The View from the Edge: The Proyecto Arqueológico Chihuahua (PAC) 1990 to 2010: An Overview

The work of the Proyecto Arqueológico Chihuahua (PAC) has played an integral role in defining the origins and characteristics of the Chihuahua culture area, also known as the Casas Grandes Regional System. PAC has developed a critical suite of radiocarbon dates for the southern zone, undertaken the first substantial investigations of the Viejo period (ca. A.D. 800textendash1200 or 1250) since the early 1960s, and added to knowledge of the southern Medio period (ca. A.D. 1250textendash1450). The project has also elucidated the chronology, settlement patterns, subsistence strategies, and technology for both periods. Results of our research indicate continuity between the Viejo period, characterized by small pithouse settlements, and the pueblo focused Medio period in the southern zone, with some poorly understood external influences from both western Mesoamerica to the south and the American Southwest to the north shaping events within the area.

Fluorescent Logic Systems for Sensing and Molecular Computation: Structure-Activity Relationships in Edge-Detection

Molecular logic-based computation continues to throw up new applications in sensing and switching, the newest of which is the edge detection of objects. The scope of this phenomenon is mapped out by the use of structure-activity relationships, where several structures of the molecules and of the objects are examined. The different angles and curvatures of the objects are followed with good-fidelity in the visualized edges, even when the objects are in reverse video.

Abundant genetic overlap between blood lipids and immune-mediated diseases indicates shared molecular genetic mechanisms

Epidemiological studies suggest a relationship between blood lipids and immune-mediated diseases, but the nature of these associations is not well understood. We used genome-wide association studies (GWAS) to investigate shared single nucleotide polymorphisms (SNPs) between blood lipids and immune-mediated diseases. We analyzed data from GWAS (n~200,000 individuals), applying new False Discovery Rate (FDR) methods, to investigate genetic overlap between blood lipid levels [triglycerides (TG), low density lipoproteins (LDL), high density lipoproteins (HDL)] and a selection of archetypal immune-mediated diseases (Crohn's disease, ulcerative colitis, rheumatoid arthritis, type 1 diabetes, celiac disease, psoriasis and sarcoidosis). We found significant polygenic pleiotropy between the blood lipids and all the investigated immune-mediated diseases. We discovered several shared risk loci between the immune-mediated diseases and TG (n = 88), LDL (n = 87) and HDL (n = 52). Three-way analyses differentiated the pattern of pleiotropy among the immune-mediated diseases. The new pleiotropic loci increased the number of functional gene network nodes representing blood lipid loci by 40%. Pathway analyses implicated several novel shared mechanisms for immune pathogenesis and lipid biology, including glycosphingolipid synthesis (e.g. FUT2) and intestinal host-microbe interactions (e.g. ATG16L1). We demonstrate a shared genetic basis for blood lipids and immune-mediated diseases independent of environmental factors. Our findings provide novel mechanistic insights into dyslipidemia and immune-mediated diseases and may have implications for therapeutic trials involving lipid-lowering and anti-inflammatory agents.

Shared common variants in prostate cancer and blood lipids

BACKGROUND: Epidemiological and clinical studies suggest comorbidity between prostate cancer (PCA) and cardiovascular disease (CVD) risk factors. However, the relationship between these two phenotypes is still not well understood. Here we sought to identify shared genetic loci between PCA and CVD risk factors.

METHODS: We applied a genetic epidemiology method based on conjunction false discovery rate (FDR) that combines summary statistics from different genome-wide association studies (GWAS), and allows identification of genetic overlap between two phenotypes. We evaluated summary statistics from large, multi-centre GWA studies of PCA (n=50 000) and CVD risk factors (n=200 000) [triglycerides (TG), low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol, systolic blood pressure, body mass index, waist-hip ratio and type 2 diabetes (T2D)]. Enrichment of single nucleotide polymorphisms (SNPs) associated with PCA and CVD risk factors was assessed with conditional quantile-quantile plots and the Anderson-Darling test. Moreover, we pinpointed shared loci using conjunction FDR.

