Uncertainty in paleohydrologic reconstructions from molecular δD values

Compound-specific δD measurements can be used for quantitative estimation of source water δD values, a useful tracer for paleohydrologic changes. Such estimates have quantifiable levels of uncertainty that are often miscalculated, resulting in inaccurate error reporting in the scientific literature that can impact paleohydrologic interpretations. Here, we summarize the uncertainties inherent to molecular δD measurements and the quantification of source water δD values, and discuss the assumptions involved when omitting various sources of uncertainty. Using standard protocols from measurement science, we derive the equations necessary to quantify these various sources of uncertainty. We show that analytical uncertainty is usually improperly estimated and that after apparent fractionation between δD values of source water and molecule, normalization of data to the VSMOW scale introduces the largest amount of uncertainty. Lastly, to facilitate systematic error reporting we provide an Uncertainty Calculator spreadsheet to conveniently calculate uncertainty in δD measurements

The influence of 14C reservoir age on interpretation of paleolimnological records from the Tibetan Plateau

There is a great deal of controversy regarding the fate of glaciers and ice fields on the Tibetan Plateau in the face of continued anthropogenic global warming. Paleoclimate reconstructions and spatial analyses aimed at mapping past climate changes are the key to understanding the climatic response of the Tibetan Plateau to changing conditions. Specifically, the numerous lakes distributed across the Tibetan Plateau can provide high-resolution (spatial and temporal) climate reconstructions to investigate past changes in the climate system. In this paper, we review the primary limitation to exploiting these valuable paleoclimate archives: errors in radiocarbon-based age models. We review the techniques that have been used to estimate 14C reservoir ages on the Tibetan Plateau and compile the published 14C reservoir ages to examine their spatial and temporal patterns and to assess the imposed chronological uncertainties. Using site-specific evaluations of Bangong Co and Lake Qinghai, we demonstrate that 14C age model uncertainties permit equally probable and contrasting interpretations of existing paleoclimate records. We also examine 14C-induced uncertainties in the spatial climatic response on the Tibetan Plateau to (1) the termination of the Last Glacial Maximum and (2) the Holocene Thermal Maximum. We conclude with recommendations for reducing uncertainties in future lake-based paleoclimate studies on the Tibetan Plateau

Large infrequent rain events dominate the hydroclimate of Rapa Nui (Easter Island)

The history of the Polynesian civilization on Rapa Nui (Easter Island) over the Common Era has come to exemplify the fragile relationship humans have with their environment. Social dynamics, deforestation, land degradation, and climatic shifts have all been proposed as important parts of the settlement history and societal transformations on Rapa Nui. Furthermore, climate dynamics of the Southeast Pacific have major global implications. While the wetlands of Rapa Nui contain critical sedimentological archives for reconstructing past hydrological change on the island, connections between the island’s hydroclimate and fundamental aspects of regional climatology are poorly understood. Here we present a hydroclimatology of Rapa Nui showing that there is a clear seasonal cycle of precipitation, with wet months receiving almost twice as much precipitation as dry months. This seasonal cycle can be explained by the seasonal shifts in the location and strength of the climatological south Pacific subtropical anticyclone. For interannual precipitation variability, we find that the occurrence of infrequent, large rain events explains 92% of the variance of the observed annual mean precipitation time series. Approximately one third (33%) of these events are associated with atmospheric rivers, 21% are associated with classic cold-front synoptic systems, and the remainder are characterized by cut-off lows and other synoptic-scale storm systems. As a group, these large rain events are most strongly controlled by the longitudinal position of the south Pacific subtropical anticyclone. The longitudinal location of this anticyclone explains 21% of the variance in the frequency of large rain events, while the remaining variance is left unexplained by any other major atmosphere-ocean dynamics. We find that over the observational era there appears to be no linear relationship between the number of large rain events and any other major climate phenomena. With the south Pacific subtropical anticyclone projected to strengthen and expand westward under global warming, our results imply that Rapa Nui will experience an increase in the number of dry years in the future

