Antagonism of the Prokineticin System Prevents and Reverses Allodynia and Inflammation in a Mouse Model of Diabetes

Neuropathic pain is a severe diabetes complication and its treatment is not satisfactory. It is associated with neuroinflammation-related events that participate in pain generation and chronicization. Prokineticins are a new family of chemokines that has emerged as critical players in immune system, inflammation and pain. We investigated the role of prokineticins and their receptors as modulators of neuropathic pain and inflammatory responses in experimental diabetes. In streptozotocin-induced-diabetes in mice, the time course expression of prokineticin and its receptors was evaluated in spinal cord and sciatic nerves, and correlated with mechanical allodynia. Spinal cord and sciatic nerve pro- and anti-inflammatory cytokines were measured as protein and mRNA, and spinal cord GluR subunits expression studied. The effect of preventive and therapeutic treatment with the prokineticin receptor antagonist PC1 on behavioural and biochemical parameters was evaluated. Peripheral immune activation was assessed measuring macrophage and T-helper cytokine production. An up-regulation of the Prokineticin system was present in spinal cord and nerves of diabetic mice, and correlated with allodynia. Therapeutic PC1 reversed allodynia while preventive treatment blocked its development. PC1 normalized prokineticin levels and prevented the up-regulation of GluN2B subunits in the spinal cord. The antagonist restored the pro-/anti-inflammatory cytokine balance altered in spinal cord and nerves and also reduced peripheral immune system activation in diabetic mice, decreasing macrophage proinflammatory cytokines and the T-helper 1 phenotype. The prokineticin system contributes to altered sensitivity in diabetic neuropathy and its inhibition blocked both allodynia and inflammatory events underlying disease.     

Community perspectives on scabies,impetigo and mass drug administration in Fiji: A qualitative study

Scabies is endemic in Fiji and is a significant cause of morbidity. Little is known about the sociocultural beliefs and practices that affect the occurrence of scabies and impetigo, or community attitudes towards the strategy of mass drug administration that is emerging as a public health option for scabies and impetigo control in Fiji and other countries. Data were collected during semi-structured interviews with 33 community members in four locations in Fiji’s Northern Division. Thematic analysis examined participants’ lived experiences of scabies and impetigo; community knowledge and perceptions about scabies and impetigo aetiology and transmission; community-based treatment and prevention measures; and attitudes towards mass drug administration. Many indigenous Fijian (iTaukei) participants noted extensive and ongoing experience of scabies and impetigo among children in their families and communities, but only one participant of Indian descent (Indo-Fijian) identified personal childhood experience of scabies. Scabies and impetigo were perceived as diseases affecting children, impacting on school attendance and families’ quality of sleep. Awareness of scabies and impetigo was considerable, but there were major misconceptions around disease causation and transmission. Traditional remedies were preferred for scabies treatment, followed by biomedicines provided by local health centres and hospitals. Treatment of close household contacts was not prioritised. Attitudes towards mass drug administration to control scabies were mostly positive, although some concerns were noted about adverse effects and hesitation to participate in the planned scabies elimination programme. Findings from this first study to document perspectives and experiences related to scabies and impetigo and their management in the Asia Pacific region illustrate that a community-centred approach to scabies and impetigo is needed for the success of control efforts in Fiji, and most likely in other affected countries. This includes community-based health promotion messaging on the social dynamics of scabies transmission, and a campaign of education and community engagement prior to mass drug administration.     

Systematic review of Atractus schach (Serpentes: Dipsadidae) species complex from the Guiana Shield with description of three new species

The Guiana Shield harbours one of the best preserved and largest extents of tropical forest on Earth and an immense biodiversity. The herpetofauna of this region remains poorly known. The species-rich snake genus Atractus contains ～140 species, many with complicated taxonomic histories, including A. schach. Examination of specimens in museums and newly collected material from French Guiana has allowed the illustration of hemipenial morphology for the first time and an expanded diagnosis. Concatenated molecular phylogenetic (mitochondrial and nuclear genes) and phenotypic (morphometrics, external and hemipenial morphology) analyses confirm non-monophyly of the A. flammigerus group and indicate that A. schach is a species complex with three new species described here. The geographic distribution of A. schach sensu stricto is restricted to Guiana, Surinam, and French Guiana north of Tumucumaque massif. Populations tentatively assigned to A. schach from the east from French Guiana in the Roura lowlands to Almeirim, and from central Amazonia between the Negro and Trombetas rivers in Brazil are also recognized as new species. Our results suggest that populations from south of the Amazon River are not conspecific with those from the Guiana Shield.

