The egocentric spatial reference frame used in dorsal-lateral prefrontal working memory in primates

The dorsal-lateral prefrontal cortex (dlPFC) has been proposed to be the site of spatial working memory (WM), and this concept has had a profound influence on functional studies of the prefrontal cortex (PFC). The concept of spatial WM has been understood to mean that the location of an object is memorized for a short period of time. However, this concept of space is a simplification. To process the spatial information, different spatial frames can be used. In this review, the authors present data from their own laboratory to argue that the dlPFC is related to the egocentric spatial information processing (ESIP) in WM. The goal of this review is to introduce and discuss the egocentric spatial reference frame (ESRF) located in the dlPFC. The ESIP in the PFC might be involved in self-recognition.     

Fish melanocortin system

Melanocortin signalling is mediated by binding to a family of G protein-coupled receptors that positively couple to adenylyl cyclase. Tetrapod species have five melanocortin (MC₁–MC₅) receptors. The number of receptors varies in fish, zebrafish, for example, having six melanocortin receptors, with two copies of the melanocortin MC₅ receptor, while pufferfish have 4 receptors with no melanocortin MC₃ receptor and one copy of melanocortin MC₅ receptor. Fish genomes also exhibit orthologue genes for agouti-signalling protein (ASP) and -related protein (AGRP). AGRP expression is confined to a small area in the hypothalamus but ASP is expressed in the skin. Fish melanocortin MC₂ receptor is specific for ACTH and requires the cooperation of accessory proteins (MRAP) to reach functional expression. The four other melanocortin MC receptors distinctively bind MSHs. The interaction of α-MSH and melanocortin MC₁ receptor plays a key point in the control of the pigmentation and mutations of melanocortin MC₁ receptor are responsible for reduced melanization. Both melanocortin MC₄ and MC₅ receptor are expressed in the hypothalamus, and central melanocortin MC₄ receptor expression is thought to regulate the energy balance through the modulation of feeding behaviour. In addition, the peripheral melanocortin system also regulates lipid metabolism by acting at hepatic melanocortin MC₂ and MC₅ receptors. Both sea bass melanocortin MC₁ and MC₄ receptors are constitutively expressed in vitro and both ASP and AGRP work as inverse agonists but only after inhibition of the phosphodiesterase system. Accordingly, the overexpression of AGRP and ASP transgenes promotes obesity and reduces melanization in zebrafish, respectively.     

The early origin of melanocortin receptors, agouti-related peptide, agouti signalling peptide, and melanocortin receptor-accessory proteins, with emphasis on pufferfishes, elephant shark, lampreys, and amphioxus

There are conflicting theories about the evolution of melanocortin MC receptors while only few studies have addressed the evolution of agouti-related peptide (AgRP) and agouti signalling peptide (ASIP), which are antagonists at the melanocortin receptors (MCRs), or the melanocortin MC₂ receptor accessory proteins (MRAP1 and MRAP2). Previously we have cloned melanocortin MC receptors (MC_a and MC_b) genes in river lamprey and here we identify orthologues to these melanocortin MC receptor sequences in the sea lamprey. We investigate the putative presence of the melanocortin MC receptor genes in lancelet (amphioxus; Branchiostoma floridae) but we find it unlikely that such gene exists, due to a sharp drop in sequence similarity beyond sequence clusters of known receptors. We show the presence of AgRP and ASIP in elephant shark, a cartilaginous fish belonging to the subclass of Elasmobranchii. However, we do not find any of these genes in lamprey or lancelet after detailed analysis of both targeted and whole proteome regular expression scans. We found MRAP2, but not MRAP1, to be present in elephant shark and sea lamprey while Fugu (T. rubripes) has both genes. This study shows that the most ancient presence of these melanocortin-related sequences is found in elephant shark and lampreys considering the current available sequence data.     

The contribution of melanocortin 1 receptor gene polymorphisms and the agouti signalling protein gene 8818A>G polymorphism to cutaneous melanoma and basal cell carcinoma in a Polish population

Abstract:  In this study, we assessed the role of melanocortin-1 receptor (MC1R) and agouti signalling protein (ASIP) polymorphisms in cutaneous melanoma and basal cell carcinoma (BCC) development in a Polish population. We enrolled 108 patients with skin malignant melanoma (MM) and 102 patients with BCC. The control group consisted of 93 non-red haired patients, without history of skin cancers and 30 healthy individuals with red hair colour (RHC) phenotype. The complete MC1R exon was sequenced and the A8818G polymorphism of the ASIP gene was analysed using the SnaPshot protocol. Selected MC1R mutations were additionally examined using a convenient minisequencing assay. The study confirmed the important role of MC1R R variants in determining physiological variation in hair and skin colour. Our data show that individuals with R mutations had a 3.7-fold increase in melanoma risk and a 3.3-fold increase in BCC risk. Especially, variant R151C significantly increased the risk of both MM and BCC. The studied ASIP polymorphism was found not to be associated with MM or BCC. Stratified analysis showed that the association between MC1R mutations and the risk of MM and BCC was not significantly influenced by subjects' pigmentation characteristics or the 8818G ASIP variant. Further research is necessary, especially involving analysis of interactions between variation in MC1R and other genes, to find out if analysis of MC1R polymorphisms could be of any importance for skin cancer prevention.     

