Source to sink: Evolution of lignin composition in the Madre de Dios River system with connection to the Amazon basin and offshore:Lignin evolution in Amazon

While lignin geochemistry has been extensively investigated in the Amazon River, little is known about lignin distribution and dynamics within deep, stratified river channels or its transformations within soils prior to delivery to rivers. We characterized lignin phenols in soils, river particulate organic matter (POM), and dissolved organic matter (DOM) across a 4 km elevation gradient in the Madre de Dios River system, Peru, as well as in marine sediments to investigate the source-to-sink evolution of lignin. In soils, we found more oxidized lignin in organic horizons relative to mineral horizons. The oxidized lignin signature was maintained during transfer into rivers, and lignin was a relatively constant fraction of bulk organic carbon in soils and riverine POM. Lignin in DOM became increasingly oxidized downstream, indicating active transformation of dissolved lignin during transport, especially in the dry season. In contrast, POM accumulated undegraded lignin downstream during the wet season, suggesting that terrestrial input exceeded in-river degradation. We discovered high concentrations of relatively undegraded lignin in POM at depth in the lower Madre de Dios River in both seasons, revealing a woody undercurrent for its transfer within these deep rivers. Our study of lignin evolution in the soil-river-ocean continuum highlights important seasonal and depth variations of river carbon components and their connection to soil carbon pools, providing new insights into fluvial carbon dynamics associated with the transfer of lignin biomarkers from source to sink

Source to sink: Evolution of lignin composition in the Madre de Dios River system with connection to the Amazon basin and offshore

While lignin geochemistry has been extensively investigated in the Amazon River, little is known about lignin distribution and dynamics within deep, stratified river channels or its transformations within soils prior to delivery to rivers. We characterized lignin phenols in soils, river particulate organic matter (POM), and dissolved organic matter (DOM) across a 4 km elevation gradient in the Madre de Dios River system, Peru, as well as in marine sediments to investigate the source-to-sink evolution of lignin. In soils, we found more oxidized lignin in organic horizons relative to mineral horizons. The oxidized lignin signature was maintained during transfer into rivers, and lignin was a relatively constant fraction of bulk organic carbon in soils and riverine POM. Lignin in DOM became increasingly oxidized downstream, indicating active transformation of dissolved lignin during transport, especially in the dry season. In contrast, POM accumulated undegraded lignin downstream during the wet season, suggesting that terrestrial input exceeded in-river degradation. We discovered high concentrations of relatively undegraded lignin in POM at depth in the lower Madre de Dios River in both seasons, revealing a woody undercurrent for its transfer within these deep rivers. Our study of lignin evolution in the soil-river-ocean continuum highlights important seasonal and depth variations of river carbon components and their connection to soil carbon pools, providing new insights into fluvial carbon dynamics associated with the transfer of lignin biomarkers from source to sink

Presynaptic External Calcium Signaling Involves the Calcium-Sensing Receptor in Neocortical Nerve Terminals

Nerve terminal invasion by an axonal spike activates voltage-gated channels, triggering calcium entry, vesicle fusion, and release of neurotransmitter. Ion channels activated at the terminal shape the presynaptic spike and so regulate the magnitude and duration of calcium entry. Consequently characterization of the functional properties of ion channels at nerve terminals is crucial to understand the regulation of transmitter release. Direct recordings from small neocortical nerve terminals have revealed that external [Ca(2+)] ([Ca(2+)](o)) indirectly regulates a non-selective cation channel (NSCC) in neocortical nerve terminals via an unknown [Ca(2+)](o) sensor. Here, we identify the first component in a presynaptic calcium signaling pathway.By combining genetic and pharmacological approaches with direct patch-clamp recordings from small acutely isolated neocortical nerve terminals we identify the extracellular calcium sensor. Our results show that the calcium-sensing receptor (CaSR), a previously identified G-protein coupled receptor that is the mainstay in serum calcium homeostasis, is the extracellular calcium sensor in these acutely dissociated nerve terminals. The NSCC currents from reduced function mutant CaSR mice were less sensitive to changes in [Ca(2+)](o) than wild-type. Calindol, an allosteric CaSR agonist, reduced NSCC currents in direct terminal recordings in a dose-dependent and reversible manner. In contrast, glutamate and GABA did not affect the NSCC currents.Our experiments identify CaSR as the first component in the [Ca(2+)](o) sensor-NSCC signaling pathway in neocortical terminals. Decreases in [Ca(2+)](o) will depress synaptic transmission because of the exquisite sensitivity of transmitter release to [Ca(2+)](o) following its entry via voltage-activated Ca(2+) channels. CaSR may detects such falls in [Ca(2+)](o) and increase action potential duration by increasing NSCC activity, thereby attenuating the impact of decreases in [Ca(2+)](o) on release probability. CaSR is positioned to detect the dynamic changes of [Ca(2+)](o) and provide presynaptic feedback that will alter brain excitability

