Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Insights into the late Holocene vegetation history of the East European forest-steppe: case study Sudzha (Kursk region, Russia)

© 2019, Springer-Verlag GmbH Germany, part of Springer Nature. Today, the East European forest-steppe is an agricultural landscape with very few remains of its former natural vegetation. The history of the transformation from natural vegetation to a human-made landscape in the area of Sudzha (Kursk region, Russia) is studied here. We compare the off-site pollen record Sudzha with three on-site pollen records obtained from the archaeological site Kurilovka-2. The sediment core Sudzha covering the last 2,500 years was taken from an oxbow lake in an area with archaeological sites of the early Slavonic period (3rd–8th centuries ce). The Sudzha pollen record indicates dominance of broadleaf forests and meadow steppes in the area from 2,500 to 200 cal year bp with two major settlement phases one between ~ 2,000 and 1,600 cal year bp (~ 50 bce to 350 ce) and the other between 1,100 and 600 cal year bp (850 and 1350 ce) followed by a total deforestation and transformation to an agricultural landscape over the last 200–300 years. Similar changes in the last 300–400 years are indicated by the three on-site pollen records. It is noteworthy, however, that the record Sudzha does not provide an intensive signal of human impact during the 5th–8th centuries ce. This points to a quite restricted spatial influence of the Early Slavonic settlements on the vegetation, leading to a relatively low contribution of palynological anthropogenic indicators to the regional pollen rain signal

Insights into the late Holocene vegetation history of the East European forest-steppe: case study Sudzha (Kursk region, Russia)

© 2019, Springer-Verlag GmbH Germany, part of Springer Nature. Today, the East European forest-steppe is an agricultural landscape with very few remains of its former natural vegetation. The history of the transformation from natural vegetation to a human-made landscape in the area of Sudzha (Kursk region, Russia) is studied here. We compare the off-site pollen record Sudzha with three on-site pollen records obtained from the archaeological site Kurilovka-2. The sediment core Sudzha covering the last 2,500 years was taken from an oxbow lake in an area with archaeological sites of the early Slavonic period (3rd–8th centuries ce). The Sudzha pollen record indicates dominance of broadleaf forests and meadow steppes in the area from 2,500 to 200 cal year bp with two major settlement phases one between ~ 2,000 and 1,600 cal year bp (~ 50 bce to 350 ce) and the other between 1,100 and 600 cal year bp (850 and 1350 ce) followed by a total deforestation and transformation to an agricultural landscape over the last 200–300 years. Similar changes in the last 300–400 years are indicated by the three on-site pollen records. It is noteworthy, however, that the record Sudzha does not provide an intensive signal of human impact during the 5th–8th centuries ce. This points to a quite restricted spatial influence of the Early Slavonic settlements on the vegetation, leading to a relatively low contribution of palynological anthropogenic indicators to the regional pollen rain signal

A Myelin Map of Trunk Folds in the Elephant Trigeminal Nucleus

Elephants have elaborate trunk skills and large, but poorly understood brains. Here we study trunk representations in elephant trigeminal nuclei, which form large protrusions on the ventral brainstem. Dense vascularization and intense cytochrome-oxidase reactivity distinguish several elongated putative trunk modules, which repeat in the anterior-posterior direction; our analysis focuses on the most anterior and largest of the units, the putative nucleus principalis trunk module. Module neuron density is low and non-neural cells outnumber neurons by ∼108:1. Dendritic trees are elongated along the axis of axon bundles (myelin stripes) transversing the trunk module. Furthermore, synchrotron X-ray phase contrast tomography suggests myelin-stripe-axons transverse the trunk module. We show a remarkable correspondence of trunk module myelin stripes and trunk folds. Myelin stripes show little relation to trigeminal neurons and stripe-axons appear to often go nowhere; these observations suggest the possibility that myelin stripes might serve to separate trunk-fold domains rather than to connect neurons. The myelin-stripes-to-folds mapping allowed to determine neural magnification factors, which changed from 1000:1 proximally to 5:1 in the trunk finger. Asian elephants have fewer (∼640,000) trunk-module neurons than Africans (∼740,000) and show enlarged representations of trunk parts involved in object wrapping. We conclude the elephant trigeminal trunk module is exquisitely organized into trunk-fold-related units