Six NSCL/P loci show associations with normal-range craniofacial variation

Objectives: Orofacial clefting is one of the most prevalent craniofacial malformations. Previous research has demonstrated that unaffected relatives of patients with non-syndromic cleft lip with/without cleft palate (NSCL/P) show distinctive facial features, which can be an expression of underlying NSCL/P susceptibility genes. These results support the hypothesis that genes involved in the occurrence of a cleft also play a role in normal craniofacial development. In this study, we investigated the influence of genetic variants associated with NSCL/P on normal-range variation in facial shape. Methods: A literature review of genome wide association studies (GWAS) investigating the genetic etiology of NSCL/P was performed, resulting in a list of 75 single nucleotide polymorphisms (SNPs) located in 38 genetic loci. Genotype data were available for 65 of these selected SNPs in three datasets with a combined sample size of 7,418 participants of European ancestry, whose 3D facial images were also available. The effect of each SNP was tested using a multivariate canonical correlation analysis (CCA) against 63 hierarchically-constructed facial segments in each of the three datasets and meta-analyzed. This allowed for the investigation of associations between SNPs known to be involved in NSCL/P and normal-range facial shape variations in a global-to-local perspective, without preselecting specific facial shape features or characteristics. Results: Six NSCL/P SNPs showed significant associations with variation in normal-range facial morphology. rs6740960 showed significant effects in the chin area (p = 3.71 × 10−28). This SNP lies in a non-coding area. Another SNP, rs227731 near the NOG gene, showed a significant effect in the philtrum area (p = 1.96 × 10−16). Three SNPs showed significant effects on the shape of the nose. rs742071 (p = 8.71 × 10−14), rs34246903 (p = 6.87 × 10−12), and rs10512248 (p = 8.4 × 10−9). Respectively, these SNPs are annotated to PAX7, MSX1, and PTCH1. Finally, rs7590268, an intron variant of THADA, showed an effect in the shape of the supraorbital ridge (p = 3.84 × 10−7). Conclusions: This study provides additional evidence NSCL/P-associated genetic variants influence normal-range craniofacial morphology, with significant effects observed for the chin, the nose, the supraorbital ridges and the philtrum area

Amyloid-β1–43 cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations

Background Alzheimer's disease (AD) mutations in amyloid precursor protein (APP) and presenilins (PSENs) could potentially lead to the production of longer amyloidogenic A beta peptides. Amongst these, A beta(1-43)is more prone to aggregation and has higher toxic properties than the long-known A beta(1-42). However, a direct effect on A beta(1-43)in biomaterials of individuals carrying genetic mutations in the known AD genes is yet to be determined. Methods N = 1431 AD patients (n = 280 early-onset (EO) andn = 1151 late-onset (LO) AD) and 809 control individuals were genetically screened forAPPandPSENs. For the first time, A beta(1-43)levels were analysed in cerebrospinal fluid (CSF) of 38 individuals carrying pathogenic or unclear rare mutations or the commonPSEN1p.E318G variant and compared with A beta(1-42)and A beta 1-40CSF levels. The soluble sAPP alpha and sAPP beta species were also measured for the first time in mutation carriers. Results A known pathogenic mutation was identified in 5.7% of EOAD patients (4.6%PSEN1, 1.07%APP) and in 0.3% of LOAD patients. Furthermore, 12 known variants with unclear pathogenicity and 11 novel were identified. Pathogenic and unclear mutation carriers showed a significant reduction in CSF A beta(1-43)levels compared to controls (p = 0.037; < 0.001). CSF A beta(1-43)levels positively correlated with CSF A beta(1-42)in both pathogenic and unclear carriers and controls (allp < 0.001). The p.E318G carriers showed reduced A beta(1-43)levels (p < 0.001), though genetic association with AD was not detected. sAPP alpha and sAPP beta CSF levels were significantly reduced in the group of unclear (p = 0.006; 0.005) and p.E318G carriers (p = 0.004; 0.039), suggesting their possible involvement in AD. Finally, using A beta(1-43)and A beta(1-42)levels, we could re-classify as "likely pathogenic" 3 of the unclear mutations. Conclusion This is the first time that A beta(1-43)levels were analysed in CSF of AD patients with genetic mutations in the AD causal genes. The observed reduction of A beta(1-43)inAPPandPSENscarriers highlights the pathogenic role of longer A beta peptides in AD pathogenesis. Alterations in A beta(1-43)could prove useful in understanding the pathogenicity of unclearAPPandPSENsvariants, a critical step towards a more efficient genetic counselling

