Erlang-based dimensioning for IPv4 Address+Port translation

International audienceAs the IPv4 address pool is being exhausted, it becomes urgent to find a way to migrate IPv4 network architectures to IPv6, or to reduce the use of IPv4 addresses. In this paper, we discuss a strategy known as ''Address + Port'' translation, which consists in several users sharing the same IPv4 address and being distinguished by a range of port numbers. Of critical importance for the feasibility of such a mechanism is the knowledge of the minimum number of ports to allocate to users so that no service degradation is perceived. To that extent, we analyse the port consumption of the most port-consuming Internet applications, web browsing, and present some aggregate port consumption curves for the student population of our campus. Our results suggest that a port range of 1000 ports is totally transparent to users (which would allow to share a single IPv4 address among 64 users),while 400 ports (i.e., 150 users per address) is sufficient for most of users. Finally, the number of users per address could be further improved by benefiting from statistical multiplexing, i.e., using dynamical instead of fixed port range allocation

Cyclooxygenase-2 Inhibition Restored Endothelium-Mediated Relaxation in Old Obese Zucker Rat Mesenteric Arteries

Metabolic syndrome is associated with reduced endothelial vasodilator function. It is also associated with the induction of cyclooxygenase-2 (COX2), which produces vasoactive prostanoids. The frequency of metabolic syndrome increases with age and aging per se is a risk factor associated with reduced endothelium-mediated relaxation. Nevertheless, the combined effect of aging and metabolic syndrome on the endothelium is less known. We hypothesized that COX2 derived prostanoids may affect endothelium function in metabolic syndrome associated with aging. We used obese Zucker rats, a model of metabolic syndrome. First order mesenteric arteries were isolated from 4- and 12-month-old rats and acetylcholine (endothelium)-dependent relaxation determined using wire-myography. Endothelium-mediated relaxation, impaired in young Zucker rats (89 versus 77% maximal relaxation; lean versus Zucker), was further reduced in old Zucker rats (72 versus 51%, lean versus Zucker). The effect of the nitric oxide-synthesis inhibitor L-NAME on the relaxation was reduced in both young and old Zucker rats without change in eNOS expression level. COX inhibition (indomethacin) improved acetylcholine-mediated relaxation in old obese rats only, suggesting involvement of vasoconstrictor prostanoids. In addition, COX2 inhibition (NS398) and TxA2/PGH2 receptor blockade (SQ29548) both improved relaxation in old Zucker rat arteries. Old Zucker rats had the highest TxB2 (TxA2 metabolite) blood level associated with increased COX2 immunostaining. Chronic COX2 blockade (Celecoxib, 3 weeks) restored endothelium-dependent relaxation in old Zucker rats to the level observed in old lean rats. Thus the combination of aging and metabolic syndrome further impairs endothelium-dependent relaxation by inducing an excessive production of COX2-derived vasoconstrictor(s); possibly TxA2

Nucleoside triphosphate diphosphohydrolase-1 ectonucleotidase is required for normal vas deferens contraction and male fertility through maintaining P2X1 receptor function

In this work, we report that Entpd1(-/-) mice, deficient for the ectonucleotidase nucleoside triphosphate diphosphohydrolase-1 (NTPDase1), produce smaller litters (27% reduction) compared with wild-type C57BL6 animals. This deficit is linked to reduced in vivo oocyte fertilization by Entpd1(-/-) males (61 ± 11% versus 88 ± 7% for Entpd1(+/+)). Normal epididymal sperm count, spermatozoa morphology, capacitation, and motility and reduced ejaculated sperm number (2.4 ± 0.5 versus 3.7 ± 0.4 million for Entpd1(+/+)) pointed to vas deferens dysfunction. NTPDase1 was localized by immunofluorescence in the tunica muscularis of the vas deferens. Its absence resulted in a major ATP hydrolysis deficiency, as observed in situ by histochemistry and in primary smooth muscle cell cultures. In vitro, Entpd1(-/-) vas deferens displayed an exacerbated contraction to ATP, a diminished response to its non-hydrolysable analog αβMeATP, and a reduced contraction to electrical field stimulation, suggesting altered P2X1 receptor function with a propensity to desensitize. This functional alteration was accompanied by a 3-fold decrease in P2X1 protein expression in Entpd1(-/-) vas deferens with no variation in mRNA levels. Accordingly, exogenous nucleotidase activity was required to fully preserve P2X1 receptor activation by ATP in vitro. Our study demonstrates that NTPDase1 is required to maintain normal P2X1 receptor functionality in the vas deferens and that its absence leads to impaired peristalsis, reduced spermatozoa concentration in the semen, and, eventually, reduced fertility. This suggests that alteration of NTPDase1 activity affects ejaculation efficacy and male fertility. This work may contribute to unveil a cause of infertility and open new therapeutic potentials

Finger creases lend a hand in Kabuki syndrome.

