The plasma concentrations of cholesterol precursor sterols and plant sterols vary over a 5- to 10-fold range among normolipidemic individuals, and provide indices of the relative rates of cholesterol ...synthesis and fractional absorption. In the present study, we examined the relative contributions of genetic and environmental factors to variation in the plasma concentrations and sterol-cholesterol ratios of five noncholesterol sterols, including the 5alpha-saturated derivative of cholesterol (cholestanol), two precursors in the cholesterol biosynthesis pathway (desmosterol and lathosterol), and two phytosterols (campesterol and sitosterol). Plasma sterol concentrations were highly stable in 30 individuals measured over a 48 week period. Regression of offspring sterol levels on the parental values indicated that plasma levels of all five noncholesterol sterols were highly heritable. Analysis of monozygotic and dizygotic twin pairs also indicated strong heritability of all five sterols. Two common sequence variations (D19H and T400K) in ABCG8, an ABC half-transporter defective in sitosterolemia, were associated with lower concentrations of plant sterols in parents, and in their offspring.Taken together, these findings indicate that variation in the plasma concentrations of noncholesterol sterols is highly heritable, and that polymorphism in ABCG8 contributes to genetic variation in the plasma concentrations of plant sterols.
The pentameric γ-aminobutyric acid type A receptors (GABAARs) are the major inhibitory ligand-gated ion channels in the central nervous system. They mediate diverse physiological functions, mutations ...in them are associated with mental disorders and they are the target of many drugs such as general anesthetics, anxiolytics and anti–convulsants. The five subunits of synaptic GABAARs are arranged around a central pore in the order β-α-β-α-γ. In the outer third of the transmembrane domain (TMD) drugs may bind to five homologous intersubunit binding sites. Etomidate binds between the pair of β – α subunit interfaces (designated as β+/α–) and R–mTFD-MPAB binds to an α+/β– and an γ+/β– subunit interface (a β– selective ligand). Ligands that bind selectively to other homologous sites have not been characterized. We have synthesized a novel photolabel, (2,6-diisopropyl-4-(3-(trifluoromethyl)-3H-diazirin-3-yl)phenyl)methanol or pTFD-di-iPr-BnOH). It is a potent general anesthetic that positively modulates agonist and benzodiazepine binding. It enhances GABA–induced currents, shifting the GABA concentration-response curve to lower concentrations. Photolabeling–protection studies show that it has negligible affinity for the etomidate sites and high affinity for only one of the two R–mTFD-MPAB sites. Exploratory site–directed mutagenesis studies confirm the latter conclusions and hint that pTFD-di-iPr-BnOH may bind between the α+/β– and α+/γ– subunits in the TMD, making it an α+ ligand. The latter α+/γ– site has not previously been implicated in ligand binding. Thus, pTFD-di-iPr-BnOH is a promising new photolabel that may open up a new pharmacology for synaptic GABAARs.
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•PTFD-di-iPr-BnOH is a potent general anesthetic and enhances GABA’s actions.•It photo-incorporates into intersubunit sites in the GABA(A)R’s transmembrane domain.•Photo-protection shows it binds at either the γ+/β– or the α+/β– subunit interface.•Similarly, it does not bind in the β+/α– subunit interfaces (etomidate sites).•Site–directed mutagenesis suggests the α+/γ– interface is another site.