Key stages of mammary gland development: Molecular mechanisms involved in the formation of the embryonic mammary gland

The development of the embryonic mammary gland involves communication between the epidermis and mesenchyme and is coordinated temporally and spatially by various signaling pathways. Although many more genes are likely to control mammary gland development, functional roles have been identified for Wnt, fibroblast growth factor, and parathyroid hormone-related protein signaling. This review describes what is known about the molecular mechanisms that regulate embryonic mammary gland development

Cities and the Transformation of Biodiversity Governance

The governing of nature has been an essential part of the story of urbanization. Whether through the conversion of rivers for transportation, the creation of urban drainage systems for wastewater removal or the installation of parks for their recreational and aesthetic value (Gandy, 2004; Gleeson and Low, 2000; Rydin, 1998), nature has played a critical role in urban development. Yet, conservationist thinking, which has dominated environmental governance and policy, has tended to equate the environment as belonging to either “rural” or “wilderness” places that needed to be protected from the encroachment of (urban) society (Owens, 1992). As a result, much of the governance of biodiversity at the urban scale during the twentieth century was focused on the designation and enforcement of protected areas (Vaccaro et al., 2013)

Affected Experiencers

Numerous languages permit an NP that is not selected by the verb to be added to a clause, with several different possible interpretations. We divide such non-selected arguments into possessor, benefactive, attitude holder, and affected experiencer categories, on the basis of syntactic and semantic differences between them. We propose a formal analysis of the affected experiencer construction. In our account, a syntactic head Aff(ect) introduces the experiencer argument, and adds a conventional implicature to the effect that any event of the type denoted by its syntactic sister is the source of the experiencer’s psychological experience. Hence, our proposal involves two tiers of meaning: the at-issue meaning of the sentence, and some not-at-issue meaning (an implicature). A syntactic head can introduce material on both tiers. Additionally, we allow two parameters of variation: (i) the height of the attachment of Aff, and (ii) how much of the semantics is at-issue and how much is an implicature. We show that these two parameters account for the attested variation across our sample of languages, as well as the significant commonalities among them. Our analysis also accounts for significant differences between affected experiencers and the other types of non-selected arguments, and we also note a generalization to the effect that purely not-at-issue non-selected arguments can only be weak or clitic pronouns

3D facial phenotyping by biometric sibling matching used in contemporary genomic methodologies

The analysis of contemporary genomic data typically operates on one-dimensional phenotypic measurements (e.g. standing height). Here we report on a data-driven, family-informed strategy to facial phenotyping that searches for biologically relevant traits and reduces multivariate 3D facial shape variability into amendable univariate measurements, while preserving its structurally complex nature. We performed a biometric identification of siblings in a sample of 424 children, defining 1,048 sib-shared facial traits. Subsequent quantification and analyses in an independent European cohort (n = 8,246) demonstrated significant heritability for a subset of traits (0.17–0.53) and highlighted 218 genome-wide significant loci (38 also study-wide) associated with facial variation shared by siblings. These loci showed preferential enrichment for active chromatin marks in cranial neural crest cells and embryonic craniofacial tissues and several regions harbor putative craniofacial genes, thereby enhancing our knowledge on the genetic architecture of normal-range facial variation

