Cystic fibrosis (CF) is a genetic disease due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The most frequent mutation (p.Phe508del) results in a misfolded protein (p.Phe508del-CFTR) with an altered transport to the membrane of the cells via the conventional protein secretion (CPS) pathway. Nevertheless, it can use unconventional protein secretion (UPS). Indeed, p.Phe508del-CFTR forms a complex with GRASP55 to assist its direct trafficking from the endoplasmic reticulum to the plasma membrane. While GRASP55 is a key player of UPS, it is also a key player of stress-induced autophagy. In parallel, the unfolded protein response (UPR), which is activated in the presence of misfolded proteins, is tightly linked to UPS and autophagy through the key effectors IRE1, PERK, and ATF6. A better understanding of how UPS, UPR, and stress-induced autophagy interact to manage protein trafficking in CF and other conditions could lead to novel therapeutic strategies. By enhancing or modulating these pathways, it may be possible to increase p.Phe508del-CFTR surface expression. In summary, this review highlights the critical roles of UPS- and UPR-induced autophagy in managing protein transport, offering new perspectives for therapeutic approaches.

Cystic Fibrosis (CF) is present due to mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, the most frequent variant being p.phe508del. The CFTR protein is a chloride (Cl-) channel which is defective and almost absent of cell membranes when the p.Phe508del mutation is present. The p.Phe508del-CFTR protein is retained in the endoplasmic reticulum (ER) and together with inflammation and infection triggers the Unfolded Protein Response (UPR). During the UPR, the Activating Transcription Factor 6 (ATF6) is activated with cleavage and then decreases the expression of p.Phe508del-CFTR. We have previously shown that the inhibition of the activation of ATF6 alleviates the p.Phe508del-CFTR defects in cells overexpressing the mutated protein. In the present paper, our aim was to inhibit the cleavage of ATF6, and thus its activation in a human bronchial cell line with endogenous p.Phe508del-CFTR expression and in bronchial cells from patients, to be more relevant to CF. This was achieved by inhibiting the protease MBTP1 which is responsible for the cleavage of ATF6. We show here that this inhibition leads to increased mRNA and p.Phe508del-CFTR expression and, consequently, to increased Cl-efflux. We also explain the mechanisms linked to these increases with the modulation of genes when MBTP1 is inhibited. Indeed, RT-qPCR assays show that genes such as HSPA1B, CEBPB, VIMP, PFND2, MAPK8, XBP1, INSIG1, and CALR are modulated. In conclusion, we show that the inhibition of MBTP1 has a beneficial effect in relevant models to CF and that this is due to the modulation of genes involved in the disease.

Just over thirty years is the span of a generation. It is also the time that has passed since the discovery of the gene responsible for cystic fibrosis. Today, it is safe to say that this discovery has revolutionized our understanding, research perspectives, and management of this disease, which was, thirty years ago, a pediatric condition with a grim prognosis. The aim of this review is to present the advances that science and medicine have brought to our understanding of the pathophysiology of the disease and its management, which in many ways, epitomizes modern molecular genetic research. Since the discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 1989, modeling the CFTR protein, deciphering its function as an ion channel, and identifying its molecular partners have led to numerous therapeutic advances. The most significant advancement in this field has been the discovery of protein modulators that can target its membrane localization and chloride channel activity. However, further progress is needed to ensure that all patients can benefit from a therapy tailored to their mutations, with the primary challenge being the development of treatments for mutations leading to a complete absence of the protein. The present review delves into the history of the multifaceted world of CF, covering main historical facts, current landscape, clinical management, emerging therapies, patient perspectives, and the importance of ongoing research, bridging science and medicine in the fight against the disease.

