Genetic Implication of a Novel Thiamine Transporter in Human Hypertension

ObjectivesThis study coupled 2 strategies—trait extremes and genome-wide pooling—to discover a novel blood pressure (BP) locus that encodes a previously uncharacterized thiamine transporter.BackgroundHypertension is a heritable trait that remains the most potent and widespread cardiovascular risk factor, although details of its genetic determination are poorly understood.MethodsRepresentative genomic deoxyribonucleic acid (DNA) pools were created from male and female subjects in the highest- and lowest-fifth percentiles of BP in a primary care population of >50,000 patients. The peak associated single-nucleotide polymorphisms were typed in individual DNA samples, as well as in twins/siblings phenotyped for cardiovascular and autonomic traits. Biochemical properties of the associated transporter were evaluated in cellular assays.ResultsAfter chip hybridization and calculation of relative allele scores, the peak associations were typed in individual samples, revealing an association between hypertension, systolic BP, and diastolic BP and the previously uncharacterized solute carrier SLC35F3. The BP genetic association at SLC35F3 was validated by meta-analysis in an independent sample from the original source population, as well as the International Consortium for Blood Pressure Genome-Wide Association Studies (across North America and western Europe). Sequence homology to a putative yeast thiamine (vitamin B1) transporter prompted us to express human SLC35F3 in Escherichia coli, which catalyzed [3H]-thiamine uptake. SLC35F3 risk-allele homozygotes (T/T) displayed decreased erythrocyte thiamine content on microbiological assay. In twin pairs, the SLC35F3 risk allele predicted heritable cardiovascular traits previously associated with thiamine deficiency, including elevated cardiac stroke volume with decreased vascular resistance, and elevated pressor responses to environmental (cold) stress. Allelic expression imbalance confirmed that cis variation at the human SLC35F3 locus influenced expression of that gene, and the allelic expression imbalance peak coincided with the hypertension peak.ConclusionsNovel strategies were coupled to position a new hypertension-susceptibility locus, uncovering a previously unsuspected thiamine transporter whose genetic variants predicted several disturbances in cardiac and autonomic function. The results have implications for the pathogenesis and treatment of systemic hypertension

Static Magnetic Field Exposure Reproduces Cellular Effects of the Parkinson's Disease Drug Candidate ZM241385

This study was inspired by coalescing evidence that magnetic therapy may be a viable treatment option for certain diseases. This premise is based on the ability of moderate strength fields (i.e., 0.1 to 1 Tesla) to alter the biophysical properties of lipid bilayers and in turn modulate cellular signaling pathways. In particular, previous results from our laboratory (Wang et al., BMC Genomics, 10, 356 (2009)) established that moderate strength static magnetic field (SMF) exposure altered cellular endpoints associated with neuronal function and differentiation. Building on this background, the current paper investigated SMF by focusing on the adenosine A(2A) receptor (A(2A)R) in the PC12 rat adrenal pheochromocytoma cell line that displays metabolic features of Parkinson's disease (PD).SMF reproduced several responses elicited by ZM241385, a selective A(2A)R antagonist, in PC12 cells including altered calcium flux, increased ATP levels, reduced cAMP levels, reduced nitric oxide production, reduced p44/42 MAPK phosphorylation, inhibited proliferation, and reduced iron uptake. SMF also counteracted several PD-relevant endpoints exacerbated by A(2A)R agonist CGS21680 in a manner similar to ZM241385; these include reduction of increased expression of A(2A)R, reversal of altered calcium efflux, dampening of increased adenosine production, reduction of enhanced proliferation and associated p44/42 MAPK phosphorylation, and inhibition of neurite outgrowth.When measured against multiple endpoints, SMF elicited qualitatively similar responses as ZM241385, a PD drug candidate. Provided that the in vitro results presented in this paper apply in vivo, SMF holds promise as an intriguing non-invasive approach to treat PD and potentially other neurological disorders

Radiation, soil water content, and temperature effects on carbon cycling in an alpine swamp meadow of the northeastern Qinghai–Tibetan Plateau

Abstract Predicted intensified climate warming will likely alter the ecosystem net carbon (C) uptake of the Qinghai–Tibetan Plateau (QTP). Variations in C sink–source responses to climate warming have been linked to water availability; however, the mechanisms by which net C uptake responds to soil water content in saturated swamp meadow ecosystems remain unclear. To explore how soil moisture and other environmental drivers modulate net C uptake in the QTP, field measurements were conducted using the eddy covariance technique in 2014, 2015, 2017, and 2018. The alpine swamp meadow presented in this study was a persistent and strong C sink of CO₂ (−168.0 ± 62.5 g C m⁻² yr⁻¹, average ± standard deviation) across the entire 4-year study period. A random forest machine-learning analysis suggested that the diurnal and seasonal variations of net ecosystem exchange (NEE) and gross primary productivity (GPP) were regulated by temperature and net radiation. Ecosystem respiration (Re), however, was found mainly regulated by the variability of soil water content (SWC) at different temporal aggregations, followed by temperature, the second contributing driver. We further explored how Re is controlled by nearly saturated soil moisture and temperature comparing two different periods featuring almost identical temperatures and significant differences on SWC and vice versa. Our data suggest that, despite the relatively abundant water supply, periods with a substantial decrease in SWC or increase in temperature produced higher Re and therefore weakened the C sink strength. Our results reveal that nearly saturated soil conditions during the growing seasons can help maintain lower ecosystem respiration rates and thus enhance the overall C sequestration capacity in this alpine swamp meadow. We argue that soil respiration and subsequent ecosystem C sink magnitude in alpine swamp meadows could likely be affected by future changes in soil hydrological conditions caused by permafrost degradation or accelerated thawing–freezing cycling due to climate warming