Structure of the Mg-Chelatase Cofactor GUN4 Reveals a Novel Hand-Shaped Fold for Porphyrin Binding

In plants, the accumulation of the chlorophyll precursor Mg-protoporphyrin IX (Mg-Proto) in the plastid regulates the expression of a number of nuclear genes with functions related to photosynthesis. Analysis of the plastid-to-nucleus signaling activity of Mg-Proto in Arabidopsis thaliana led to the discovery of GUN4, a novel porphyrin-binding protein that also dramatically enhances the activity of Mg-chelatase, the enzyme that synthesizes Mg-Proto. GUN4 may also play a role in both photoprotection and the cellular shuttling of tetrapyrroles. Here we report a 1.78-Å resolution crystal structure of Synechocystis GUN4, in which the porphyrin-binding domain adopts a unique three dimensional fold with a “cupped hand” shape. Biophysical and biochemical analyses revealed the specific site of interaction between GUN4 and Mg-Proto and the energetic determinants for the GUN4 • Mg-Proto interaction. Our data support a novel protective function for GUN4 in tetrapyrrole trafficking. The combined structural and energetic analyses presented herein form the physical-chemical basis for understanding GUN4 biological activity, including its role in the stimulation of Mg-chelatase activity, as well as in Mg-Proto retrograde signaling

Enhancement of Notch receptor maturation and signaling sensitivity by Cripto-1

Cripto-1 associates with Notch1 in the endoplasmic reticulum and Golgi to enhance Notch1 localization to lipid rafts and its maturation

Genome-wide gene expression profiling identifies overlap with malignant adrenocortical tumours and novel mechanisms of inefficient steroidogenesis in familial ACTH-independent macronodular adrenal hyperplasia.

ACTH-independent macronodular adrenal hyperplasia (AIMAH) is a rare cause of sporadic or familial late-onset Cushing's syndrome. It is a cytologically benign disease, of unknown pathogenesis, and characterised by inefficient steroidogenesis, ascribed to differential cellular localisation of steroidogenic enzymes. The objectives were to determine the molecular mechanisms involved in the pathogenesis of familial AIMAH tumours and the mechanisms of their inefficient steroidogenesis. Using Affymetrix Human GeneChip® HumanGene 1.0 ST arrays, we compared the genome-wide gene expression profile of two AIMAH nodules from each of three affected siblings with normal adrenal cortex and analysed the data for differential expression and using Ingenuity Pathway Analysis, Gene Set Enrichment Analysis and Motif Activity Response Analysis. Expression profiling identified: (i) that amongst the most highly differentially expressed genes were ones known to have involvement in tumorigenesis and metastasis; (ii) enrichment for differentially expressed genes in sporadic AIMAH and other benign and malignant adrenocortical tumours and (iii) reduced activity of key transcriptional regulators (Steroidogenic factor-1, SF-1 and transcription factor Sp1, Sp1) of steroidogenic enzymes. Genome-wide gene expression studies of familial AIMAH nodules have identified overlap with malignant adrenocortical tumours, which is intriguing given the benign biological behaviour of these tumours. This requires further study. Novel mechanisms of inefficient steroidogenesis were also identified

Differential Analysis of Ovarian and Endometrial Cancers Identifies a Methylator Phenotype