The aminopyrrolidine amide PF-429242 is a specific inhibitor of the Site-1 Protease which is responsible for the cleavage, and thus the activation of the Activating Transcription Factor6 that down regulates many genes, during the Unfolded Protein Response. We hypothesized that PF-429242 could be used to prevent the ATF6-dependent down regulation of some genes. We chose the CFTR gene encoding the CFTR chloride channel as a model because it is down-regulated by ATF6 in Cystic Fibrosis. We evaluated the action of PF-429242 in human bronchial cells expressing the most frequent mutation of CFTR (p.Phe508del) found in patients. We observed that PF-429242 increases the synthesis of the mRNA and the protein encoded by the CFTR gene harbouring the mutation. We also observed that PF-429242 alleviates the defects of the p.Phe508del-CFTR channel in human Cystic Fibrosis cells. Our results suggest that aminopyrrolidine amide is a potential therapeutic target for Cystic Fibrosis that could also have beneficial effects in other diseases involving CFTR, such as the Chronic Obstructive Pulmonary Disease.

Disorders of the autosomal dominant polycystic kidney disease (ADPKD) spectrum are characterized by the development of kidney cysts and progressive kidney function decline. PKD1 and PKD2, encoding polycystin (PC)1 and 2, are the two major genes associated with ADPKD; other genes include IFT140, GANAB, DNAJB11, and ALG9. Genetic testing remains inconclusive in ∼7% of the families. We performed whole-exome sequencing in a large multiplex genetically unresolved (GUR) family affected by ADPKD-like symptoms and identified a monoallelic frameshift variant (c.703_704delCA) in ALG5. ALG5 encodes an endoplasmic-reticulum-resident enzyme required for addition of glucose molecules to the assembling N-glycan precursors. To identify additional families, we screened a cohort of 1,213 families with ADPKD-like and/or autosomal-dominant tubulointerstitial kidney diseases (ADTKD), GUR (n = 137) or naive to genetic testing (n = 1,076), by targeted massively parallel sequencing, and we accessed Genomics England 100,000 Genomes Project data. Four additional families with pathogenic variants in ALG5 were identified. Clinical presentation was consistent in the 23 affected members, with non-enlarged cystic kidneys and few or no liver cysts; 8 subjects reached end-stage kidney disease from 62 to 91 years of age. We demonstrate that ALG5 haploinsufficiency is sufficient to alter the synthesis of the N-glycan chain in renal epithelial cells. We also show that ALG5 is required for PC1 maturation and membrane and ciliary localization and that heterozygous loss of ALG5 affects PC1 maturation. Overall, our results indicate that monoallelic variants of ALG5 lead to a disorder of the ADPKD-spectrum characterized by multiple small kidney cysts, progressive interstitial fibrosis, and kidney function decline.

In cystic fibrosis (CF), p.Phe508del is the most frequent mutation in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. The p.Phe508del-CFTR protein is retained in the ER and rapidly degraded. This retention likely triggers an atypical Unfolded Protein Response (UPR) involving ATF6, which reduces the expression of p.Phe508del-CFTR. There are still some debates on the role of the UPR in CF: could it be triggered by the accumulation of misfolded CFTR proteins in the endoplasmic reticulum as was proposed for the most common CFTR mutation p.Phe508del? Or, is it the consequence of inflammation and infection that occur in the disease? In this review, we summarize recent findings on UPR in CF and show how infection, inflammation and UPR act together in CF. We propose to rethink their respective role in CF and to consider them as a whole.

We previously reported a 40-transcripts signature marking the normal mucosa to colorectal adenocarcinoma transition. Eight of these mRNAs also showed splicing alterations, including a specific intron 3 retention in tissue metalloprotease inhibitor I (TIMP1), which decreased during the early steps of colorectal cancer progression. To decipher the mechanism of intron 3 retention/splicing, we first searched for putative RNA binding protein binding sites onto the TIMP1 sequence. We identified potential serine arginine rich splicing factor 1 (SRSF1) and heterogeneous nuclear RiboNucleoProtein A1 (hnRNPA1) binding sites at the end of intron 3 and the beginning of exon 4, respectively. RNA immunoprecipitation showed that hnRNPA1, but not SRSF1 could bind to the corresponding region in TIMP1 pre-mRNA in live cells. Furthermore, using a TIMP1-based ex vivo minigene approach, together with a plasmon resonance in vitro RNA binding assay, we confirmed that hnRNPA1 could indeed bind to wild type TIMP1 exon 4 pre-mRNA and control TMP1 intron 3 splicing, the interaction being abolished in presence of a mutant sequence that disrupted this site. These results indicated that hnRNPA1, upon binding to TIMP1 exon 4, was a positive regulator of intron 3 splicing. We propose that this TIMP1-intron 3 + transcript belongs to the class of nuclear transcripts with “detained” introns, an abundant molecular class, including in cancer.

