Chimera patterns and subthreshold oscillations in two-dimensional networks of fractally coupled leaky integrate-and-fire neurons.

We discuss the effects that fractal coupling induces on chimera states in a network of leaky integrate-and-fire (LIF) oscillators arranged in a two-dimensional toroidal geometry. We provide evidence that the introduction of a hierarchical coupling topology in the form of a Sierpinski carpet gives rise to complex spatial structures such as multiple spots, stripe-and-grid chimeras, as well as traveling waves and subthreshold oscillations. Unlike in the case of typical nonlocal connectivity, when tuning the coupling strength to small positive values a spot chimera is formed with internal structure reminiscent of the fractal connectivity scheme. This is in line with previous results for one-dimensional networks, where hierarchical connectivity also induces chimeras with stratified spatial arrangements. In the case of negative coupling, cooperative effects produce subthreshold oscillating regions with traveling active islands crossing through them. Subthreshold oscillations and traveling waves are frequently reported in biological neural network experiments.

Neocerebellar Crus I Abnormalities Associated with a Speech and Language Disorder Due to a Mutation in FOXP2.

Bilateral volume reduction in the caudate nucleus has been established as a prominent brain abnormality associated with a FOXP2 mutation in affected members of the 'KE family', who present with developmental orofacial and verbal dyspraxia in conjunction with pervasive language deficits. Despite the gene's early and prominent expression in the cerebellum and the evidence for reciprocal cerebellum-basal ganglia connectivity, very little is known about cerebellar abnormalities in affected KE members. Using cerebellum-specific voxel-based morphometry (VBM) and volumetry, we provide converging evidence from subsets of affected KE members scanned at three time points for grey matter (GM) volume reduction bilaterally in neocerebellar lobule VIIa Crus I compared with unaffected members and unrelated controls. We also show that right Crus I volume correlates with left and total caudate nucleus volumes in affected KE members, and that right and total Crus I volumes predict the performance of affected members in non-word repetition and non-verbal orofacial praxis. Crus I also shows bilateral hypo-activation in functional MRI in the affected KE members relative to controls during non-word repetition. The association of Crus I with key aspects of the behavioural phenotype of this FOXP2 point mutation is consistent with recent evidence of cerebellar involvement in complex motor sequencing. For the first time, specific cerebello-basal ganglia loops are implicated in the execution of complex oromotor sequences needed for human speech.

Source apportionment of PM10 and PM2.5 in major urban Greek agglomerations using a hybrid source-receptor modeling process.

A hybrid source-receptor modeling process was assembled, to apportion and infer source locations of PM10 and PM2.5 in three heavily-impacted urban areas of Greece, during the warm period of 2011, and the cold period of 2012. The assembled process involved application of an advanced computational procedure, the so-called Robotic Chemical Mass Balance (RCMB) model. Source locations were inferred using two well-established probability functions: (a) the Conditional Probability Function (CPF), to correlate the output of RCMB with local wind directional data, and (b) the Potential Source Contribution Function (PSCF), to correlate the output of RCMB with 72h air-mass back-trajectories, arriving at the receptor sites, during sampling. Regarding CPF, a higher-level conditional probability function was defined as well, from the common locus of CPF sectors derived for neighboring receptor sites. With respect to PSCF, a non-parametric bootstrapping method was applied to discriminate the statistically significant values. RCMB modeling showed that resuspended dust is actually one of the main barriers for attaining the European Union (EU) limit values in Mediterranean urban agglomerations, where the drier climate favors build-up. The shift in the energy mix of Greece (caused by the economic recession) was also evidenced, since biomass burning was found to contribute more significantly to the sampling sites belonging to the coldest climatic zone, particularly during the cold period. The CPF analysis showed that short-range transport of anthropogenic emissions from urban traffic to urban background sites was very likely to have occurred, within all the examined urban agglomerations. The PSCF analysis confirmed that long-range transport of primary and/or secondary aerosols may indeed be possible, even from distances over 1000km away from study areas.

Non-invasive cerebellar stimulation--a consensus paper.