International audienceKabuki syndrome (KS) is a rare syndrome associating malformations with intellectual deficiency and numerous visceral, orthopedic, endocrinological, immune and autoimmune complications. The early establishment of a diagnostic of KS leads to better care of the patients and therefore prevents complications such as perception deafness, severe complications of auto-immune diseases or obesity. However, the diagnosis of KS remains difficult because based on the appreciation of facial features combined with other highly variable features. We describe a novel sign, namely the attenuation and/or congenital absence of the IPD crease of the third and fourth fingers associated with limitation of flexion of the corresponding joints, which seems to be specific of KS and could help the clinician to diagnose KS

The c.429_452 duplication of the ARX gene: a unique developmental-model of limb kinetic apraxia:

BACKGROUND: The c.429_452dup24 of the ARX gene is a rare genetic anomaly, leading to X-Linked Intellectual Disability without brain malformation. While in certain cases c.429_452dup24 has been associated with specific clinical patterns such as Partington syndrome, the consequence of this mutation has been also often classified as "non-specific Intellectual Disability". The present work aims at a more precise description of the clinical features linked to the c.429_452dup24 mutation. METHODS: We clinically reviewed all affected patients identified in France over a five-year period, i.e. 27 patients from 12 different families. Detailed cognitive, behavioural, and motor evaluation, as well as standardized videotaped assessments of oro-lingual and gestural praxis, were performed. In a sub-group of 13 ARX patients, kinematic and MRI studies were further accomplished to better characterize the motor impairment prevalent in the ARX patients group. To ensure that data were specific to the ARX gene mutation and did not result from low-cognitive functioning per se, a group of 27 age- and IQ-matched Down syndrome patients served as control. RESULTS: Neuropsychological and motor assessment indicated that the c.429_452dup24 mutation constitutes a recognizable clinical syndrome: ARX patients exhibiting Intellectual Disability, without primary motor impairment, but with a very specific upper limb distal motor apraxia associated with a pathognomonic hand-grip. Patients affected with the so-called Partington syndrome, which involves major hand dystonia and orolingual apraxia, exhibit the most severe symptoms of the disorder. The particular "reach and grip" impairment which was observed in all ARX patients, but not in Down syndrome patients, was further characterized by the kinematic data: (i) loss of preference for the index finger when gripping an object, (ii) major impairment of fourth finger deftness, and (iii) a lack of pronation movements. This lack of distal movement coordination exhibited by ARX patients is associated with the loss of independent digital dexterity and is similar to the distortion of individual finger movements and posture observed in Limb Kinetic Apraxia. CONCLUSION: These findings suggest that the ARX c.429_452dup24 mutation may be a developmental model for Limb Kinetic Apraxia

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

Echappement tumoral lors de la chimiothérapie : un choix entre sénescence et apoptose dans des tumeurs hétérogènes

International audienceMots clés Chimiothérapie Sénescence Apoptose Hétérogénéité Résistance Cancer colorectal Résumé Contrer la résistance tumorale est un enjeu majeur des traitements de chimiothérapie. Plusieurs mécanismes d'arrêt inhibent le cycle cellulaire mais alors que ceux-ci semblaient définitifs, des études récentes décrivent l'adaptation des cellules et soulignent l'importance des contrôles mitotiques et post-mitotiques. L'ensemble de ces évènements doit donc être pris en compte pour comprendre la réponse aux chimiothérapies et identifier des marqueurs prédictifs de résistance. Cependant, pour définir ces capacités d'adaptation, il faut également considérer les réponses suppressives induites par ces points de contrôle, l'apoptose et la sénescence. L'apoptose semble un mécanisme suppresseur plus efficace, si l'on considère qu'obtenir une cellule morte est un objectif plus pertinent que de conserver une cellule tumorale arrêtée mais toujours vivante et influençant son environnement. Cependant, comparer ces mécanismes pourrait supposer que toutes les cellules au sein d'une tumeur choisissent exclusivement l'une ou l'autre des réponses. Illustrée dans le cancer colorectal, l'hétérogénéité intra-tumorale, définie comme la présence de clones et altérations différents, est certainement responsable d'une hétérogénéité de réponse au sein d'une même tumeur. De plus, les notions de cellules souches, de plasticité et de micro-environnement complexifient la théorie des stratégies thérapeutiques. La coexistence de cellules proliférantes ou dédifférenciées, de cellules tumorales ou stromales ainsi que leurs relations assurent en effet des capacités d'adaptation efficaces. Au-delà de la compréhension des méca-nismes de réponse et du choix entre apoptose et sénescence, l'hétérogénéité des cellules à cibler, leur plasticité et leur interdépendance restent donc des défis majeurs pour les futures thérapies anticancéreuses. Reçu le 16 octobre 2015 Accepté le 29 octobre 2015 Disponible sur internet le : 4 janvier 2016 tome 103 > n81 > janvier 2016 http://dx