Inherited variation at MC1R and ASIP and association with melanoma‐specific survival

Melanocortin‐1 receptor (MC1R) is a marker of melanoma risk in populations of European ancestry. However, MC1R effects on survival are much less studied. We investigated associations between variation at MC1R and survival in an international, population‐based series of single primary melanoma patients enrolled into the Genes, Environment, and Melanoma study. MC1R genotype data was available for 2,200 participants with a first incident primary melanoma diagnosis. We estimated the association of MC1R genotypes with melanoma‐specific survival (i.e., death caused by melanoma) and overall survival using COX proportional hazards modeling, adjusting for established prognostic factors for melanoma. We also conducted stratified analyses by Breslow thickness, tumor site, phenotypic index, and age. In addition, we evaluated haplotypes involving polymorphisms near the Agouti signaling protein gene (ASIP) locus for their impacts on survival. Melanoma‐specific survival was inversely associated with carriage of MC1R variants in the absence of consensus alleles compared to carriage of at least one consensus allele (hazard ratio (HR) = 0.60; 95% confidence interval (CI): 0.40, 0.90). MC1R results for overall survival were consistent with no association. We did not observe any statistical evidence of heterogeneity of effect estimates in stratified analyses. We observed increased hazard of melanoma‐specific death among carriers of the risk haplotype TG near the ASIP locus (HR = 1.37; 95% CI: 0.91, 2.04) when compared to carriers of the most common GG haplotype. Similar results were noted for overall survival. Upon examining the ASIP TG/TG diplotype, we observed considerably increased hazard of melanoma‐specific death (HR = 5.11; 95% CI: 1.88, 13.88) compared to carriers of the most common GG/GG diplotype. Our data suggest improved melanoma‐specific survival among carriers of two inherited MC1R variants.     

Variants at chromosome 20 (ASIP locus) and melanoma risk

Agouti signaling protein (ASIP) locus on chromosome 20q11 is implicated, as shown by genome‐wide association studies, in phenotype variation and melanoma risk. We genotyped 837 melanoma cases and 1,154 controls for 21 single nucleotide polymorphisms (SNPs) informative for 495 polymorphisms at the locus. Our data showed an increased risk of melanoma (odds ratio [OR] 1.27, 95% confidence interval [95% CI] 1.03–1.57) in carriers of the rs4911414 variant, located 120 kb upstream of ASIP. The main effect of rs4911414, as reported previously, was in tandem with a 10 kb adjacent polymorphism rs1015362; two constituted risk‐associated haplotype/diplotype. Except for rs1015363, none of the 12 tagging SNPs, genotyped to cover 239.9 kb region with polymorphisms linked to rs4911414 and rs1015362, were associated with melanoma. Our data confirmed a previous association of melanoma risk (OR 1.82, 95% CI 1.37–2.41) with rs4911442, located in intron 5 of the nuclear receptor coactivator 6 (NCOA6) gene. The rs910871, one of the six variants, genotyped to cover NCOA6, showed an association with melanoma risk (OR 1.33, 95% CI 1.04–1.70). Both, rs4911442 and rs910871 were in moderate linkage with a, previously reported, risk‐associated rs910873 polymorphism. A haplotype from the variants within NCOA6 showed an association with risk of melanoma (OR 1.49, 95% CI 1.17–1.88). Interaction between risk‐associated polymorphisms and previously genotyped melanocortin receptor 1 (MC1R) variants, in our study, was not statistically significant. Nevertheless, the carriers of the variant alleles over the background of MC1R variants were at a higher risk than the carriers not enriched for MC1R variants. Our data confirmed the association of different variants at chromosome 20q11 with melanoma risk.     

hASIP基因在乳腺癌中的表达及其意义

目的:检测hASIP基因在人乳腺癌中的表达并分析其与临床病理指标的相关性,进一步探讨hASIP与乳腺癌的关系。方法:以RT-PCR法检测人乳腺癌及癌旁组织中hASIP的表达情况,并与临床及病理常用指标作对照分析。结果:hASIP-a在癌组织中的表达率为92.5%(49/53),在癌旁组织中的表达率为75.5%(40/53),两者之间有统计学差异(P<0.05)。hASIP-b在癌组织中的表达率为54.7%(29/53),在癌旁组织中的表达率为43.4%(23/53),两者之间无统计学差异(P>0.05)。以癌旁组织为参照,hASIP-a在癌组织中表达上调的占64.2%(34/53);hASIP-b在癌组织中表达上调的占32.1%(17/53)。两者之间有显著统计学差异(P<0.01)。hASIP-a高表达与乳腺癌病人年龄>50岁、肿瘤分期早、ER阳性、病理为除浸润性导管癌外的其它浸润性癌相关(P<0.05)。结论:hASIP-a在人乳腺癌中存在高表达。乳腺癌病人年龄>50岁、肿瘤分期早、ER阳性、病理为除浸润性导管癌外的其它浸润性癌,可能是hASIP-a高表达的相关因素。