The field of neurostimulation of the cerebellum either with transcranial magnetic stimulation (TMS; single pulse or repetitive (rTMS)) or transcranial direct current stimulation (tDCS; anodal or cathodal) is gaining popularity in the scientific community, in particular because these stimulation techniques are non-invasive and provide novel information on cerebellar functions. There is a consensus amongst the panel of experts that both TMS and tDCS can effectively influence cerebellar functions, not only in the motor domain, with effects on visually guided tracking tasks, motor surround inhibition, motor adaptation and learning, but also for the cognitive and affective operations handled by the cerebro-cerebellar circuits. Verbal working memory, semantic associations and predictive language processing are amongst these operations. Both TMS and tDCS modulate the connectivity between the cerebellum and the primary motor cortex, tuning cerebellar excitability. Cerebellar TMS is an effective and valuable method to evaluate the cerebello-thalamo-cortical loop functions and for the study of the pathophysiology of ataxia. In most circumstances, DCS induces a polarity-dependent site-specific modulation of cerebellar activity. Paired associative stimulation of the cerebello-dentato-thalamo-M1 pathway can induce bidirectional long-term spike-timing-dependent plasticity-like changes of corticospinal excitability. However, the panel of experts considers that several important issues still remain unresolved and require further research. In particular, the role of TMS in promoting cerebellar plasticity is not established. Moreover, the exact positioning of electrode stimulation and the duration of the after effects of tDCS remain unclear. Future studies are required to better define how DCS over particular regions of the cerebellum affects individual cerebellar symptoms, given the topographical organization of cerebellar symptoms. The long-term neural consequences of non-invasive cerebellar modulation are also unclear. Although there is an agreement that the clinical applications in cerebellar disorders are likely numerous, it is emphasized that rigorous large-scale clinical trials are missing. Further studies should be encouraged to better clarify the role of using non-invasive neurostimulation techniques over the cerebellum in motor, cognitive and psychiatric rehabilitation strategies.

Gene expression profiling in subcutaneous, visceral and epigastric adipose tissues of patients with extreme obesity.

OBJECTIVE: The goal of the present study was to identify differences in gene expression between SAT, VAT and EAT depots in Class III severely obese individuals. DESIGN: Human subcutaneous (SAT) and visceral (VAT) adipose tissues exhibit differential gene expression profiles. There is little information, however, about the other proximal white adipose tissue, epigastric (EAT), in terms of its function and contribution to metabolism. SUBJECTS AND METHODS: Using RNA from adipose biospecimens obtained from Class III severely obese patients undergoing open Roux-en-Y gastric bypass surgery, we compared gene expression profiles between SAT, VAT and EAT, using microarrays validated by real-time quantitative PCR. RESULTS: The three depots were found to share 1907 genes. VAT had the greatest number of genes (66) expressed exclusively in this depot, followed by SAT (23), and then EAT (14). Moreover, VAT shared more genes with EAT (65) than with SAT (38). Further analyses using ratios of SAT/EAT, VAT/EAT and SAT/VAT identified specific as well as overlapping networks and pathways of genes representing dermatological diseases, inflammation, cell cycle and growth, cancer and development. Targeted analysis of genes, having a role in adipose tissue development and function, revealed that Peroxisome proliferator-activated receptor Gamma Coactivator 1-alpha (PGC1-α) that regulates the precursor of the hormone Irisin (FNCD5) were abundantly expressed in all three fat depots, along with fibroblast growth factors (FGF) FGF1, FGF7 and FGF10, whereas, FGF19 and FGF21 were undetectable. CONCLUSIONS: These data indicate that EAT has more in common with VAT, suggesting similar metabolic potential. The human epigastric adipose depot could have a significant functional role in metabolic diseases and should be further investigated.

Concentrations and source apportionment of PM10 and associated elemental and ionic species in a lignite-burning power generation area of southern Greece.

