Mucuna pruriens (Velvet bean) Rescues Motor, Olfactory, Mitochondrial and Synaptic Impairment in PINK1(B9) Drosophila melanogaster Genetic Model of Parkinson's Disease

The fruit fly Drosophila melanogaster (Dm) mutant for PTEN-induced putative kinase 1 (PINK1B9) gene is a powerful tool to investigate physiopathology of Parkinson's disease (PD). Using PINK1B9 mutant Dm we sought to explore the effects of Mucuna pruriens methanolic extract (Mpe), a L-Dopa-containing herbal remedy of PD. The effects of Mpe on PINK1B9 mutants, supplied with standard diet to larvae and adults, were assayed on 3–6 (I), 10–15 (II) and 20–25 (III) days old flies. Mpe 0.1% significantly extended lifespan of PINK1B9 and fully rescued olfactory response to 1-hexanol and improved climbing behavior of PINK1B9 of all ages; in contrast, L-Dopa (0.01%, percentage at which it is present in Mpe 0.1%) ameliorated climbing of only PINK1B9 flies of age step II. Transmission electron microscopy analysis of antennal lobes and thoracic ganglia of PINK1B9 revealed that Mpe restored to wild type (WT) levels both T-bars and damaged mitochondria. Western blot analysis of whole brain showed that Mpe, but not L-Dopa on its own, restored bruchpilot (BRP) and tyrosine hydroxylase (TH) expression to age-matched WT control levels. These results highlight multiple sites of action of Mpe, suggesting that its effects cannot only depend upon its L-Dopa content and support the clinical observation of Mpe as an effective medication with intrinsic ability of delaying the onset of chronic L-Dopa-induced long-term motor complications. Overall, this study strengthens the relevance of using PINK1B9 Dm as a translational model to study the properties of Mucuna pruriens for PD treatment

Vitamin D responsive elements within the HLA-DRB1 promoter region in Sardinian multiple sclerosis associated alleles

Vitamin D response elements (VDREs) have been found in the promoter region of the MS-associated allele HLA-DRB1*15:01, suggesting that with low vitamin D availability VDREs are incapable of inducing *15:01 expression allowing in early life autoreactive T-cells to escape central thymic deletion. The Italian island of Sardinia exhibits a very high frequency of MS and high solar radiation exposure. We test the contribution of VDREs analysing the promoter region of the MS-associated DRB1 *04:05, *03:01, *13:01 and *15:01 and non-MS-associated *16:01, *01, *11, *07:01 alleles in a cohort of Sardinians (44 MS patients and 112 healthy subjects). Sequencing of the DRB1 promoter region revealed a homozygous canonical VDRE in all *15:01, *16:01, *11 and in 45/73 *03:01 and in heterozygous state in 28/73 *03:01 and all *01 alleles. A new mutated homozygous VDRE was found in all *13:03, *04:05 and *07:01 alleles. Functionality of mutated and canonical VDREs was assessed for its potential to modulate levels of DRB1 gene expression using an in vitro transactivation assay after stimulation with active vitamin D metabolite. Vitamin D failed to increase promoter activity of the *04:05 and *03:01 alleles carrying the new mutated VDRE, while the *16:01 and *03:01 alleles carrying the canonical VDRE sequence showed significantly increased transcriptional activity. The ability of VDR to bind the mutant VDRE in the DRB1 promoter was evaluated by EMSA. Efficient binding of VDR to the VDRE sequence found in the *16:01 and in the *15:01 allele reduced electrophoretic mobility when either an anti-VDR or an anti-RXR monoclonal antibody was added. Conversely, the Sardinian mutated VDRE sample showed very low affinity for the RXR/VDR heterodimer. These data seem to exclude a role of VDREs in the promoter region of the DRB1 gene in susceptibility to MS carried by DRB1* alleles in Sardinian patients

Resilient inter-carrier traffic engineering for internet peering interconnections