Gene polymorphisms in association with emerging cardiovascular risk markers in adult women

<p>Abstract</p> <p>Background</p> <p>Evidence on the associations of emerging cardiovascular disease risk factors/markers with genes may help identify intermediate pathways of disease susceptibility in the general population. This population-based study is aimed to determine the presence of associations between a wide array of genetic variants and emerging cardiovascular risk markers among adult US women.</p> <p>Methods</p> <p>The current analysis was performed among the National Health and Nutrition Examination Survey (NHANES) III phase 2 samples of adult women aged 17 years and older (sample size n = 3409). Fourteen candidate genes within <it>ADRB2, ADRB3, CAT, CRP, F2, F5, FGB, ITGB3, MTHFR, NOS3, PON1, PPARG, TLR4</it>, and <it>TNF </it>were examined for associations with emerging cardiovascular risk markers such as serum C-reactive protein, homocysteine, uric acid, and plasma fibrinogen. Linear regression models were performed using SAS-callable SUDAAN 9.0. The covariates included age, race/ethnicity, education, menopausal status, female hormone use, aspirin use, and lifestyle factors.</p> <p>Results</p> <p>In covariate-adjusted models, serum C-reactive protein concentrations were significantly (P value controlling for false-discovery rate ≤ 0.05) associated with polymorphisms in <it>CRP </it>(rs3093058, rs1205)<it>, MTHFR </it>(rs1801131)<it>, and ADRB3 </it>(rs4994). Serum homocysteine levels were significantly associated with <it>MTHFR </it>(rs1801133).</p> <p>Conclusion</p> <p>The significant associations between certain gene variants with concentration variations in serum C-reactive protein and homocysteine among adult women need to be confirmed in further genetic association studies.</p

Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity.

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels

Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to similar to 370,000 women, we identify 389 independent signals (P <5 x 10(-8)) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain similar to 7.4% of the population variance in age at menarche, corresponding to similar to 25% of the estimated heritability. We implicate similar to 250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility

Genome-wide analysis identifies 12 loci influencing human reproductive behavior.

The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits

Elevated intracranial pressure and cerebral edema following permanent MCA occlusion in an ovine model

INTRODUCTION: Malignant middle cerebral artery (MCA) stroke has a disproportionately high mortality due to the rapid development of refractory space-occupying cerebral edema. Animal models are essential in developing successful anti-edema therapies; however to date poor clinical translation has been associated with the predominately used rodent models. As such, large animal gyrencephalic models of stroke are urgently needed. The aim of the study was to characterize the intracranial pressure (ICP) response to MCA occlusion in our recently developed ovine stroke model. MATERIALS AND METHODS: 30 adult female Merino sheep (n = 8-12/gp) were randomized to sham surgery, temporary or permanent proximal MCA occlusion. ICP and brain tissue oxygen were monitored for 24 hours under general anesthesia. MRI, infarct volume with triphenyltetrazolium chloride (TTC) staining and histology were performed. RESULTS: No increase in ICP, radiological evidence of ischemia within the MCA territory but without space-occupying edema, and TTC infarct volumes of 7.9+/-5.1% were seen with temporary MCAO. Permanent MCAO resulted in significantly elevated ICP, accompanied by 30% mortality, radiological evidence of space-occupying cerebral edema and TTC infarct volumes of 27.4+/-6.4%. CONCLUSIONS: Permanent proximal MCAO in the sheep results in space-occupying cerebral edema, raised ICP and mortality similar to human malignant MCA stroke. This animal model may prove useful for pre-clinical testing of anti-edema therapies that have shown promise in rodent studies.Adam J. Wells, Robert Vink, Stephen C. Helps, Steven J. Knox, Peter C. Blumbergs, Renée J. Turne

Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity

The present work was largely supported by a grant from the US National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (R01HL118305). The full list of acknowledgments appears in the Supplementary Notes 3 and 4.Peer reviewedPublisher PD