Ambient concentrations of PM10 and associated elemental and ionic species were measured over the cold and the warm months of 2010 at an urban and two rural sites located in the lignite-fired power generation area of Megalopolis in Peloponnese, southern Greece. The PM10 concentrations at the urban site (44.2 ± 33.6 µg m(-3)) were significantly higher than those at the rural sites (23.7 ± 20.4 and 22.7 ± 26.9 µg m(-3)). Source apportionment of PM10 and associated components was accomplished by an advanced computational procedure, the robotic chemical mass balance model (RCMB), using chemical profiles for a variety of local fugitive dust sources (power plant fly ash, flue gas desulfurization wet ash, feeding lignite, infertile material from the opencast mines, paved and unpaved road dusts, soil), which were resuspended and sampled through a PM10 inlet onto filters and then chemically analyzed, as well as of other common sources such as vehicular traffic, residential oil combustion, biomass burning, uncontrolled waste burning, marine aerosol, and secondary aerosol formation. Geological dusts (road/soil dust) were found to be major PM10 contributors in both the cold and warm periods of the year, with average annual contribution of 32.6 % at the urban site vs. 22.0 and 29.0 % at the rural sites. Secondary aerosol also appeared to be a significant source, contributing 22.1 % at the urban site in comparison to 30.6 and 28.7 % at the rural sites. At all sites, the contribution of biomass burning was most significant in winter (28.2 % at the urban site vs. 14.6 and 24.6 % at the rural sites), whereas vehicular exhaust contribution appeared to be important mostly in the summer (21.9 % at the urban site vs. 11.5 and 10.5 % at the rural sites). The highest contribution of fly ash (33.2 %) was found at the rural site located to the north of the power plants during wintertime, when winds are favorable. In the warm period, the highest contribution of fly ash was found at the rural site located to the south of the power plants, although it was less important (7.2 %). Moderate contributions of fly ash were found at the urban site (5.4 and 2.7 % in the cold and the warm period, respectively). Finally, the mine field was identified as a minor PM10 source, occasionally contributing with lignite dust and/or deposited wet ash dust under dry summer conditions, with the summertime contributions ranging between 3.1 and 11.0 % among the three sites. The non-parametric bootstrapped potential source contribution function analysis was further applied to localize the regions of sources apportioned by the RCMB. For the majority of sources, source regions appeared as being located within short distances from the sampling sites (within the Peloponnesse Peninsula). More distant Greek areas of the NNE sector also appeared to be source regions for traffic emissions and secondary calcium sulfate dust.

The role of the Agouti-Related Protein in energy balance regulation.

The Agouti-Related Protein (AgRP) is a powerful orexigenic peptide that increases food intake when ubiquitously overexpressed or when administered centrally. AgRP-deficiency, on the other hand, leads to increased metabolic rate and a longer lifespan when mice consume a high fat diet. In humans, AgRP polymorphisms have been consistently associated with resistance to fatness in Blacks and Whites and resistance to the development of type-2 diabetes in African Blacks. Systemically administered AgRP accumulates in the liver, the adrenal gland and fat tissue while recent findings suggest that AgRP may also have inverse agonist effects, both centrally and peripherally. AgRP could thus modulate energy balance via different actions. Its absence or reduced functionality may offer a benefit both in terms of bringing about negative energy balance in obesigenic environments, as well as leading to an increased lifespan.

A rare mutation in AgRP, +79G>A, affects promoter activity.

The agouti-related protein is a powerful orexigenic peptide. A rare mutation, +79G>A, was identified in its minimal promoter in two white carriers. Comparison of the 45-year-old male proband, who was also a carrier of the common Ala67Thr polymorphism, with an age- and weight-matching wild-type population showed marginal differences for resting metabolic rate (RMR) and body mass index. The second carrier however was an obese 57-year-old female with reduced RMR. Functional analysis in hypothalamus- and periphery-derived cell lines showed reduced promoter activity for the +79A allele in the adrenocortical cells only, suggesting that it could affect the peripheral expression levels of AgRP. The +79G>A mutation could predispose to body weight gain (as suggested by the phenotype of the second carrier), but it could only affect the proband at an older age as he may be protected by the Ala67Thr polymorphism that is associated with resistance to late-onset fatness.

Agouti-related protein promoter variant associated with leanness and decreased risk for diabetes in West Africans.