http://www.zoobank.org/urn:lsid:zoobank.org:pub:A7AE40BC-4716-4302-B3BE-1F43600B0A72     

Modeling squid axon Na+ channel by a nucleation and growth kinetic mechanism

A kinetic model accounting for all salient features of the Na⁺ channel of the squid giant axon is provided. The model furnishes explanations for the Cole-Moore-like effect, the rising phase of the ON gating current and the slow ‘intermediate component’ of its decaying phase, as well as the gating charge immobilization. Experimental ON ionic currents are semi-quantitatively simulated by the use of only three free parameters, upon assuming that the Na⁺ channel opening proceeds along with the stepwise aggregation of its four domains, while they are moving their gating charge outward under depolarizing conditions. The inactivation phase of the ON ionic current is interpreted by a progressive electrostatic attraction between the positively charged ‘hinged lid’ containing the hydrophobic IFM triad and its receptor inside the channel pore, as the stepwise outward movement of the S4 segments of the Na⁺ channel progressively increases the negative charge attracting the triad to its receptor. The Na⁺ channel closing is assumed to proceed by repolarization-induced disaggregation of its domains, accompanied by inward movement of their gating charge. The phenomenon of ‘gating charge immobilization’ can be explained by assuming that gradual structural changes of the receptor over the time course of depolarization strengthen the interaction between the IFM triad and its receptor, causing a slow release of the gating charge during the subsequent repolarization.     

Quantifying personal exposure to air pollution from smartphone‐based location data

Personal exposure assessment is a challenging task that requires both measurements of the state of the environment as well as the individual's movements. In this paper, we show how location data collected by smartphone applications can be exploited to quantify the personal exposure of a large group of people to air pollution. A Bayesian approach that blends air quality monitoring data with individual location data is proposed to assess the individual exposure over time, under uncertainty of both the pollutant level and the individual location. A comparison with personal exposure obtained assuming fixed locations for the individuals is also provided. Location data collected by the Earthquake Network research project are employed to quantify the dynamic personal exposure to fine particulate matter of around 2500 people living in Santiago (Chile) over a 4‐month period. For around 30% of individuals, the personal exposure based on people movements emerges significantly different over the static exposure. On the basis of this result and thanks to a simulation study, we claim that even when the individual location is known with nonnegligible error, this helps to better assess personal exposure to air pollution. The approach is flexible and can be adopted to quantify the personal exposure based on any location‐aware smartphone application.     

Genetic variants modify the effect of age on APOE methylation in the Genetics of Lipid Lowering Drugs and Diet Network study

Although apolipoprotein E (APOE) variants are associated with age-related diseases, the underlying mechanism is unknown and DNA methylation may be a potential one. With methylation data, measured by the Infinium Human Methylation 450 array, from 993 participants (age ranging from 18 to 87 years) in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study, and from Encyclopedia of DNA Elements (ENCODE) consortium, combined with published methylation datasets, we described the methylation pattern of 13 CpG sites within APOE locus, their correlations with gene expression across cell types, and their relationships with age, plasma lipids, and sequence variants. Based on methylation levels and the genetic regions, we categorized the 13 APOE CpG sites into three groups: Group 1 showed hypermethylation (> 50%) and were located in the promoter region, Group 2 exhibited hypomethylation (< 50%) and were located in the first two exons and introns, and Group 3 showed hypermethylation (> 50%) and were located in the exon 4. APOE methylation was negatively correlated with gene expression (minimum r = −0.66, P = 0.004). APOE methylation was significantly associated with age (minimum P = 2.06E-08) and plasma total cholesterol (minimum P = 3.53E-03). Finally, APOE methylation patterns differed across APOE ε variants (minimum P = 3.51E-05) and the promoter variant rs405509 (minimum P = 0.01), which further showed a significant interaction with age (P = 0.03). These findings suggest that methylation may be a potential mechanistic explanation for APOE functions related to aging and call for further molecular mechanistic studies.