An efficient method to uniquely identify every individual would have value in quality control and sample tracking of large collections of cell lines or DNA as is now often the case with whole genome ...association studies. Such a method would also be useful in forensics. SNPs represent the best markers for such purposes. We have developed a globally applicable resource of 92 SNPs for individual identification (IISNPs) with extremely low probabilities of any two unrelated individuals from anywhere in the world having identical genotypes. The SNPs were identified by screening over 500 likely/candidate SNPs on samples of 44 populations representing the major regions of the world. All 92 IISNPs have an average heterozygosity >0.4 and the F st values are all <0.06 on our 44 populations making these a universally applicable panel irrespective of ethnicity or ancestry. No significant linkage disequilibrium (LD) occurs for all unique pairings of 86 of the 92 IISNPs (median LD = 0.011) in all of the 44 populations. The remaining 6 IISNPs show strong LD in most of the 44 populations for a small subset (7) of the unique pairings in which they occur due to close linkage. 45 of the 86 SNPs are spread across the 22 human autosomes and show very loose or no genetic linkage with each other. These 45 IISNPs constitute an excellent panel for individual identification including paternity testing with associated probabilities of individual genotypes less than 10⁻¹⁵, smaller than achieved with the current panels of forensic markers. This panel also improves on an interim panel of 40 IISNPs previously identified using 40 population samples. The unlinked status of the subset of 45 SNPs we have identified also makes them useful for situations involving close biological relationships. Comparisons with random sets of SNPs illustrate the greater discriminating power, efficiency, and more universal applicability of this IISNP panel to populations around the world. The full set of 86 IISNPs that do not show LD can be used to provide even smaller genotype match probabilities in the range of 10⁻³¹-10⁻³⁵ based on the 44 population samples studied.
Use of electronic cigarettes (e-cigarettes) is increasing. Measures of exposure to known tobacco-related toxicants among e-cigarette users will inform potential health risks to individual product ...users.
To estimate concentrations of tobacco-related toxicants among e-cigarette users and compare these biomarker concentrations with those observed in combustible cigarette users, dual users, and never tobacco users.
A population-based, longitudinal cohort study was conducted in the United States in 2013-2014. Cross-sectional analysis was performed between November 4, 2016, and October 5, 2017, of biomarkers of exposure to tobacco-related toxicants collected by the Population Assessment of Tobacco and Health Study. Participants included adults who provided a urine sample and data on tobacco use (N = 5105).
The primary exposure was tobacco use, including current exclusive e-cigarette users (n = 247), current exclusive cigarette smokers (n = 2411), and users of both products (dual users) (n = 792) compared with never tobacco users (n = 1655).
Geometric mean concentrations of 50 individual biomarkers from 5 major classes of tobacco product constituents were measured: nicotine, tobacco-specific nitrosamines (TSNAs), metals, polycyclic aromatic hydrocarbons (PAHs), and volatile organic compounds (VOCs).
Of the 5105 participants, most were aged 35 to 54 years (weighted percentage, 38%; 95% CI, 35%-40%), women (60%; 95% CI, 59%-62%), and non-Hispanic white (61%; 95% CI, 58%-64%). Compared with exclusive e-cigarette users, never users had 19% to 81% significantly lower concentrations of biomarkers of exposure to nicotine, TSNAs, some metals (eg, cadmium and lead), and some VOCs (including acrylonitrile). Exclusive e-cigarette users showed 10% to 98% significantly lower concentrations of biomarkers of exposure, including TSNAs, PAHs, most VOCs, and nicotine, compared with exclusive cigarette smokers; concentrations were comparable for metals and 3 VOCs. Exclusive cigarette users showed 10% to 36% lower concentrations of several biomarkers than dual users. Frequency of cigarette use among dual users was positively correlated with nicotine and toxicant exposure.
Exclusive use of e-cigarettes appears to result in measurable exposure to known tobacco-related toxicants, generally at lower levels than cigarette smoking. Toxicant exposure is greatest among dual users, and frequency of combustible cigarette use is positively correlated with tobacco toxicant concentration. These findings provide evidence that using combusted tobacco cigarettes alone or in combination with e-cigarettes is associated with higher concentrations of potentially harmful tobacco constituents in comparison with using e-cigarettes alone.
An enantio- and diastereoselective Pd-catalysed (3 + 2) cycloaddition of bis(trifluoroethyl) 2-vinyl-cyclopropane-1,1-dicarboxylate (VCP) with cyclic sulfamidate imine-derived 1-azadienes (SDAs) has ...been developed. These reactions provide highly functionalized spiroheterocycles having three contiguous stereocentres, including a tetrasubstituted carbon bearing an oxygen functionality. The two geminal trifluoroethyl ester moieties can be manipulated in a facially selective manner to afford more diversely decorated spirocycles with four contiguous stereocentres. In addition, diastereoselective reduction of the imine moiety can also afford a fourth stereocentre and exposes the important 1,2-amino alcohol functionality.
Formation of valuable spiroheterocycles with multiple contiguous stereogenic centres from palladium-catalysed enantioselective (3 + 2) cycloaddition reactions of sulfamidate-derived azadienes and vinylcyclopropanes.
According to a 2013–2014 survey of nearly 46,000 U.S. adults and youths, 28% of adults were current users of tobacco and 9% of youths had used tobacco in the previous 30 days. Approximately 40% of ...users used multiple products, with cigarettes plus e-cigarettes the most common combination.