OBJECTIVE: The role of the central melanocortin system in the development of obesity has been extensively studied. Single-nucleotide polymorphisms (SNPs) within several candidate genes have been associated with food intake and obesity-related phenotypes; however, few of these associations have been replicated. SNPs in the agouti-related protein (AGRP) gene coding (Ala67Thr, 199G/A) and promoter (-38C/T) have been reported to be associated with body mass index (BMI), fat mass (FM) and percent body fat, in populations of European and African descent. In this study, we evaluated the association between the functional AGRP -38C/T promoter SNP and weight-related traits, namely BMI, FM and fat-free mass (FFM), as well as diabetes status. DESIGN: An association study of the AGRP -38C/T SNP and indices of obesity and diabetes status. SUBJECTS: A well-characterized population of 538 West Africans from Ghana and Nigeria recruited in the AADM (Africa America Diabetes Mellitus) study (mean age 52 years, 41.3% males, 71% diabetic). MEASUREMENTS: Genotyping of the AGRP -38C/T SNP, BMI, FM, FFM and fasting plasma glucose. RESULTS: Women carrying two copies of the variant T allele had significantly lower BMI (OR=0.47; 95% CI, 0.25-0.87). Also, men with at least one copy of the variant T allele were over two times less likely to be diabetic than other men (OR=0.44; 95% CI, 0.22-0.89). CONCLUSION: Our results replicate previous findings and implicate the AGRP -38C/T SNP in the regulation of body weight in West Africans.

Functional dimorphism of two hAgRP promoter SNPs in linkage disequilibrium.

The agouti related protein (AgRP) exerts its anabolic effects on food intake by antagonising the alpha-melanocyte stimulating hormone (alpha-MSH) at its receptors, melanocortin receptors 3 and 4 (MC3R and MC4R). A single nucleotide polymorphism (SNP) in the promoter of the human AgRP (hAgRP), -38C>T, was associated with low body fatness. The -38T allele that was associated with low body fatness also resulted in lower promoter activity. Here we report a novel SNP, -3019G>A, again in the promoter of hAgRP, which is in complete linkage disequilibrium (LD) with the -38C>T SNP (linked alleles: -3019A/-38T and -3019G/-38C). Functional analyses in a human adrenal and two mouse hypothalamus cell lines showed that the -3019A allele had significantly higher promoter activity. Hence, the two linked alleles (-3019A and -38T) had opposite effects on promoter function and yet they were both associated with low body fatness. The region encompassing the -38C>T SNP had approximately 1000-fold higher activity than the region encompassing the -3019G>A SNP, potentially determining the net functional effect between these two SNPs.

The agouti-related protein and body fatness in humans.

OBJECTIVE: The objective of this study was to examine the impact of a single nucleotide polymorphism (SNP) (-38C>T) in the promoter of the human agouti-related protein (hAgRP) gene on promoter affinity for transcription factors (TFs) and its possible association with body composition phenotypes. DESIGN: Electrophoretic mobility shift assays for the functional studies and association analyses for the population studies. SUBJECTS AND METHODS: Nuclear extracts were isolated from the mouse hypothalamus cell line GT1-7 and subjected to binding assays using oligonucleotide probes corresponding to the -38C>T region and an antibody for the E12/E47 TFs. Individuals (n = 259) from the HERITAGE Family Study were genotyped for the -38C>T SNP and used in the association studies. RESULTS: Electrophoretic mobility shift and supershift assays confirmed binding of the E12/E47 TF to the -38C>T site in a genotype-dependent manner. The T allele was found exclusively in the black subjects while the genotype with the higher binding affinity, CC, was significantly associated with high BMI, fat mass, and percent body fat in the black subjects of the HERITAGE Family Study. CONCLUSIONS: The E12/E47 TF could play a role in the regulation of hAgRP expression while the population studies suggest that the TT genotype of the -38C>T SNP could play a protective role against the development of obesity in the black population of the HERITAGE Family Study.

Extent of linkage disequilibrium between the androgen receptor gene CAG and GGC repeats in human populations: implications for prostate cancer risk.

