A 300-year record of sedimentation in a small tilled catena in Hungary based on δ13C, δ15N, and C/N distribution

Purpose Soil erosion is one of the most serious hazards that endanger sustainable food production. Moreover, it has marked effects on soil organic carbon (SOC) with direct links to global warming. At the same time, soil organic matter (SOM) changes in composition and space could influence these processes. The aim of this study was to predict soil erosion and sedimentation volume and dynamics on a typical hilly cropland area of Hungary due to forest clearance in the early eighteenth century. Materials and methods Horizontal soil samples were taken along two parallel intensively cultivated complex convex-concave slopes from the eroded upper parts at mid-slope positions and from sedimentation in toe-slopes. Samples were measured for SOC, total nitrogen (TN) content, and SOMcompounds (δ13C, δ15N, and photometric indexes). They were compared to the horizons of an in situ non-eroded profile under continuous forest. On the depositional profile cores, soil depth prior to sedimentation was calculated by the determination of sediment thickness. Results and discussion Peaks of SOC in the sedimentation profiles indicated thicker initial profiles, while peaks in C/N ratio and δ13C distribution showed the original surface to be ~ 20 cm lower. Peaks of SOC were presumed to be the results of deposition of SOC-enriched soil from the upper slope transported by selective erosion of finer particles (silts and clays). Therefore, changes in δ13C values due to tillage and delivery would fingerprint the original surface much better under the sedimentation scenario than SOC content. Distribution of δ13C also suggests that the main sedimentation phase occurred immediately after forest clearance and before the start of intense cultivation with maize. Conclusions This highlights the role of relief in sheet erosion intensity compared to intensive cultivation. Patterns of δ13C indicate the original soil surface, even in profiles deposited as sediment centuries ago. The δ13C and C/N decrease in buried in situ profiles had the same tendency as recent forest soil, indicating constant SOM quality distribution after burial. Accordingly, microbiological activity, root uptake, and metabolism have not been effective enough to modify initial soil properties

The what, why and how of aromatase inhibitors: hormonal agents for treatment and prevention of breast cancer

The third-generation aromatase inhibitors (AIs) anastrozole, exemestane and letrozole have largely replaced tamoxifen as the preferred treatment for hormone receptor – positive breast cancer in postmenopausal women. Approximately 185,000 new cases of invasive breast cancer are diagnosed yearly, and at least half of these women are both postmenopausal and eligible for adjuvant therapy with AIs. In addition, AIs are currently being tested as primary prevention therapy in large randomised trials involving tens of thousands of women at increased risk for breast cancer. Given the volume of use, internists will increasingly see postmenopausal women who are taking or considering treatment with AIs. Physicians need to be able to: (i) briefly discuss the pros and cons of using a selective estrogen receptor modulator such as tamoxifen or raloxifene vs. an AI for risk reduction and (ii) recognise and manage AI-associated adverse events. The primary purpose of this review is to help internists with these two tasks

Evolution of the patellar sesamoid bone in mammals

The patella is a sesamoid bone located in the major extensor tendon of the knee joint, in the hindlimb of many tetrapods. Although numerous aspects of knee morphology are ancient and conserved among most tetrapods, the evolutionary occurrence of an ossified patella is highly variable. Among extant (crown clade) groups it is found in most birds, most lizards, the monotreme mammals and almost all placental mammals, but it is absent in most marsupial mammals as well as many reptiles. Here, we integrate data from the literature and first-hand studies of fossil and recent skeletal remains to reconstruct the evolution of the mammalian patella. We infer that bony patellae most likely evolved between four and six times in crown group Mammalia: in monotremes, in the extinct multituberculates, in one or more stem-mammal genera outside of therian or eutherian mammals and up to three times in therian mammals. Furthermore, an ossified patella was lost several times in mammals, not including those with absent hindlimbs: once or more in marsupials (with some re-acquisition) and at least once in bats. Our inferences about patellar evolution in mammals are reciprocally informed by the existence of several human genetic conditions in which the patella is either absent or severely reduced. Clearly, development of the patella is under close genomic control, although its responsiveness to its mechanical environment is also important (and perhaps variable among taxa). Where a bony patella is present it plays an important role in hindlimb function, especially in resisting gravity by providing an enhanced lever system for the knee joint. Yet the evolutionary origins, persistence and modifications of a patella in diverse groups with widely varying habits and habitats—from digging to running to aquatic, small or large body sizes, bipeds or quadrupeds—remain complex and perplexing, impeding a conclusive synthesis of form, function, development and genetics across mammalian evolution. This meta-analysis takes an initial step toward such a synthesis by collating available data and elucidating areas of promising future inquiry

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

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

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

Current and emerging opportunities for molecular simulations in structure-based drug design

An overview of the current capabilities and limitations of molecular simulation of biomolecular complexes in the context of computer-aided drug design is provided. Steady improvements in computer hardware coupled with more refined representations of energetics are leading to a new appreciation of the driving forces of molecular recognition. Molecular simulations are poised to more frequently guide the interpretation of biophysical measurements of biomolecular complexes. Ligand design strategies emerge from detailed analyses of computed structural ensembles. The feasibility of routine applications to ligand optimization problems hinges upon successful extensive large scale validation studies and the development of protocols to intelligently automate computations