The pentameric γ-aminobutyric acid type A receptors (GABA
Rs) are the major inhibitory ligand-gated ion channels in the central nervous system. They mediate diverse physiological functions, mutations ...in them are associated with mental disorders and they are the target of many drugs such as general anesthetics, anxiolytics and anti-convulsants. The five subunits of synaptic GABA
Rs are arranged around a central pore in the order β-α-β-α-γ. In the outer third of the transmembrane domain (TMD) drugs may bind to five homologous intersubunit binding sites. Etomidate binds between the pair of β - α subunit interfaces (designated as β
/α
) and R-mTFD-MPAB binds to an α
/β
and an γ
/β
subunit interface (a β
selective ligand). Ligands that bind selectively to other homologous sites have not been characterized. We have synthesized a novel photolabel, (2,6-diisopropyl-4-(3-(trifluoromethyl)-3H-diazirin-3-yl)phenyl)methanol or pTFD-di-iPr-BnOH). It is a potent general anesthetic that positively modulates agonist and benzodiazepine binding. It enhances GABA-induced currents, shifting the GABA concentration-response curve to lower concentrations. Photolabeling-protection studies show that it has negligible affinity for the etomidate sites and high affinity for only one of the two R-mTFD-MPAB sites. Exploratory site-directed mutagenesis studies confirm the latter conclusions and hint that pTFD-di-iPr-BnOH may bind between the α
/β
and α
/γ
subunits in the TMD, making it an α
ligand. The latter α
/γ
site has not previously been implicated in ligand binding. Thus, pTFD-di-iPr-BnOH is a promising new photolabel that may open up a new pharmacology for synaptic GABA
Rs.
Infection remains the leading cause of morbidity and mortality in patients with multiple myeloma because of the cumulative effect of disease, treatment, and host-related factors. Given that ...infectious risk is cumulative through the course of the disease, preventing infections is paramount. Optimal preventive strategies include vaccination against common pathogens, antimicrobial prophylaxis, infection control measures, and immunoglobulin replacement in a small subset of patients; however, there are no universally accepted guidelines for infection prevention. This Review provides a consensus statement from a panel of 36 experts with global representation, which was convened by The International Myeloma Society to review existing literature and current guidelines, address issues associated with the risk of infection and prevention of infectious complications in multiple myeloma in the context of emerging therapies, and offer recommendations for preventing these complications.
Many ecosystems face multiple invaders, and interactions among invasive and native species may complicate conservation efforts for imperiled species. Examination of fine‐scale resource selection can ...be used to detect patterns in habitat selection resulting from species interactions and assess the value of specific resources, including invasive plants, to wildlife. We used animal location data with mixed‐effects resource selection models to examine seasonal competitive interactions and species‐specific selection for forage and cover resources by an imperiled native lagomorph, the New England cottontail Sylvilagus transitionalis and its nonnative competitor, the eastern cottontail S. floridanus in the eastern Hudson Valley, NY. We found evidence that resource selection by New England cottontails depended on the relative prevalence of eastern cottontails to New England cottontails. Where eastern cottontails were less prevalent New England cottontail selected for resources characteristic of early successional shrublands. Where eastern cottontails were more prevalent, New England cottontails selected for resources characteristic of later successional shrublands. New England cottontail use of certain invasive shrubs depended on the prevalence of eastern cottontails relative to New England cottontails, suggesting response to invasive plants is confounded by interactions with a nonnative competitor. Our results further emphasize the need for conservation efforts to consider invasive management within the ecosystem context. We demonstrate the utility of resource selection studies to assist in this regard by exploring competitive interactions in the absence of removal studies, while simultaneously assessing the impact of habitat components such as invasive vegetation on species of conservation concern. Synthesis and applications Resource selection studies can be directly applied to inform ongoing species conservation where multiple invaders are present or where species interactions influence resource selection. Fine‐scale assessments of resource selection, similar to those presented here, can be used to selectively manage habitat to benefit desired species within the ecosystem context.
We present strong evidence that the prevalence of a nonnative competitor alters resource selection and promotes use of an invasive shrub by an imperiled native cottontail. We identify seasonal shifts in selection that could facilitate displacement of residents and identify resources to selectively manage to benefit desired over undesired species.
