Sex and Geographic Differences in Health of the Early Inhabitants of the Mariana Islands

The early inhabitants of the Mariana Islands encountered numerous challenges that likely affected their health, including island size, vulnerability to natural disasters, availability of resources, and shifts in climate. Other factors that could have led to differences in health include biological sex, social status, diet, and genetic factors (e.g., host resistance). This article examines the effects of environment and biological sex on the health of the earliest inhabitants of the Mariana Islands through an analysis of indicators of health recorded in skeletons from Guam, Rota, Tinian, and Saipan. The indicators of health investigated include cribra orbitalia (CO), linear enamel hypoplasia (LEH), stature, trauma, infection, and dental disease (antemortem tooth loss [AMTL], dental caries, alveolar defect, dental calculus, and attrition). Betel staining of teeth is also examined. To determine if there are differences attributable to sex, male and female data are compared for each island separately and then for all the islands combined. To examine differences between islands, separate comparisons of these indicators are made for males and females. Examining islands separately, no significant sex differences were observed for CO, spondylolysis, fractures, treponemal infection, AMTL, or dental calculus. Significant sex differences were observed for LEH, betel-stained teeth, and the other dental pathologies. With few exceptions, sex differences in the observed indicators were consistent across islands. Observing male and female health across the islands revealed no significant differences for stature, trauma or infections. For the remaining indicators, significant differences were observed. Similarities in health between Guam and Rota in the south and Tinian and Saipan located farther north suggest that geography, environmental constraints, and social and cultural networking were important variables affecting the health and lives of the early inhabitants of the Mariana Islands

The effect of pH on glucoamylase production, glycosylation and chemostat evolution of Aspergillus niger

The effect of ambient pH on production and glycosylation of glucoamylase (GAM) and on the generation of a morphological mutant produced by Aspergillus niger strain B1 (a transformant containing an additional 20 copies of the homologous GAM glaA gene) was studied. We have shown that a change in the pH from 4 to 5.4 during continuous cultivation of the A. niger B1 strain instigates or accelerates the spontaneous generation of a morphological mutant (LB). This mutant strain produced approx. 50% less extracellular protein and GAM during both chemostat and batch cultivation compared to another strain with parental-type morphology (PS). The intracellular levels of GAM were also lower in the LB strain. In addition, cultivation of the original parent B1 strain in a batch-pulse bioreactor at pH 5.5 resulted in a 9-fold drop in GAM production and a 5-fold drop in extracellular protein compared to that obtained at pH 4. Glycosylation analysis of the glucoamylases purified from shake-flask cultivation showed that both principal forms of GAM secreted by the LB strain possessed enhanced galactosylation (2-fold), compared to those of the PS. Four diagnostic methods (immunostaining, mild methanolysis, mild acid hydrolysis and β-galactofuranosidase digestion) provided evidence that the majority of this galactose was of the furanoic conformation. The GAMs produced during batch-pulse cultivation at pH 5.5 similarly showed an approx. 2-fold increase in galactofuranosylation compared to pH 4. Interestingly, in both cases the increased galactofuranosylation appears primarily restricted to the O-linked glycan component. Ambient pH therefore regulates both GAM production and influences its glycosylation

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD

Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p 10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10−392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group

Sustainable mining in tropical, biodiverse landscapes: Environmental challenges and opportunities in the archipelagic Philippines

The rising demand for critical metals presents a major economic opportunity for mineral-rich countries. For a sustainable transition to a low-carbon future, it is essential to minimise impacts of mineral resource development to the environment, ecosystems, and societies of these nations. Although there has been considerable progress in the social aspects of the mining sector, environmental metrics are not showing comparable improvement. The Philippines exemplifies this challenge as a country that aims to conserve its exceptional biodiversity to maximise ecosystem services while expanding mining activities for economic growth, in a geographical setting with high mineral potential and vulnerability to natural hazards and climate change. Similar to many mining areas, environmental baselines are mostly non-existent, compounded by a legacy of mining impacts despite an established policy framework. We review issues associated with large- and small-scale mining and identify underlying research challenges and opportunities in the Philippines. Potential environmental research pathways include (i) innovative approaches for catchment scale characterisation and identification of contaminant sources; (ii) quantifying and predicting contaminant transport; (iii) deployment of flexible monitoring devices for larger-scale water quality monitoring programmes; (iv) tailings dam monitoring and management; and (v) resource assessment and metal recovery in ores and tailings. By integrating geomorphological tools with geochemical data, as well as 2D/3D numerical modelling techniques, it becomes possible to predict and understand the behaviour and fate of contaminants across different spatial and temporal scales. The development of cost-effective water quality assessment devices and protocols can help overcome logistical challenges in monitoring a wider range of hydrological conditions. Advanced applications of remote sensing, combined with machine learning, and geophysical monitoring systems provide new opportunities to detect mining footprints and observe change in tailings dams more effectively. Potential impacts of mine wastes can be further minimised by exploring innovative technologies such as the use of metal-accumulating native plant species and environmentally safe solvents to reprocess modern and legacy tailings. Insights from these pathways will enable the realisation of a more sustainable mining future, through the incorporation of findings into existing and future governmental and small- and large-scale mining policy and practice. This will lead to sustainable development for society, particularly in nations that are well positioned to benefit from sustainable mineral resource development

Methodological developments in qualitative longitudinal research:the advantages and challenges of regular telephone contact with participants in a qualitative longitudinal interview study

BACKGROUND: Qualitative longitudinal research is an evolving methodology, particularly within health care research. It facilitates a nuanced understanding of how phenomena change over time and is ripe for innovative approaches. However, methodological reflections which are tailored to health care research are scarce. This article provides a synthesised and practical account of the advantages and challenges of maintaining regular telephone contact between interviews with participants in a qualitative longitudinal study. METHODS: Participants with metastatic colorectal cancer were interviewed at 3 time points over the course of a year. Half the group also received monthly telephone calls to explore the added value and the feasibility of capturing change as close to when it was occurring as possible. RESULTS: The data gathered from the telephone calls added context to the participants’ overall narrative and informed subsequent interviews. The telephone calls meant we were able to capture change close to when it happened and there was a more evolved, and involved, relationship between the researcher and the participants who were called on a monthly basis. However, ethical challenges were amplified, boundaries of the participant/researcher relationship questioned, and there was the added analytical burden. CONCLUSIONS: The telephone calls facilitated a more nuanced understanding of the illness experience to emerge, when compared with the interview only group. The findings suggest that intensive telephone contact may be justified if retention is an issue, when the phenomena being studied is unpredictable and when participants feel disempowered or lack control. These are potential issues for research involving participants with long-term illness

Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10-5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10-5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10-10, odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis