Haplotype block structure study of the CFTR gene. Most variants are associated with the M470 allele in several European populations

An average of about 1700 CFTR (cystic fibrosis transmembrane conductance regulator) alleles from normal individuals from different European populations were extensively screened for DNA sequence variation. A total of 80 variants were observed: 61 coding SNSs (results already published), 13 noncoding SNSs, three STRs, two short deletions, and one nucleotide insertion. Eight DNA variants were classified as non-CF causing due to their high frequency of occurrence. Through this survey the CFTR has become the most exhaustively studied gene for its coding sequence variability and, though to a lesser extent, for its noncoding sequence variability as well. Interestingly, most variation was associated with the M470 allele, while the V470 allele showed an 'extended haplotype homozygosity' (EHH). These findings make us suggest a role for selection acting either on the M470V itself or through an hitchhiking mechanism involving a second site. The possible ancient origin of the V allele in an 'out of Africa' time frame is discussed

Transcription factor 7-like 2 (TCF7L2) variant is associated with familial breast cancer risk: a case-control study

BACKGROUND: The transcription factor 7-like 2 (TCF7L2) is a critical component of the Wnt/β-catenin pathway. Aberrant TCF7L2 expression modifies Wnt signaling and mediates oncogenic effects through the upregulation of c-MYC and cyclin D. Genetic alterations in TCF7L2 may therefore affect cancer risk. Recently, TCF7L2 variants, including the microsatellite marker DG10S478 and the nearly perfectly linked SNP rs12233372, were identified to associate with type 2 diabetes. METHODS: We investigated the effect of the TCF7L2 rs12255372 variant on familial breast cancer (BC) risk by means of TaqMan allelic discrimination, analyzing BRCA1/2 mutation-negative index patients of 592 German BC families and 735 control individuals. RESULTS: The T allele of rs12255372 showed an association with borderline significance (OR = 1.19, 95% C.I. = 1.01-1.42, P = 0.04), and the Cochran-Armitage test for trend revealed an allele dose-dependent association of rs12255372 with BC risk (P(trend )= 0.04). CONCLUSION: Our results suggest a possible influence of TCF7L2 rs12255372 on the risk of familial BC

TP53-binding protein variants and breast cancer risk: a case-control study

INTRODUCTION: The TP53-binding protein (53BP1) has been shown to influence TP53-mediated transcriptional activation, thus playing a pivotal role in DNA damage signalling. Genetic aberrations in TP53 and in ATM and CHEK2 predispose to cancer. We have therefore examined the effects of 53BP1 single nucleotide polymorphisms (D353E, G412S, and K1136Q) and the novel 53BP1 6bp deletion (1347_1352delTATCCC) on breast cancer risk. METHODS: Allelic discrimination was performed to investigate the frequencies of 53BP1 D353E, G412S, and K1136Q and of 1347_1352delTATCCC in 353 patients with breast cancer and 960 control individuals. RESULTS: No significant association of 53BP1 D353E, G412S, or K1136Q with breast cancer risk was detected. 53BP1 1347_1352delTATCCC, leading to the loss of an isoleucine and a proline residue, showed a nonsignificant inverse association with breast cancer risk (odds ratio = 0.61, 95% confidence interval = 0.22 to 1.68, P = 0.34). CONCLUSION: The lack of association casts doubt on the putative effects of D353E, G412S, and K1136Q on breast cancer risk. Investigating a larger study cohort might elucidate the influence of the 6bp deletion 1347_1352delTATCCC. Studying the functional effect and the impact of this variant on the risk of other cancers may be revealing

Full-Length L1CAM and Not Its Δ2Δ27 Splice Variant Promotes Metastasis through Induction of Gelatinase Expression

Tumour-specific splicing is known to contribute to cancer progression. In the case of the L1 cell adhesion molecule (L1CAM), which is expressed in many human tumours and often linked to bad prognosis, alternative splicing results in a full-length form (FL-L1CAM) and a splice variant lacking exons 2 and 27 (SV-L1CAM). It has not been elucidated so far whether SV-L1CAM, classically considered as tumour-associated, or whether FL-L1CAM is the metastasis-promoting isoform. Here, we show that both variants were expressed in human ovarian carcinoma and that exposure of tumour cells to pro-metastatic factors led to an exclusive increase of FL-L1CAM expression. Selective overexpression of one isoform in different tumour cells revealed that only FL-L1CAM promoted experimental lung and/or liver metastasis in mice. In addition, metastasis formation upon up-regulation of FL-L1CAM correlated with increased invasive potential and elevated Matrix metalloproteinase (MMP)-2 and -9 expression and activity in vitro as well as enhanced gelatinolytic activity in vivo. In conclusion, we identified FL-L1CAM as the metastasis-promoting isoform, thereby exemplifying that high expression of a so-called tumour-associated variant, here SV-L1CAM, is not per se equivalent to a decisive role of this isoform in tumour progression