While studies have implicated alleles at the CAG and GGC trinucleotide repeats of the androgen receptor gene with high-grade, aggressive prostate cancer disease, little is known about the normal range of variation for these two loci, which are separated by about 1.1 kb. More importantly, few data exist on the extent of linkage disequilibrium (LD) between the two loci in different human populations. Here we present data on CAG and GGC allelic variation and LD in six diverse populations. Alleles at the CAG and GGC repeat loci of the androgen receptor were typed in over 1000 chromosomes from Africa, Asia, and North America. Levels of linkage disequilibrium between the two loci were compared between populations. Haplotype variation and diversity were estimated for each population. Our results reveal that populations of African descent possess significantly shorter alleles for the two loci than non-African populations (P<0.0001). Allelic diversity for both markers was higher among African Americans than any other population, including indigenous Africans from Sierra Leone and Nigeria. Analysis of molecular variance revealed that approx. 20% of CAG and GGC repeat variance could be attributed to differences between the populations. All non-African populations possessed the same common haplotype while the three populations of African descent possessed three divergent common haplotypes. Significant LD was observed in our sample of healthy African Americans. The LD observed in the African American population may be due to several reasons; recent migration of African Americans from diverse rural communities following urbanization, recurrent gene flow from diverse West African populations, and admixture with European Americans. This study represents the largest genotyping effort to be performed on the two androgen receptor trinucleotide repeat loci in diverse human populations.

The gene structure and minimal promoter of the human agouti related protein.

The murine agouti related protein (mAGRP) is upregulated in obese and diabetic mice and stimulates hyperphagia when administered intracerebroventricularly (i.c.v.) or when overexpressed in transgenic mice. The human ortholog, hAGRP, has been isolated and has similar molecular and physiological properties. Here, we report the complete gene structure of the human AGRP gene and upstream regions with differential promoter activity. A polymorphism, A67T, in the third exon was identified but was not associated with obesity- or type 2 diabetes-related phenotypes. Putative binding sites for transcription factors were identified in the promoter of the gene including recognition sites for the signal transducers and activators of transcription (STATs) that may potentially mediate leptin's action in the hypothalamus. The upstream non-coding exon had significant promoter activity in a periphery- but not so in a hypothalamus-derived cell line, suggesting that it might contain the minimal promoter required for expression of the short transcript of hAGRP in the periphery.

A role for the Agouti-Related Protein promoter in obesity and type 2 diabetes.

The murine Agouti-Related Protein (mAGRP) is upregulated in obese and diabetic mice and can stimulate hyperphagia when overexpressed in transgenic models. Here we report upstream nucleotide sequences of the human hAGRP gene with putative recognition sites for transcription factors including a site for the STAT transactivators. A polymorphism (-38C-->T) was identified in the promoter region and the C/C genotype had significantly higher promoter activity and affinity for transcription factors as tested in periphery- and hypothalamus-derived cell lines. The polymorphic site could affect the expression levels of hAGRP and the high expressing C/C genotype was significantly associated with high BMI and type 2 diabetes in Africans.

Haplotype diversity and linkage disequilibrium at human G6PD: recent origin of alleles that confer malarial resistance.

The frequencies of low-activity alleles of glucose-6-phosphate dehydrogenase in humans are highly correlated with the prevalence of malaria. These "deficiency" alleles are thought to provide reduced risk from infection by the Plasmodium parasite and are maintained at high frequency despite the hemopathologies that they cause. Haplotype analysis of "A-" and "Med" mutations at this locus indicates that they have evolved independently and have increased in frequency at a rate that is too rapid to be explained by random genetic drift. Statistical modeling indicates that the A- allele arose within the past 3840 to 11,760 years and the Med allele arose within the past 1600 to 6640 years. These results support the hypothesis that malaria has had a major impact on humans only since the introduction of agriculture within the past 10,000 years and provide a striking example of the signature of selection on the human genome.

Ancestral proportions and admixture dynamics in geographically defined African Americans living in South Carolina.