Despite improved outcomes in the past 30 years, less than half of all women diagnosed with epithelial ovarian cancer live five years beyond their diagnosis. Although typically treated as a single disease, epithelial ovarian cancer includes several distinct histological subtypes, such as papillary serous and endometrioid carcinomas. To address whether the morphological differences seen in these carcinomas represent distinct characteristics at the molecular level we analyzed DNA methylation patterns in 11 papillary serous tumors, 9 endometrioid ovarian tumors, 4 normal fallopian tube samples and 6 normal endometrial tissues, plus 8 normal fallopian tube and 4 serous samples from TCGA. For comparison within the endometrioid subtype we added 6 primary uterine endometrioid tumors and 5 endometrioid metastases from uterus to ovary. Data was obtained from 27,578 CpG dinucleotides occurring in or near promoter regions of 14,495 genes. We identified 36 locations with significant increases or decreases in methylation in comparisons of serous tumors and normal fallopian tube samples. Moreover, unsupervised clustering techniques applied to all samples showed three major profiles comprising mostly normal samples, serous tumors, and endometrioid tumors including ovarian, uterine and metastatic origins. The clustering analysis identified 60 differentially methylated sites between the serous group and the normal group. An unrelated set of 25 serous tumors validated the reproducibility of the methylation patterns. In contrast, >1,000 genes were differentially methylated between endometrioid tumors and normal samples. This finding is consistent with a generalized regulatory disruption caused by a methylator phenotype. Through DNA methylation analyses we have identified genes with known roles in ovarian carcinoma etiology, whereas pathway analyses provided biological insight to the role of novel genes. Our finding of differences between serous and endometrioid ovarian tumors indicates that intervention strategies could be developed to specifically address subtypes of epithelial ovarian cancer

Mechanism of Neuronal versus Endothelial Cell Uptake of Alzheimer's Disease Amyloid β Protein

Alzheimer's disease (AD) is characterized by significant neurodegeneration in the cortex and hippocampus; intraneuronal tangles of hyperphosphorylated tau protein; and accumulation of β-amyloid (Aβ) proteins 40 and 42 in the brain parenchyma as well as in the cerebral vasculature. The current understanding that AD is initiated by the neuronal accumulation of Aβ proteins due to their inefficient clearance at the blood-brain-barrier (BBB), places the neurovascular unit at the epicenter of AD pathophysiology. The objective of this study is to investigate cellular mechanisms mediating the internalization of Aβ proteins in the principle constituents of the neurovascular unit, neurons and BBB endothelial cells. Laser confocal micrographs of wild type (WT) mouse brain slices treated with fluorescein labeled Aβ40 (F-Aβ40) demonstrated selective accumulation of the protein in a subpopulation of cortical and hippocampal neurons via nonsaturable, energy independent, and nonendocytotic pathways. This groundbreaking finding, which challenges the conventional belief that Aβ proteins are internalized by neurons via receptor mediated endocytosis, was verified in differentiated PC12 cells and rat primary hippocampal (RPH) neurons through laser confocal microscopy and flow cytometry studies. Microscopy studies have demonstrated that a significant proportion of F-Aβ40 or F-Aβ42 internalized by differentiated PC12 cells or RPH neurons is located outside of the endosomal or lysosomal compartments, which may accumulate without degradation. In contrast, BBME cells exhibit energy dependent uptake of F-Aβ40, and accumulate the protein in acidic cell organelle, indicative of endocytotic uptake. Such a phenomenal difference in the internalization of Aβ40 between neurons and BBB endothelial cells may provide essential clues to understanding how various cells can differentially regulate Aβ proteins and help explain the vulnerability of cortical and hippocampal neurons to Aβ toxicity

Interactions between Natural Populations of Human and Rodent Schistosomes in the Lake Victoria Region of Kenya: A Molecular Epidemiological Approach

One of the world's most prevalent neglected diseases is schistosomiasis, which infects approximately 200 million people worldwide. Schistosoma mansoni is transmitted to humans by skin penetration by free-living larvae that develop in freshwater snails. The origin of this species is East Africa, where it coexists with its sister species, S. rodhaini. Interactions between these species potentially influence their epidemiology, ecology, and evolutionary biology, because they infect the same species of hosts and can hybridize. Over two years, we examined their distribution in Kenya to determine their degree of overlap geographically, within snail hosts, and in the water column as infective stages. Both species were spatially and temporally patchy, although S. mansoni was eight times more common than S. rodhaini. Both species overlap in the time of day they were present in the water column, which increases the potential for the species to coinfect the same host and interbreed. Peak infective time for S. mansoni was midday and dawn and dusk for S. rodhaini. Three snails were coinfected, which was more common than expected by chance. These findings indicate a lack of obvious isolating mechanisms to prevent hybridization, raising the intriguing question of how the two species retain separate identities