Summary: When analyzing sequence data, genetic variants are considered one by one, taking no account of whether or not they are found in the same individual. However, variant combinations might be key players in some diseases as variants that are neutral on their own can become deleterious when associated together. GEMPROT is a new analysis tool that allows, from a phased vcf file, to visualize the consequences of the genetic variants on the protein. At the level of an individual, the program shows the variants on each of the two protein sequences and the Pfam functional protein domains. When data on several individuals are available, GEMPROT lists the haplotypes found in the sample and can compare the haplotype distributions between different sub-groups of individuals. By offering a global visualization of the gene with the genetic variants present, GEMPROT makes it possible to better understand the impact of combinations of genetic variants on the protein sequence. Availability and implementation: GEMPROT is freely available at https://github.com/ TaniaCuppens/GEMPROT. An on-line version is also available at http://med-laennec.univ-brest.fr/ GEMPROT/. Contact: tania.cuppens@inserm.fr or emmanuelle.genin@inserm.fr Supplementary information: Supplementary data are available at Bioinformatics online.

Après ligamentoplastie du ligament croisé antérieur (LCA), la récupération musculaire est souvent comparée aux asymétries lors des sauts monopodaux en longueur, mais rarement à des exercices fonctionnels avec déplacements verticaux. L’objectif de cette étude est d’analyser ces asymétries et de déterminer les corrélations avec la force musculaire. Nous avons inclus 12 sportifs ayant bénéficié d’une ligamentoplastie isolée du LCA. Nous avons réalisé une analyse vidéographique 2D d’exercices fonctionnels avec des déplacements verticaux (montée de genoux, talon-fesse, saut monopodal vertical répété, squat jump). Nous avons également réalisé une mesure concentrique de la force musculaire isocinétique du quadriceps et des ischio-jambiers sur appareil Biodex à la vitesse de 90°/s et 240°/s. Nous avons cherché des corrélations entre les asymétries vidéographiques et les asymétries de force musculaire. La reproductibilité de l’analyse vidéographique est très satisfaisante. Le déficit de force musculaire du quadriceps est fortement corrélé à la différence entre les hauteurs de hanche lors du squat jump (valeurs maximales : r = 0,70 et amplitudes : r = 0,85) et l’amplitude d’angle du genou lors du squat jump (r = 0,71). Il existe une asymétrie de hauteur de hanche pour les exercices de sauts répétés et le squat jump avec une ascension verticale moins importante côté lésé. L’articulation du genou du côté lésé est moins mobile que du côté sain lors des montées de genoux (p = 0,01), des sauts répétés (p = 0,04) et du squat jump (p = 0,01). Le déficit de force musculaire du quadriceps est corrélé aux asymétries lors des sauts de type squat jump. L’ascension verticale de la hanche est moins élevée du côté lésé lors des sauts. Le genou du côté lésé est moins mobile que du côté sain et c’est l’articulation la plus perturbée au niveau des tests. After anterior cruciate ligament (ACL) ligamentoplasty, muscular recovery is often compared to asymmetries in monopodal length jumps, but rarely to functional exercises with vertical displacements. The objective of this study is to analyze these asymmetries and to determine the correlations with the muscular force. We included 12 athletes who had an ACL isolated ligamentoplasty. We performed a 2D videographic analysis of functional exercises with vertical displacements (knee up, heel-buttock, repeated vertical monopodal jump, squat jump). We also performed a concentric measurement of isokinetic muscle strength of the quadriceps and hamstrings on a Biodex device at a rate of 90°/s and 240°/s. And we looked for correlations between videographic asymmetries and muscle strength asymmetries. The reproducibility of video analysis is very good. Muscle strength deficit of the quadriceps is strongly correlated with the difference between the hip heights during the squat jump (maximum values: r = 0.70 and amplitudes: r = 0.85) as well as with the amplitude of angle knee during the squat jump (r = 0.71). There is asymmetry of hip height for repeated monopodal jump and squat jump with a smaller vertical ascent on the injured side. And the knee joint on the injured side is less mobile than on the healthy side during knee up (P = 0.01), repeated jumps (P = 0.04) and squat jump (P = 0.01). The quadriceps muscle strength deficit is correlated with asymmetries during squat jump. The vertical ascent of the hip is lower on the injured side than on the healthy side when jumping. The knee of the injured side is less mobile than the healthy side, and is the most affected joint.