RESULTS: We found the strongest enrichment of P-values in PCA was conditional on LDL and conditional on TG. In contrast, we found only weak enrichment conditional on HDL or conditional on the other traits investigated. Conjunction FDR identified altogether 17 loci; 10 loci were associated with PCA and LDL, 3 loci were associated with PCA and TG and additionally 4 loci were associated with PCA, LDL and TG jointly (conjunction FDR <0.01). For T2D, we detected one locus adjacent to HNF1B.

CONCLUSIONS: We found polygenic overlap between PCA predisposition and blood lipids, in particular LDL and TG, and identified 17 pleiotropic gene loci between PCA and LDL, and PCA and TG, respectively. These findings provide novel pathobiological insights and may have implications for trials using targeting lipid-lowering agents in a prevention or cancer setting.

Molecular subtyping of primary prostate cancer reveals specific and shared target genes of different ETS rearrangements

This work aimed to evaluate whether ETS transcription factors frequently involved in rearrangements in prostate carcinomas (PCa), namely ERG and ETV1, regulate specific or shared target genes. We performed differential expression analysis on nine normal prostate tissues and 50 PCa enriched for different ETS rearrangements using exon-level expression microarrays, followed by in vitro validation using cell line models. We found specific deregulation of 57 genes in ERG-positive PCa and 15 genes in ETV1-positive PCa, whereas deregulation of 27 genes was shared in both tumor subtypes. We further showed that the expression of seven tumor-associated ERG target genes (PLA1A, CACNA1D, ATP8A2, HLA-DMB, PDE3B, TDRD1, and TMBIM1) and two tumor-associated ETV1 target genes (FKBP10 and GLYATL2) was significantly affected by specific ETS silencing in VCaP and LNCaP cell line models, respectively, whereas the expression of three candidate ERG and ETV1 shared targets (GRPR, KCNH8, and TMEM45B) was significantly affected by silencing of either ETS. Interestingly, we demonstrate that the expression of TDRD1, the topmost overexpressed gene of our list of ERG-specific candidate targets, is inversely correlated with the methylation levels of a CpG island found at -66 bp of the transcription start site in PCa and that TDRD1 expression is regulated by direct binding of ERG to the CpG island in VCaP cells. We conclude that ETS transcription factors regulate specific and shared target genes and that TDRD1, FKBP10, and GRPR are promising therapeutic targets and can serve as diagnostic markers for molecular subtypes of PCa harboring specific fusion gene rearrangements.

Understanding Graduate Recruitment, Development and Retention for the Enhancement of Talent Management: Sharpening “the edge” of Graduate Talent

Graduates are deemed to be a key source of talent within many organisations and thus recruiting, developing and retaining them is viewed as a logical talent management (TM) strategy. However, there has been little attention paid to university graduates as part of an organisation’s TM strategy. Such a specific focus addresses the need for further research into the segmentation of talent pools and the specific challenges different talent pools are likely to create. This research, which utilised a qualitative data collection strategy, examined the experiences and practices of six large UK organisations in relation to graduate TM. Drawing from Gallardo-Gallardo, Dries and González-Cruz’s (2013. What is the meaning of ‘talent’ in the world of work? Human Resource Management Review, 23, 290–300.) framework for the conceptualisation of talent, the findings from this research indicate and explain why graduate employers are frequently compelled to use the object approach (talent as characteristics of people) due to the unique characteristics that recent graduates possess, even though other studies have found that a subject approach (talent as people and what they do) is preferred by most employers. Ultimately, employers conceptualise graduate talent by what they describe as ‘the edge’ which needs to be ‘sharpened’ to fully realise the potential that graduates offer.

Site Distribution at the Edge of the Palaeolithic World: A Nutritional Niche Approach