A Model of Collective Interpretation

We propose a cognitively plausible formal model of collective interpretation. The model represents how members of a collective interact to interpret their environment. Current theories of collective interpretation focus on how heedful communication among members of a collective (i.e., how much individuals pay attention to others' interpretations) improves interpretive performance; their general assumption is that heed tends to be uniformly beneficial. By unpacking the micromechanisms that underlie such performance, our model reveals a more complex story. Heedfulness can benefit interpretive performance. It can help collectives properly interpret situations that are especially ambiguous, unknown, or novel. Conversely, heedfulness also generates conformity pressures that induce agents to give too much weight to others' interpretations, even if erroneous, thereby potentially degrading interpretive performance. These two effects join into a nonmonotonic trajectory that represents how heed relates to interpretive performance: due to its beneficial properties, performance increases with heed until it peaks before degrading due to conformity pressures. The form of this nonmonotonic relationship is contingent on the nature of the task: ambiguous situations make collectives vulnerable to too much heed: ambiguity ignites conformism; novel situations make collectives dependent on heed: novelty requires multiple eyes to be seen. In addition to these results, our model offers a flexible platform that future work can use to explore collective interpretation in a variety of organizational and supraorganizational contexts.We propose a cognitively plausible formal model of collective interpretation. The model represents how members of a collective interact to interpret their environment. Current theories of collective interpretation focus on how heedful communication among members of a collective (i.e., how much individuals pay attention to others' interpretations) improves interpretive performance; their general assumption is that heed tends to be uniformly beneficial. By unpacking the micromechanisms that underlie such performance, our model reveals a more complex story. Heedfulness can benefit interpretive performance. It can help collectives properly interpret situations that are especially ambiguous, unknown, or novel. Conversely, heedfulness also generates conformity pressures that induce agents to give too much weight to others' interpretations, even if erroneous, thereby potentially degrading interpretive performance. These two effects join into a nonmonotonic trajectory that represents how heed relates to interpretive performance: due to its beneficial properties, performance increases with heed until it peaks before degrading due to conformity pressures. The form of this nonmonotonic relationship is contingent on the nature of the task: ambiguous situations make collectives vulnerable to too much heed: ambiguity ignites conformism; novel situations make collectives dependent on heed: novelty requires multiple eyes to be seen. In addition to these results, our model offers a flexible platform that future work can use to explore collective interpretation in a variety of organizational and supraorganizational contexts

Dental metric standards for sex estimation in archaeological populations from Iran

Sex estimation of skeletal remains is one of the major components of forensic identification of unknown individuals. Teeth are a potential source of information on sex and are often recovered in archaeological or forensic contexts due to their post-mortem longevity. Currently there is limited data on dental sexual dimorphism of archaeological populations from Iran. This dissertation represents the first study to provide a dental sex estimation method for Iron Age populations. The current study was conducted on the skeletal remains of 143 adults from two Iron Age populations in close temporal and geographic proximity in the Solduz Valley (West Azerbaijan Province of Iran). 2D and 3D cervical mesiodistal and buccolingual and root volume measurements of maxillary and mandibular teeth were used to investigate the degree of sexual dimorphism in permanent dentition and to assess their applicability in sex estimation. In total 1327, 457, and 480 anterior and posterior teeth were used to collect 2D cervical, 3D cervical, and root volume measurements respectively. 2D cervical measurements were taken using Hillson-Fitzgerald dental calliper and 3D measurements were collected using CT images provided by Open Research Scan Archive (ORSA) - Penn Museum. 3D models of the teeth were created using manual segmentation in the Amira 6.01 software package. Since tooth density largely differs from crown to apex, root segmentation required two threshold levels: the segmentation of the root from the jaw and the segmentation of the crown from the root. Thresholds used for root segmentation were calculated using the half maximum height protocol of Spoor et al. (1993) for each skull, and thresholds used for crown segmentation were set visually for each tooth separately. Data was analysed using discriminant function analysis and posterior probabilities were calculated for all produced formulae where sex was previously assessed from morphological features of pelvis and skull. Bootstrapping was used to account for small sample sizes in the analysis. Statistical analysis was carried out using SPSS 23. The percentage of sexual dimorphism was also used to quantify the amount of sexual dimorphism in the sample. The results showed that incisors and canines were the most sexually dimorphic teeth, providing percentages of correct sex classification between 80% and 100% depending on the measurement used. Root volume measurement was shown to be the most sexually dimorphic variable providing an accuracy of over 90% in all functions. The present study provided the first dental metric standards for sex estimation using odontometric data in Iranian archaeological populations. Dental measurements, particularly root volume measurements, were found to be of value for sex assessment and the method presented here could be a useful tool for establishing accurate demographic data from skeletal remains of the Iron Age from Iran