Abstract—We present a novel resilient routing policy for controlling the routing across peering links between Internet carriers. Our policy is aimed at offering more dependability and better performance to the routing decision with respect to the current practice (e.g., hot-potato routing). Our work relies on a non-cooperative game framework, called Peering Equilibrium MultiPath (PEMP), that has been recently proposed. PEMP allows two carrier providers to coordinate a multipath route selection for critical flows across peering links, while preserving their respective interests and independence. In this paper, we propose a resilient PEMP execution policy accounting for the occurrence of potential impairments (traffic matrix variations, intra-AS and peering link failures) that may occur in both peering networks. We mathematically define how to produce robust equilibrium sets and describe how to appropriately react to unexpected network impairments that might take place. The results from extensive simulations show that, under a realistic failure scenario, our policy adaptively prevents from peering link congestions and excessive route deviations after failures. Index Terms—Routing resiliency, Internet reliability, peering management, game theory, BGP, inter-domain routing, multipath routing

A Resilient Routing Policy for Peering Management

Abstract—We present a novel resilient routing policy for controlling the routing across peering links between Internet carriers. Our policy is aimed at offering more dependability and better performance to the routing decision with respect to the current practice (e.g., hot-potato routing). Our work relies on a non-cooperative game framework, called Peering Equilibrium MultiPath (PEMP), that has been recently proposed. PEMP allows two carrier providers to coordinate a multipath route selection for critical flows across peering links, while preserving their respective interests and independence. In this paper, we propose a resilient PEMP execution policy accounting for the occurrence of potential impairments (traffic matrix variations, intra-AS and peering link failures) that may occurr in both peering networks. We mathematically define how to produce robust equilibrium sets and describe how to appropriately react to unexpected network impairments that might take place. The results from extensive simulations show that, under a realistic failure scenario, our policy adaptively prevents from peering link congestions and excessive route deviations after failures 1. I

The Sardinian autoimmunity study: 3. Studies on circulating antithyroid antibodies in Sardinian schoolchildren: Relationship to goiter prevalence and thyroid function

he relationship among iodine intake, goiter prevalence, and thyroid autoimmunity remains controversial. In the present article, we report the prevalence of antithyroid antibodies (ATA) in relation to iodine intake, frequency of goiter, and thyroid function in a large group of Sardinian schoolchildren living in areas with borderline iodine sufficiency, or mild to moderate iodine deficiency. A total of 8,040 schoolchildren (4,194 males, 3,846 females, ages 6-15 years) from 29 communities were examined between 1986-1994. Thyroid size was assessed by palpation, according to the Pan American Health Organization (PAHO) criteria. In all cases antimicrosomal (MAb) or antithyroid peroxidase antibodies (TPOAb) and thyrotropin (TSH) were assayed. Urinary iodine was determined in a subgroup of 820 children. ATA was detected in 235 (2.92%) sera (88 males, 2.12%; 147 females, 3.82%; chi2 = 20.41, p < 0.0001). ATA prevalence ranged between 0.0%-7.3% in the 29 communities without any geographical correlation with goiter prevalence and urinary iodine excretion. However, ATA was more frequently detected in goitrous children, especially in females. The presence of ATA was not age-dependent in males, whereas a significant increase of ATA was observed in females older than 11 years of age. Seventy-seven (0.96%) children showed borderline to slightly increased serum TSH (>5.2-32 mU/L). Increased serum TSH concentration was more frequently found in children with ATA, especially at higher titers. In summary, our study in Sardinian schoolchildren indicates: (1) ATA display geographical heterogeneity, which seems to be unrelated to goiter prevalence and/or to iodine supply; (2) ATA are more frequently detected in females older than 11 years of age, suggesting that puberty has a role in determining the predominance in females of thyroid autoimmunity; (3) although most goitrous children are ATA-negative, the prevalence of ATA is increased in children with enlarged glands; (4) ATA is associated with an increased prevalence of subclinical hypothyroidism