The risk of graft failure after anterior cruciate ligament (ACL) reconstructions with hamstring or patellar tendon was evaluated in a French population of athletes.

SUMMARY:When analyzing sequence data, genetic variants are considered one by one, taking no account of whether or not they are found in the same individual. However, variant combinations might be key players in some diseases as variants that are neutral on their own can become deleterious when associated together. GEMPROT is a new analysis tool that allows, from a phased vcf file, to visualize the consequences of the genetic variants on the protein. At the level of an individual, the program shows the variants on each of the two protein sequences and the Pfam functional protein domains. When data on several individuals are available, GEMPROT lists the haplotypes found in the sample and can compare the haplotype distributions between different sub-groups of individuals. By offering a global visualization of the gene with the genetic variants present, GEMPROT makes it possible to better understand the impact of combinations of genetic variants on the protein sequence.AVAILABILITY AND IMPLEMENTATION:GEMPROT is freely available at https://github.com/TaniaCuppens/GEMPROT. An on-line version is also available at http://med-laennec.univ-brest.fr/GEMPROT/.SUPPLEMENTARY INFORMATION:Supplementary data are available at Bioinformatics online.

Objectifs Determiner l’influence du type de chirurgie sur la frequence des recidives a travers une population sportive. Materiel et methode Entre janvier 2011 et novembre 2014, les auteurs ont interroge telephoniquement 3526 sportifs ayant beneficie d’une chirurgie du ligament croise anterieur aux ischio-jambiers (DIDT) ou au tendon patellaire (TP), a partir du 11 e mois postoperatoire. Au niveau statistique, une analyse multivariee avec ajustement sur les criteres a l’inclusion (âge, sexe, niveau sportif, sports pratiques) a ete realisee prenant la frequence de recidives comme critere principal et les delais de recidives comme critere secondaire. Resultats Les 1307 sportifs ayant repondu avaient les memes caracteristiques que ceux de la population initiale. Le taux de reponse a ete de 37 %. Nous avons exclu les chirurgies n’etant pas des DIDT ou des TP, ainsi que les ruptures controlaterales survenues en cours d’etude, ce qui a permis d’obtenir 955 sportifs, dont 713 DIDT et 242 TP. La frequence des recidives apres DIDT etait de 6,5 %, contre 21 % pour les TP (difference significative [ p  = 0,007]). La moyenne des delais de ruptures iteratives etait de 10,7 mois pour les DIDT contre 17,4 mois pour un TP ( p  = 0,008). L’âge influence significativement la frequence des recidives, interessant davantage les moins de 25 ans que les plus âges ( p p  = 0,140) toutes chirurgies confondues : les joueurs reprenant la competition avant le 8 e mois avaient 7,1 % de risque de recidives contre 3,8 % apres le 8 e mois. Conclusion Les taux de recidives apres DIDT sont statistiquement plus eleves que ceux apres TP. Les moins de 25 ans ont un risque plus eleve que les sujets plus âges. Bien que statistiquement non significatifs dans cette etude, le niveau et les delais de reprise de la competition pourraient etre des facteurs de risque de recidives. Des travaux incluant des populations plus larges seraient interessants a mener.