We analyzed admixture in samples of six different African-American populations from South Carolina: Gullah-speaking Sea Islanders in coastal South Carolina, residents of four counties in the "Low Country" (Berkeley, Charleston, Colleton, and Dorchester), and persons living in the city of Columbia, located in central South Carolina. We used a battery of highly informative autosomal, mtDNA, and Y-chromosome markers. Two of the autosomal markers (FY and AT3) are linked and lie 22 cM apart on chromosome 1. The results of this study indicate, in accordance with previous historical, cultural, and anthropological evidence, a very low level of European admixture in the Gullah Sea Islanders (m = 3.5 +/- 0.9%). The proportion of European admixture is higher in the Low Country (m ranging between 9. 9 +/- 1.8% and 14.0 +/- 1.9%), and is highest in Columbia (m = 17.7 +/- 3.1%). A sex-biased European gene flow and a small Native American contribution to the African-American gene pool are also evident in these data. We studied the pattern of pairwise allelic associations between the FY locus and the nine other autosomal markers in our samples. In the combined sample from the Low Country (N = 548), a high level of linkage disequilibrium was observed between the linked markers, FY and AT3. Additionally, significant associations were also detected between FY and 4 of the 8 unlinked markers, suggesting the existence of significant genetic structure in this population. A continuous gene flow model of admixture could explain the observed pattern of genetic structure. A test conditioning on the overall admixture of each individual showed association of ancestry between the two linked markers (FY and AT3), but not between any of the unlinked markers, as theory predicts. Thus, even in the presence of genetic structure due to continuous gene flow or some other factor, it is possible to differentiate associations due to linkage from spurious associations due to genetic structure.

Induction of uncoupling protein expression in brown and white adipose tissue by leptin.

Deposition of excess body fat occurs when energy intake chronically exceeds energy expenditure. In ob/ob mice, the absence of leptin affects both components of the energy balance equation, and the mice become morbidly obese after weaning. Treatment of ob/ob mice with exogenous leptin reduces body weight by decreasing food intake and stimulating energy utilization, but even when saline- and leptin-injected ob/ob mice are pair-fed, mice receiving leptin lose significantly more weight. Therefore, the purpose of the present study was to test the hypotheses that uncoupling protein-1 (UCP1) expression is reduced in adipose tissue from ob/ob mice and is restored by treatment with exogenous leptin. Lean and ob/ob mice (5-6 weeks old) were housed at 23 C and treated with leptin (20 microg/g BW x day) for 3 days before they were killed. Compared with levels in lean littermates, UCP1 messenger RNA (mRNA) and protein levels were lower in brown adipose tissue (BAT) and retroperitoneal white adipose tissue (WAT) from ob/ob mice. Treatment of ob/ob mice with leptin reduced body weight and produced a 4- to 5-fold increase in UCP1 mRNA levels in both interscapular BAT and retroperitoneal WAT. The increases in UCP1 mRNA were accompanied by comparable increases in UCP1 protein in mitochondrial preparations from each tissue. Given that the sole known function of UCP1 is to uncouple oxidative phosphorylation, the present results are consistent with the conclusion that leptin stimulates energy utilization in ob/ob mice by increasing thermogenic activity and capacity (UCP1). In addition, the present results suggest that decreased UCP1 expression in BAT and WAT of ob/ob mice is in part responsible for their increased metabolic efficiency and propensity to become obese.

Endogenous mutations in human uncoupling protein 3 alter its functional properties.

Human uncoupling protein (UCP3) is a mitochondrial transmembrane carrier that uncouples oxidative phosphorylation and is a candidate gene for obesity. Expression of native human UCP3 mutations in yeast showed complete loss (R70W), significant reduction (R143X), or no effect (V102I and IVS6+1G > A) on the uncoupling activity of UCP3. It is concluded that certain mutations in UCP3 alter its functional impact on membrane potential (deltaphi), possibly conferring susceptibility to develop metabolic diseases.

Effects of mutations in the human uncoupling protein 3 gene on the respiratory quotient and fat oxidation in severe obesity and type 2 diabetes.

Human uncoupling protein 3 (UCP3) is a mitochondrial transmembrane carrier that uncouples oxidative ATP phosphorylation. With the capacity to participate in thermogenesis and energy balance, UCP3 is an important obesity candidate gene. A missense polymorphism in exon 3 (V102I) was identified in an obese and diabetic proband. A mutation introducing a stop codon in exon 4 (R143X) and a terminal polymorphism in the splice donor junction of exon 6 were also identified in a compound heterozygote that was morbidly obese and diabetic. Allele frequencies of the exon 3 and exon 6 splice junction polymorphisms were determined and found to be similar in Gullah-speaking African Americans and the Mende tribe of Sierra Leone, but absent in Caucasians. Moreover, in exon 6-splice donor heterozygotes, basal fat oxidation rates were reduced by 50%, and the respiratory quotient was markedly increased compared with wild-type individuals, implicating a role for UCP3 in metabolic fuel partitioning.