disease subgroups. The primary objective of this study was to characterize diversity of complement (C4) and C4-Human Endogenous Retrovirus (HERV) gene copy numbers in SLE. We also sought to assess the association of C4 and C4-HERV CNs with serum complement levels, autoantibodies, disease phenotypes and activity. Finally, we checked the association of C4 and HERV CNs with specific HLA alleles. Genomic DNA from 70 SLE and 90 healthy controls of south Indian Tamil origin were included. Demographic, clinical and serological data was collected in a predetermined proforma. CNs of C4A and C4B genes and the frequency of insertion of 6.4kb HERV within C4 gene (C4AL, C4BL) was determined using droplet digital polymerase chain reaction (ddPCR). A four digit high resolution HLA genotyping was done using next generation sequencing. In our cohort, the total C4 gene copies ranged from 2 to 6. Compared to controls, presence of two or less copies of C4A gene was associated with SLE risk (p = 0.005; OR = 2.79; 95% CI = 1.29–6.22). Higher frequency of HERV insertion in C4A than in C4B increases such risk (p = 0.000; OR = 12.67; 95% CI = 2.80-115.3). AL-AL-AL-BS genotype was significantly higher in controls than SLE (9%vs1%, p = 0.04; OR = 0.15, 95% CI = 0.00-0.16). Distribution of HLA alleles was not different in SLE compared to controls as well as in SLE subjects with ≤ 2 copies and > 2 copies of C4A, but HLA allele distribution was diverse in subjects with C4B ≤ 2 copies and > 2 copies. Finally, there was no correlation between the C4 and the C4-HERV diversity and complement levels, autoantibodies, disease phenotypes and activity. In conclusion, our data show that, low C4A copy number and higher insertion of HERV-K in C4A increases the risk for SLE. C4 and C4-HERV CNs did not correlate with serum complements, autoantibodies, disease phenotypes and activity in SLE. Further validation in a larger homogenous SLE cohort is needed.

Mutations in the gene encoding surfactant protein C (SFTPC) have led to a broad range of phenotypes from neonatal respiratory distress syndrome to adult interstitial lung disease. We previously identified the c.435G>C variant in the SFTPC gene associated with fatal neonatal respiratory distress syndrome in an infant girl. Although this variation is predicted to change glutamine (Q) at position 145 to histidine (H), its position at the last base of exon 4 and the severity of the phenotype suggested that it might also induce a splicing defect. To test this hypothesis, we used hybrid minigene, biochemical and immunofluorescence tools to decipher the molecular mechanism of the mutation. Immunoblotting and confocal imaging showed similar maturation and localization of wild-type and Q145H proteins, but hybrid minigene analysis showed complete exon 4 skipping. Since the exon 4 is in frame, a putative truncated protein of 160 amino acids would be produced. We have shown that this truncated protein had an altered intracellular trafficking and maturation. The c.435G>C mutation is deleterious not because of its amino acid substitution but because of its subsequent splicing defect and should be referred to as r.325_435del and p.Leu109_Gln145del. The absence of residual full-length transcripts fully explained the severity of the phenotype we observed in the infant.

Si la nécessité de l’adoption au niveau de l’Union européenne d’une politique volontariste et ambitieuse de gestion des risques des substances chimiques pour l’environnement et la santé apparaît incontestable et justifiée, force est de constater que, plusieurs années après son entrée en vigueur, REACH est loin de faire l’unanimité.Dans le contexte économique actuel, les entreprises ont en effet de plus en plus de mal à supporter les contraintes administratives et les coûts induits que fait peser sur elles REACH. De nombreux industriels appellent donc de leurs vœux une révision de REACH qui tienne mieux compte des difficultés qu’ils rencontrent au quotidien dans la gestion de leurs activités. REACH : the expected effects reach beyond the chemical industry – A testimonyThe need to adopt at the EU level a deliberate, ambitious policy for managing the risks of chemicals to the environment and human health seems indisputably justified. Several years after its enforcement however, REACH is still far from unanimously accepted. In the current business cycle, it is harder for corporations to put up with the administrative restrictions and costs incurred by applying this regulation. Several industrialists are calling for a review of REACH that would take into account the difficulties they encounter in everyday business.

// ABSTRACT IN ENGLISH: The need to adopt at the EU level a deliberate, ambitious policy for managing the risks of chemicals to the environment and human health seems indisputably justified. Several years after its enforcement however, REACH is still far from unanimously accepted. In the current business cycle, it is harder for corporations to put up with the administrative restrictions and costs incurred by applying this regulation. Several industrialists are calling for a review of REACH that would take into account the difficulties they encounter in everyday business. // ABSTRACT IN FRENCH: Si la nécessité de l'adoption au niveau de l'Union européenne d'une politique volontariste et ambitieuse de gestion des risques des substances chimiques pour l'environnement et la santé apparaît incontestable et justifiée, force est de constater que, plusieurs années après son entrée en vigueur, REACH est loin de faire l'unanimité. Dans le contexte économique actuel, les entreprises ont en effet de plus en plus de mal à supporter les contraintes administratives et les coûts induits que fait peser sur elles REACH. De nombreux industriels appellent donc de leurs vux une révision de REACH qui tienne mieux compte des difficultés qu'ils rencontrent au quotidien dans la gestion de leurs activités. Reproduced by permission of Bibliothèque de Sciences Po