Adiponectin has a variety of metabolic effects on obesity, insulin sensitivity, and atherosclerosis. To identify genes influencing variation in plasma adiponectin levels, we performed genome-wide ...linkage and association scans of adiponectin in two cohorts of subjects recruited in the Genetic Epidemiology of Metabolic Syndrome Study. The genome-wide linkage scan was conducted in families of Turkish and southern European (TSE, n = 789) and Northern and Western European (NWE, N = 2,280) origin. A whole genome association (WGA) analysis (500K Affymetrix platform) was carried out in a set of unrelated NWE subjects consisting of approximately 1,000 subjects with dyslipidemia and 1,000 overweight subjects with normal lipids. Peak evidence for linkage occurred at chromosome 8p23 in NWE subjects (lod = 3.10) and at chromosome 3q28 near ADIPOQ, the adiponectin structural gene, in TSE subjects (lod = 1.70). In the WGA analysis, the single-nucleotide polymorphisms (SNPs) most strongly associated with adiponectin were rs3774261 and rs6773957 (P < 10(-7)). These two SNPs were in high linkage disequilibrium (r(2) = 0.98) and located within ADIPOQ. Interestingly, our fourth strongest region of association (P < 2 x 10(-5)) was to an SNP within CDH13, whose protein product is a newly identified receptor for high-molecular-weight species of adiponectin. Through WGA analysis, we confirmed previous studies showing SNPs within ADIPOQ to be strongly associated with variation in adiponectin levels and further observed these to have the strongest effects on adiponectin levels throughout the genome. We additionally identified a second gene (CDH13) possibly influencing variation in adiponectin levels. The impact of these SNPs on health and disease has yet to be determined.
An understanding of genetic diversity and population structure is important to the conservation of declining species within fragmented habitats. These issues become critical for small, isolated ...populations, in which stochasticity is a main driver of genetic change and possibly of population extinction. In eastern New York and New England the endemic New England cottontail has declined due to habitat loss and fragmentation. As a species that exhibits metapopulation dynamics, habitat fragmentation can have profound implications for its persistence. We examined genetic diversity, population structure, and effective population size (N
e
) of New England cottontails in New York, a purported remnant stronghold for the species. We amplified ten microsatellite loci from tissues collected from live-captures and from fecal pellets. We investigated potential hierarchical population structuring using programs STRUCTURE and BAPS. STRUCTURE identified four hierarchical tiers consisting of nine clusters, and BAPS clustering was highly consistent with that given by STRUCTURE. Most populations displayed significant genetic differentiation (F
ST
= 0.04–0.34) and little to no evidence of ongoing connectivity. Low genetic diversity was observed based on allelic richness (2.2–3.0), and all populations had critically low effective population sizes (N
e
; 2.7–57.1). Observed trends in population subdivision, genetic diversity, and N
e
were consistent with reported trends in the state-endangered Maine-New Hampshire populations, and not indicative of a genetic stronghold within New York. Instead, the small and isolated populations observed here imply a breakdown in metapopulation functionality indicative of conditions faced by the species range-wide and an immediate need for human intervention to restore connectivity and rebuild populations.
Bioluminescence (BL) potential observations registered high BL potential emissions during the polar night of January 2012 at the mouth of a fjord Rijpfjorden (northern Svalbard, Norway). Notably, ...observations of BL potential at this location were significantly higher in the upper 50 m than observed BL potential at offshore stations located on the shelf-slope areas and in the deeper water off northern Svalbard. In the present paper, we address questions as to why the values of BL potential in the fjord are higher than at offshore stations and what the role of advection is in the observed elevation of BL potential values in the fjord in comparison to offshore stations. We utilized the ensemble approach when changes in BL potential are modeled with the advection-diffusion-source (ADS) model, and the focus is on modeling and predictions of a large ensemble of averaged values of BL potential over a specific domain of interest at the fjord mouth. Results of the modeling have demonstrated increases in ensemble members with BL potential values larger than or equal to the specific threshold in comparison to corresponding ensemble members in the initial distribution. Even when we introduced mortality rates in our simulations (values from 0.1 to 0.3 day
−1
), increases in ensemble members with higher than the threshold value were more than 3.7 times larger in comparison to ensemble members in the initial distribution. The interpretation of our results is that during the polar night, the fjord represents an area where bioluminescent organisms from offshore aggregate through advection and mixing.
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