Cystic fibrosis (CF) is the most common autosomal recessive disease in Caucasians caused by mutations in the gene encoding the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) chloride (Cl-) channel regulated by protein kinases, phosphatases, divalent cations and by protein-protein interactions. Among protein-protein interactions, we previously showed that Annexin A5 (AnxA5) binds to CFTR and is involved in the channel localization within membranes and in its Cl- channel function. The deletion of phenylalanine at position 508 (F508del) is the most common mutation in CF which leads to an altered protein (F508del-CFTR) folding with a nascent protein retained within the ER and is quickly degraded. We previously showed that AnxA5 binds to F508del-CFTR and that its increased expression due to a Gonadoliberin (GnRH) augments Cl- efflux in cells expressing F508del-CFTR. The aim of the present work was to use the GnRH analog buserelin which is already used in medicine. Human nasal epithelial cells from controls and CF patients (F508del/F508del) were treated with buserelin and we show here that the treatment alleviates Cl- channel defects in CF cells. Using proteomics we highlighted some proteins explaining this result. Finally, we propose that buserelin is a potential new pharmaceutical compound that can be used in CF and that bronchus can be targeted since we show here that they express GnRH-R.

Cystic Fibrosis is the most common lethal autosomal recessive disorder in the white population, affecting among other organs, the lung, the pancreas and the liver. Whereas Cystic Fibrosis is a monogenic disease, many studies reveal a very complex relationship between genotype and clinical phenotype. Indeed, the broad phenotypic spectrum observed in Cystic Fibrosis is far from being explained by obvious genotype-phenotype correlations and it is admitted that Cystic Fibrosis disease is the result of multiple factors, including effects of the environment as well as modifier genes. Our objective was to highlight new modifier genes with potential implications in the lung, pancreatic and liver outcomes of the disease. For this purpose we performed a system biology approach which combined, database mining, literature mining, gene expression study and network analysis as well as pathway enrichment analysis and protein-protein interactions. We found that IFI16, CCNE2 and IGFBP2 are potential modifiers in the altered lung function in Cystic Fibrosis. We also found that EPHX1, HLA-DQA1, HLA-DQB1, DSP and SLC33A1, GPNMB, NCF2, RASGRP1, LGALS3 and PTPN13, are potential modifiers in pancreas and liver, respectively. Associated pathways indicate that immune system is likely involved and that Ubiquitin C is probably a central node, linking Cystic Fibrosis to liver and pancreatic disease. We highlight here new modifier genes with potential implications in Cystic Fibrosis. Nevertheless, our in silico analysis requires functional analysis to give our results a physiological relevance.

Objective: Compare the clinical outcomes of different knee braces in the early phase of rehabilitation after anterior cruciate ligament reconstruction (ACLR) in athletes. Materials and methods: We conducted a retrospective database study of athletes during early rehabilitation in a tertiary referral hospital between 1 February 2008 and 30 October 2010 after ACLR using bone patellar tendon bone (BPTB) or hamstring autograft. Differences in mid-patellar knee circumference, pain, and range of motion were assessed at admission. All patients followed the same rehabilitation protocol. Patients who had complications preventing them from following the assigned rehabilitation program were analyzed separately. Patients who completed their rehabilitation program were also assessed for thigh muscle atrophy, extension deficit >= 2 degrees, quality of walking, PPLP1 and subjective IKDC scores. The type and frequency of complications and their frequency was documented. The above-mentioned parameters were analyzed in 3 different groups: rigid brace in full extension, articulated brace (0 degrees-90 degrees for first 3 weeks then 0-120 degrees) or no brace. Results: The analysis included 969 patients. Rehabilitation started at 4.5 +/- 2.9 days after surgery and ended at 32.4 +/- 3.0 days postoperative. At the beginning, flexion was lower in patients with a rigid brace (P < 0.01). There was no difference in the frequency or severity of complications between the three study groups, nor was there a significant difference in the clinical outcomes listed above. Conclusion: Postoperative bracing after ACLR has not beneficial effect on clinical outcomes and the complication rate. Patients who wore the rigid brace had limited flexion early on. (C) 2017 Elsevier Masson SAS. All rights reserved.