This paper presents data from the English Channel area of Britain and Northern France on the spatial distribution of Lower to early Middle Palaeolithic pre-MIS5 interglacial sites which are used to test the contention that the pattern of the richest sites is a real archaeological distribution and not of taphonomic origin. These sites show a marked concentration in the middle-lower reaches of river valleys with most being upstream of, but close to, estimated interglacial tidal limits. A plant and animal database derived from Middle-Late Pleistocene sites in the region is used to estimate the potentially edible foods and their distribution in the typically undulating landscape of the region. This is then converted into the potential availability of macronutrients (proteins, carbohydrates, fats) and selected micronutrients. The floodplain is shown to be the optimum location in the nutritional landscape (nutriscape). In addition to both absolute and seasonal macronutrient advantages the floodplains could have provided foods rich in key micronutrients, which are linked to better health, the maintenance of fertility and minimization of infant mortality. Such places may have been seen as ‘good (or healthy) places’ explaining the high number of artefacts accumulated by repeated visitation over long periods of time and possible occupation. The distribution of these sites reflects the richest aquatic and wetland successional habitats along valley floors. Such locations would have provided foods rich in a wide range of nutrients, importantly including those in short supply at these latitudes. When combined with other benefits, the high nutrient diversity made these locations the optimal niche in northwest European mixed temperate woodland environments. It is argued here that the use of these nutritionally advantageous locations as nodal or central points facilitated a healthy variant of the Palaeolithic diet which permitted habitation at the edge of these hominins’ range.

Nuclear cataract shows significant familial aggregation in an older population after adjustment for possible shared environmental factors.

PURPOSE: To quantify the association between siblings in age-related nuclear cataract, after adjusting for known environmental and personal risk factors. METHODS: All participants (probands) in the Salisbury Eye Evaluation (SEE) project and their locally resident siblings underwent digital slit lamp photography and were administered a questionnaire to assess risk factors for cataract including: age, gender, lifetime sun exposure, smoking and diabetes history, and use of alcohol and medications such as estrogens and steroids. In addition, blood pressure, body mass index, and serum antioxidants were measured in all participants. Lens photographs were graded by trained observers masked to the subjects' identity, using the Wilmer Cataract Grading System. The odds ratio for siblings for affectedness with nuclear cataract and the sibling correlation of nuclear cataract grade, after adjusting for covariates, were estimated with generalized estimating equations. RESULTS: Among 307 probands (mean age, 77.6 +/- 4.5 years) and 434 full siblings (mean age, 72.4 +/- 7.4 years), the average sibship size was 2.7 per family. After adjustment for covariates, the probability of development of nuclear cataract was significantly increased (odds ratio [OR] = 2.07, 95% confidence interval [CI], 1.30-3.30) among individuals with a sibling with nuclear cataract (nuclear grade > or = 3.0). The final fitted model indicated a magnitude of heritability for nuclear cataract of 35.6% (95% CI: 21.0%-50.3%) after adjustment for the covariates. CONCLUSIONS: Findings in this study are consistent with a genetic effect for age-related nuclear cataract, a common and clinically significant form of lens opacity.

Cortical, but not posterior subcapsular, cataract shows significant familial aggregation in an older population after adjustment for possible shared environmental factors.

PURPOSE:

To quantify the risk for age-related cortical cataract and posterior subcapsular cataract (PSC) associated with having an affected sibling after adjusting for known environmental and personal risk factors.

DESIGN:

Sibling cohort study.

PARTICIPANTS:

Participants in the ongoing Salisbury Eye Evaluation (SEE) study (n = 321; mean age, 78.1+/-4.2 years) and their locally resident siblings (n = 453; mean age, 72.6+/-7.4 years) were recruited at the time of Rounds 3 and 4 of the SEE study. INTERVENTION/TESTING METHODS: Retroillumination photographs of the lens were graded for the presence of cortical cataract and PSC with the Wilmer grading system. The residual correlation between siblings' cataract grades was estimated after adjustment for a number of factors (age; gender; race; lifetime exposure to ultraviolet-B light; cigarette, alcohol, estrogen, and steroid use; serum antioxidants; history of diabetes; blood pressure; and body mass index) suspected to be associated with the presence of cataract.

RESULTS:

The average sibship size was 2.7 per family. Multivariate analysis revealed the magnitude of heritability (h(2)) for cortical cataract to be 24% (95% CI, 6%-42%), whereas that for PSC was not statistically significant (h(2) 4%; 95% CI, 0%-11%) after adjustment for the covariates. The model revealed that increasing age, female gender, a history of diabetes, and black race increased the odds of cortical cataract, whereas higher levels of provitamin A were protective. A history of diabetes and steroid use increased the odds for PSC.

CONCLUSIONS:

This study is consistent with a significant genetic effect for age-related cortical cataract but not PSC.