Approximately 30% of alleles causing genetic disorders generate premature termination codons (PTCs), which are usually associated with severe phenotypes. However, bypassing the deleterious stop codon can lead to a mild disease outcome. Splicing at NAGNAG tandem splice sites has been reported to result in insertion or deletion (indel) of three nucleotides. We identified such a mechanism as the origin of the mild to asymptomatic phenotype observed in cystic fibrosis patients homozygous for the E831X mutation (2623G>T) in the CFTR gene. Analyses performed on nasal epithelial cell mRNA detected three distinct isoforms, a considerably more complex situation than expected for a single nucleotide substitution. Structure-function studies and in silico analyses provided the first experimental evidence of an indel of a stop codon by alternative splicing at a NAGNAG acceptor site. In addition to contributing to proteome plasticity, alternative splicing at a NAGNAG tandem site can thus remove a disease-causing UAG stop codon. This molecular study reveals a naturally occurring mechanism where the effect of either modifier genes or epigenetic factors could be suspected. This finding is of importance for genetic counseling as well as for deciding appropriate therapeutic strategies.

Critical illness is associated with hypercatabolism, systemic inflammatory dysregulation and low serum concentration of testosterone (T) leading to intensive care unit (ICU) acquired weakness and altered outcome. T supplementation benefit has been reported in several illnesses but data in non-burned ICU patients are scarce. In this context, the purpose of the TestICUs-1 study was to assess the pharmacokinetic and safety of T-gel administration in ICU patients. TestICUs-1 was an open, monocentric, randomized controlled study carried out in ICU patients receiving vasopressors, and mechanical ventilation for at least two days. Exclusion criteria included prostate or breast cancer, PSA levels >4 ng/mL and age ≥ 80 years. The T group received a 14-day administration of T transdermal gel (Androgel©). The primary endpoint was the percentage of patients with serum Total T value within normal ranges on days 4, 7, 10 and 14. The safety of T-gel was also assessed. 30 patients were included, 19 (63 %) were men. At inclusion, none of the men and half of the women presented a serum Total T values within normal range. On days 4, 7, 10 and 14, the percentage of patients with a normal serum Total T value did not differ between T administered patients and controls. No significant differences between groups were reported in terms of cardiovascular events and cytolysis. The administration of T-gel did not increase significantly the percentage of patients with normal serum T values as compared to control. •Critical illness is associated with hypogonadism, ICU-acquired weakness, and adverse outcomes.•The TestICUs-1 trial evaluated pharmacokinetics and safety of testosterone gel in non-burned ICU patients.•30 mechanically ventilated, vasopressor-dependent patients were randomized to receive testosterone gel or placebo.•Testosterone supplementation did not increase the proportion of patients achieving normal serum testosterone levels.•The study was not powered to assess safety outcomes, including mortality or nosocomial infections.

Olfactory cues of individuals of the same species or from different species may induce changes in behaviors and physiological reactions in mammals. However, there are few studies on the influence of human odor on animal behavior and welfare, especially those of rodents and farm animals. The present study aimed to investigate whether the odor of a stressed human (in sweat) would modify the behavior of mice and cows. We hypothesized that laboratory and farm animals can perceive human emotions though olfactory cues and that human emotional chemosignals can modify their behavioral reactions and welfare. Two odors of human axillary sweat were collected from engineering students ( n  = 25, 14 females and 11 males; 21.1 ± 0.7 years old, range: 19–23 years old): a “stress” odor collected after an exam and a “non-stress” odor collected after a standard class. Two experiments were then conducted to test the discrimination of these two odors by male mice ( n  = 20) under standard conditions and by cows ( n  = 10) under farm conditions. During the experiments, the behavioral responses of the animals to both odors (through a dispenser for the mice and a bucket for the cows) were observed. The mice produced significantly ( p  = 0.004) more fecal pellets with the stress odor dispenser than with the non-stress-odor dispenser. The cows spent significantly ( p  = 0.04) more time smelling the non-stress-odor bucket than control. For both species, the other behaviors observed did not differ significantly between the odors. Mice and cows seemed to perceive and react to stressful human chemosignals. Mice showed physiological reactions that indicated stress in response to the stress odor of humans, while cows showed preference reactions in response to the non-stress odor of humans. This preliminary study showed that laboratory and farm animals, such as male mice and cows, seemed to discriminate certain odors emitted by humans that were likely related to different emotions. Animals may recognize stressful human chemosignals, associate these signals with negative husbandry practices or human–animal relationships, and consequently modify their behavior.