Cystic Fibrosis (CF) is the most frequent fatal genetic disease in Caucasian populations. Mutations in the chloride channel CF Transmembrane Conductance Regulator (CFTR) gene are responsible for functional defects of the protein and multiple associated dysregulations. The most common mutation in patients with CF, F508del-CFTR, causes defective CFTR protein folding. Thus minimal levels of the receptor are expressed at the cell surface as the mutated CFTR is retained in the endoplasmic reticulum (ER) where it correlates with defective calcium (Ca2+) homeostasis. In this study, we discovered that the Ca2+ binding protein Calumenin (CALU) is a key regulator in the maintenance of ER-Ca2+ calcium homeostasis in both wild type and F508del-CFTR expressing cells. Calumenin modulates SERCA pump activity without drastically affecting ER-Ca2+ concentration. In addition, reducing Calumenin expression in CF cells results in a partial restoration of CFTR activity, highlighting a potential function of Calumenin in CFTR maturation. These findings demonstrate a pivotal role for Calumenin in CF cells, providing insights into how modulation of Calumenin expression or activity may be used as a potential therapeutic tool to correct defects in F508del-CFTR.

La lésion des muscles ischio-jambiers est la principale blessure liée à la pratique de l’athlétisme mais aussi dans les autres sports d’accélération et de sprints, avec des conséquences importantes en terme d’arrêt de pratique sportive et de risque de récidive. Dans une démarche de prévention, une meilleure connaissance des mécanismes et facteurs de risque de ces lésions semble pertinente. Cela implique une meilleure compréhension des déterminants biomécaniques et musculaires de la performance lors de l’accélération en sprint, c’est-à-dire la capacité à produire une force horizontale importante au sol (i.e. orienter la poussée dans la direction du mouvement) tout en augmentant la vitesse de course. Les muscles ischio-jambiers sembleraient jouer un rôle important dans cette capacité. L’évaluation des propriétés mécaniques du sprint et notamment du profil force–vitesse et des paramètres de force horizontale maximale théorique (FH0) et vitesse maximale théorique (V0) est possible en situation réelle de pratique de terrain avec des outils de mesure simples. Des études ont rapporté une modification du profil force–vitesse et une diminution de FH0 dans les suites d’une lésion musculaire des ischio-jambiers, conséquence de la lésion. Il existe des liens étroits entre la fonction et la force des ischio-jambiers et la force horizontale en sprint. Cette mesure du profil force–vitesse pourrait être utilisée pour guider la reprise du sprint après une lésion musculaire des ischio-jambiers, mais également pour dépister les sujets à risque de blessures de ces mêmes muscles.Hamstring muscle injury is the main injury related to athletics, but also other sports including acceleration and sprints, with important consequences (time-loss of sport and reinjury risk). In a prevention approach, a better knowledge of risk factors and mechanisms of these lesions seem relevant, and it can pass through a better understanding of the biomechanical and muscular determinants of performance in sprint and acceleration. The ability to produce a horizontal force on the ground (i.e. orienting the total push backward [or ground force reaction forward]), and to do so despite the increase in running speed, is an important determinant of sprint performance. The hamstring muscles seem to play an important role in this key ability. Evaluation of mechanical properties of sprint including the force–velocity profile and maximum theoretical horizontal force (FH0) and maximum theoretical speed (V0) in sprint is possible in real-practice conditions with simple tools. Studies have reported a change in the force–velocity profile and decrease in FH0 following hamstring muscle injury, which could be a consequence of the injury. This approach to analyze the hamstring propulsion function at a maximum acceleration sprint looks promising given the very functional and ecological character in a field evaluation, close links between the function and strength of hamstring and the horizontal force sprint, and these encouraging preliminary scientific results. This force–velocity profile evaluation could be used to guide the return to sprint and allow authorization to maximum sprint after hamstring muscle injury, but also to screen athletes at risk of hamstring muscle injury.