Six NSCL/P Loci Show Associations With Normal-Range Craniofacial Variation

Objectives: Orofacial clefting is one of the most prevalent craniofacial malformations. Previous research has demonstrated that unaffected relatives of patients with non-syndromic cleft lip with/without cleft palate (NSCL/P) show distinctive facial features, which can be an expression of underlying NSCL/P susceptibility genes. These results support the hypothesis that genes involved in the occurrence of a cleft also play a role in normal craniofacial development. In this study, we investigated the influence of genetic variants associated with NSCL/P on normal-range variation in facial shape.Methods: A literature review of genome wide association studies (GWAS) investigating the genetic etiology of NSCL/P was performed, resulting in a list of 75 single nucleotide polymorphisms (SNPs) located in 38 genetic loci. Genotype data were available for 65 of these selected SNPs in three datasets with a combined sample size of 7,418 participants of European ancestry, whose 3D facial images were also available. The effect of each SNP was tested using a multivariate canonical correlation analysis (CCA) against 63 hierarchically-constructed facial segments in each of the three datasets and meta-analyzed. This allowed for the investigation of associations between SNPs known to be involved in NSCL/P and normal-range facial shape variations in a global-to-local perspective, without preselecting specific facial shape features or characteristics.Results: Six NSCL/P SNPs showed significant associations with variation in normal-range facial morphology. rs6740960 showed significant effects in the chin area (p = 3.71 × 10−28). This SNP lies in a non-coding area. Another SNP, rs227731 near the NOG gene, showed a significant effect in the philtrum area (p = 1.96 × 10−16). Three SNPs showed significant effects on the shape of the nose. rs742071 (p = 8.71 × 10−14), rs34246903 (p = 6.87 × 10−12), and rs10512248 (p = 8.4 × 10−9). Respectively, these SNPs are annotated to PAX7, MSX1, and PTCH1. Finally, rs7590268, an intron variant of THADA, showed an effect in the shape of the supraorbital ridge (p = 3.84 × 10−7).Conclusions: This study provides additional evidence NSCL/P-associated genetic variants influence normal-range craniofacial morphology, with significant effects observed for the chin, the nose, the supraorbital ridges and the philtrum area

The impact of mass gatherings and holiday traveling on the course of an influenza pandemic: a computational model

<p>Abstract</p> <p>Background</p> <p>During the 2009 H1N1 influenza pandemic, concerns arose about the potential negative effects of mass public gatherings and travel on the course of the pandemic. Better understanding the potential effects of temporal changes in social mixing patterns could help public officials determine if and when to cancel large public gatherings or enforce regional travel restrictions, advisories, or surveillance during an epidemic.</p> <p>Methods</p> <p>We develop a computer simulation model using detailed data from the state of Georgia to explore how various changes in social mixing and contact patterns, representing mass gatherings and holiday traveling, may affect the course of an influenza pandemic. Various scenarios with different combinations of the length of the mass gatherings or traveling period (range: 0.5 to 5 days), the proportion of the population attending the mass gathering events or on travel (range: 1% to 50%), and the initial reproduction numbers R₀(1.3, 1.5, 1.8) are explored.</p> <p>Results</p> <p>Mass gatherings that occur within 10 days before the epidemic peak can result in as high as a 10% relative increase in the peak prevalence and the total attack rate, and may have even worse impacts on local communities and travelers' families. Holiday traveling can lead to a second epidemic peak under certain scenarios. Conversely, mass traveling or gatherings may have little effect when occurring much earlier or later than the epidemic peak, e.g., more than 40 days earlier or 20 days later than the peak when the initial R₀= 1.5.</p> <p>Conclusions</p> <p>Our results suggest that monitoring, postponing, or cancelling large public gatherings may be warranted close to the epidemic peak but not earlier or later during the epidemic. Influenza activity should also be closely monitored for a potential second peak if holiday traveling occurs when prevalence is high.</p

The development of indicators and core indicators for sustainable development: a state of the art review

Experience with the establishment of indicators for sustainable development shows that it is scientifically feasible, most useful for communication with the public and a necessary navigation instrument to establish measures pertaining to the sustainability process objective. Usually, long lists of indicators were established to describe the complexity of sustainable development. More recently, these rather technical lists have been reduced to sets of core indicators. This paper compares the shortlists for the USA, the UK and Sweden, and shows that six indicators (GDP, greenhouse gas emissions, crime rate, employment, education level and life expectancy) are used by each of them. In spite of limitations related to the way the indicators are measured and the phasing out of specific national priorities, these commonly used measures might provide a backbone for other countries to develop their core indicator lists. This strategy is probably the most feasible as long as we have no widely accepted aggregated indicators.criteria; indicators; sustainable development; models; policy frameworks behind indicators; selection of core indicators; shortlists of indicators; USA; UK; Sweden.