Ossification of the ligamentum flavum in a nineteenth-century skeletal population sample from Ireland:Using bioarchaeology to reveal a neglected spine pathology

Ossification of the ligamentum flavum of the spine (OLF) is rarely reported in individuals of European ancestry. It has, however, been observed in archaeological skeletons from Europe. The aim of this study was to revisit OLF rates, utilising a mid-nineteenth-century skeletal sample from Ireland. The hypothesis was that the OLF prevalence rate was similar to studies on non-Europeans. Spines from 345 individuals were analysed, and the extent of OLF recorded on the cranial and caudal attachment sites of each vertebra using the following classification system: Grade 0 (no change); Grade 1 (<2 mm); Grade 2 (2–4 mm); Grade 3 (≥4 mm). OLF was observed at prevalence rates of 83.6%. There was no disparity in prevalence based on sex, except for individuals aged 36–45 years at death in which the male rate was higher. Advancing age was a determining factor in the OLF occurrence with an onset in young adulthood (18–25 years), and most severe grades occurring over the age of 25 years. OLF coincides with spinal osteoarthritis, spondylosis deformans and Schmorl’s nodes in both sexes, and with intervertebral osteochondrosis in females. The results of this study indicate that OLF is likely to be an understudied rather than rare condition in European populations

Seeking for solutions within a project setting

There has been increasing attention focused on the importance of ‘solution selling’ in the often very close relationships that characterize business-to-business marketing. While an extant predominantly product-centric view of solutions prevails in the literature, this has recently been juxtaposed with a more process-oriented view. We review such a process-oriented solution model briefly, and focus on the managerial challenge of how firms make this process-oriented approach work in practice. We argue that, in parallel to adopting a process-oriented approach, companies also have to focus their attention specifically on how to mobilize the different parties in order to amalgamate the perspectives and orientations between the interacting counterparts. We propose an interaction process model of how this ‘collective mind’ is achieved, using as an example a study of the United Kingdom’s Lean Aerospace Initiative (UK LAI), a large project with a specific solution in mind – improving the global competitiveness of the UK’s Aerospace industry. We use our model to show how the three main groups of actors (Government bodies, four Universities, and the aerospace companies themselves) interact in their pursuit of co-creating their collective solutions

A comparison of three established age estimation methods on an adult Spanish sample.

Most current methods for adult skeletal age-at-death estimation are based on American samples comprising individuals of European and African ancestry. Our limited understanding of population variability hampers our efforts to apply these techniques to various skeletal populations around the world, especially in global forensic contexts. Further, documented skeletal samples are rare, limiting our ability to test our techniques. The objective of this paper is to test three pelvic macroscopic methods (1-Suchey-Brooks; 2- Lovejoy; 3- Buckberry and Chamberlain) on a documented modern Spanish sample. These methods were selected because they are popular among Spanish anthropologists and because they never have been tested in a Spanish sample. The study sample consists of 80 individuals (55 ♂ and 25 ♀) of known sex and age from the Valladolid collection. Results indicate that in all three methods, levels of bias and inaccuracy increase with age. The Lovejoy method performs poorly (27%) compared with Suchey-Brooks (71%) and Buckberry and Chamberlain (86%). However, the levels of correlation between phases and chronological ages are low and comparable in the three methods (< 0.395). The apparent accuracy of the Suchey-Brooks and Buckberry and Chamberlain methods is largely based on the broad width of the methods" estimated intervals. This study suggests that before systematic application of these three methodologies in Spanish populations, further statistical modeling and research into the co-variance of chronological age with morphological change is necessary. Future methods should be developed specific to various world populations, and should allow for both precision and flexibility in age estimation