Cystic fibrosis (CF), one of the most common fatal hereditary disorders, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The CFTR gene product is a multidomain adenosine triphosphate-binding cassette (ABC) protein that functions as a chloride (Cl−) channel that is regulated by intracellular magnesium [Mg2+]i. The most common mutations in CFTR are a deletion of a phenylalanine residue at position 508 (ΔF508-CFTR, 70–80 % of CF phenotypes) and a Gly551Asp substitution (G551D-CFTR, 4–5 % of alleles), which lead to decreased or almost abolished Cl− channel function, respectively. Magnesium ions have to be finely regulated within cells for optimal expression and function of CFTR. Therefore, the melastatin-like transient receptor potential cation channel, subfamily M, member 7 (TRPM7), which is responsible for Mg2+ entry, was studies and [Mg2+]i measured in cells stably expressing wildtype CFTR, and two mutant proteins (ΔF508-CFTR and G551D-CFTR). This study shows for the first time that [Mg2+]i is decreased in cells expressing ΔF508-CFTR and G551D-CFTR mutated proteins. It was also observed that the expression of the TRPM7 protein is increased; however, membrane localization was altered for both ΔF508del-CFTR and G551D-CFTR. Furthermore, both the function and regulation of the TRPM7 channel regarding Mg2+ is decreased in the cells expressing the mutated CFTR. Ca2+ influx via TRPM7 were also modified in cells expressing a mutated CFTR. Therefore, there appears to be a direct involvement of TRPM7 in CF physiopathology. Finally, we propose that the TRPM7 activator Naltriben is a new potentiator for G551D-CFTR as the function of this mutant increases upon activation of TRPM7 by Naltriben.

Cystic fibrosis results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-dependent protein kinase A (PKA) and ATP-regulated chloride channel. Here, we demonstrate that nucleoside diphosphate kinase B (NDPK-B, NM23-H2) forms a functional complex with CFTR. In airway epithelia forskolin/IBMX significantly increases NDPK-B co-localisation with CFTR whereas PKA inhibitors attenuate complex formation. Furthermore, an NDPK-B derived peptide (but not its NDPK-A equivalent) disrupts the NDPK-B/CFTR complex in vitro (19-mers comprising amino acids 36-54 from NDPK-B or NDPK-A). Overlay (Far-Western) and Surface Plasmon Resonance (SPR) analysis both demonstrate that NDPK-B binds CFTR within its first nucleotide binding domain (NBD1, CFTR amino acids 351-727). Analysis of chloride currents reflective of CFTR or outwardly rectifying chloride channels (ORCC, DIDS-sensitive) showed that the 19-mer NDPK-B peptide (but not its NDPK-A equivalent) reduced both chloride conductances. Additionally, the NDPK-B (but not NDPK-A) peptide also attenuated acetylcholine-induced intestinal short circuit currents. In silico analysis of the NBD1/NDPK-B complex reveals an extended interaction surface between the two proteins. This binding zone is also target of the 19-mer NDPK-B peptide, thus confirming its capability to disrupt NDPK-B/CFTR complex. We propose that NDPK-B forms part of the complex that controls chloride currents in epithelia.

Plusieurs moyens d’évaluation des capacités proprioceptives du genou existent. Ceux-ci sont basés sur l’évaluation du sens kinesthésique ou de la posture. Pour le sens kinesthésique, on retrouve 2 tests fréquemment utilisés et bien validés dans la littérature. Le Joint Position Sense (JPS) permet de mesurer en passif ou en actif la capacité à détecter la position d’un membre dans l’espace. Le Threshold for Detection Motion (TDPM) consiste à mesurer la capacité à ressentir le mouvement à partir d’une phase immobile. À travers la littérature et notre expérience, il nous semble que le TDPM est le test le plus pertinent pour le suivi de pathologies. Concernant l’évaluation de la posture, la plateforme proprioceptive apparaît être l’outil le plus adéquat. À partir de plusieurs études personnelles, nous avons précisé sa reproductibilité et redéfini des normes en position bipodale et monopodale. Nous avons également étudié l’impact du feedback visuel sur les résultats et comparé les valeurs normales avec une population ayant bénéficié d’une chirurgie du ligament croisé antérieur. La reproductibilité est satisfaisante mais variable en fonction des paramètres analysés. Le feedback visuel permet une stratégie d’adaptation avec une diminution de la surface de déplacement. On retrouve des différences significatives des profils posturaux entre la population saine et celle ayant bénéficié d’une chirurgie du ligament croisé antérieur. Par contre, il n’existe pas de différence entre la jambe saine et la jambe opérée, ce qui semble confirmer l’hypothèse de modifications centrales proprioceptives avec retentissement bilatéral d’une lésion unilatérale. Si la rééducation proprioceptive doit s’attacher à améliorer les capacités proprioceptives du membre lésé, elle ne doit donc pas oublier le membre considéré comme sain.