Smoking is responsible for more U.S. deaths annually than the acquired immunodeficiency syndrome, use of alcohol and illegal drugs, motor vehicle accidents, murders, and suicides combined.
1
With recent data suggesting higher smoking-attributable mortality than previously estimated,
2
the medical community is urged to make tobacco control a high priority.
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The prevalence of current use of cigarettes has declined during the past 50 years, from 42% of adults in 1965 to less than 20% in 2014,
4
,
5
but disparities in cigarette smoking across demographic subgroups (particularly according to race or ethnic group, educational attainment, and socioeconomic status) have widened during the past . . .
We assessed factors related to smoke-free policies among a cross-sectional, nationally representative, random-digit-dial sample (landline and cell phone) of US multiunit housing residents (n = 418). ...Overall, 29% reported living in smoke-free buildings, while 79% reported voluntary smoke-free home rules. Among those with smoke-free home rules, 44% reported secondhand smoke incursions in their unit. Among all respondents, 56% supported smoke-free building policy implementation. These findings suggest that smoke-free building policies are needed to protect multiunit housing residents from secondhand smoke in their homes.
The histone acetyltransferase HBO1 (MYST2, KAT7) is indispensable for postgastrulation development, histone H3 lysine 14 acetylation (H3K14Ac), and the expression of embryonic patterning genes. In ...this study, we report the role of HBO1 in regulating hematopoietic stem cell function in adult hematopoiesis. We used 2 complementary cre-recombinase transgenes to conditionally delete Hbo1 (Mx1-Cre and Rosa26-CreERT2). Hbo1-null mice became moribund due to hematopoietic failure with pancytopenia in the blood and bone marrow 2 to 6 weeks after Hbo1 deletion. Hbo1-deleted bone marrow cells failed to repopulate hemoablated recipients in competitive transplantation experiments. Hbo1 deletion caused a rapid loss of hematopoietic progenitors. The numbers of lineage-restricted progenitors for the erythroid, myeloid, B-, and T-cell lineages were reduced. Loss of HBO1 resulted in an abnormally high rate of recruitment of quiescent hematopoietic stem cells (HSCs) into the cell cycle. Cycling HSCs produced progenitors at the expense of self-renewal, which led to the exhaustion of the HSC pool. Mechanistically, genes important for HSC functions were downregulated in HSC-enriched cell populations after Hbo1 deletion, including genes essential for HSC quiescence and self-renewal, such as Mpl, Tek(Tie-2), Gfi1b, Egr1, Tal1(Scl), Gata2, Erg, Pbx1, Meis1, and Hox9, as well as genes important for multipotent progenitor cells and lineage-specific progenitor cells, such as Gata1. HBO1 was required for H3K14Ac through the genome and particularly at gene loci required for HSC quiescence and self-renewal. Our data indicate that HBO1 promotes the expression of a transcription factor network essential for HSC maintenance and self-renewal in adult hematopoiesis.
•In the absence of HBO1, H3K14ac is lost, and hematopoietic stem cells differentiate into progenitors at the expense of self-renewal.•HBO1 governs stem cell quiescence and self-renewal by promoting gene transcription, including Gata2, Mpl, Erg, Pbx1, Meis1, and Hoxa9.
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A formal palladium‐catalyzed decarboxylative (4+2) cycloaddition reaction between 4‐vinylbenzoxazinanones and 2‐nitro‐1,3‐enynes has been developed to produce highly valuable, densely functionalized ...tetrahydroquinolines in moderate to excellent yields with high diastereoselectivity under mild reaction conditions. The optimised protocol tolerates a range of substituted 2‐nitro‐1,3‐enynes, which represent an under‐utilized class of dipolarophile for transition‐metal catalyzed cycloadditions. The employed reaction methodology facilitates efficient cycloaddition with both N‐H‐ and N‐Ts‐4‐vinylbenzoxazinanone dipole precursors. The stereochemistry of the major and minor diastereomeric (4+2) cycloadducts was determined by single crystal X‐ray analyses. A mechanistic rationale for the high intrinsic diastereoselectivity and preliminary enantioselective experiments are also presented. The tetrahydroquinoline cycloadduct products feature numerous pendant functionalities, including a vinyl handle, an internal alkyne motif and a nitro functionality (which functions as a latent C‐3 nitrogen substituent) for further synthetic manipulations.
The Pd‐catalyzed decarboxylative (4+2) cycloaddition reaction of N‐H‐ and N‐Ts‐4‐vinylbenzoxazinanones with 2‐nitro‐1,3‐enyne dipolarophiles gives valuable tetrahydroquinoline products in high yields with excellent diastereoselectivities. These cycloaddition reactions constitute the first example of a dipolarophile with a single strong activating group (i. e. 2‐nitro‐1,3‐enynes) reacting with 4‐vinylbenzoxazinanone derived Pd‐stabilized zwitterionic dipoles.
In previously untreated patients with HCV genotype 1 infection without cirrhosis, the rate of sustained virologic response was 94% with 8 weeks of ledipasvir–sofosbuvir, 93% with 8 weeks of ...ledipasvir–sofosbuvir plus ribavirin, and 95% with 12 weeks of ledipasvir–sofosbuvir.
More than 3 million people in the United States are chronically infected with the hepatitis C virus (HCV).
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,
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Although the number of new infections has been declining for decades, HCV-related morbidity and mortality are projected to continue rising for another 20 years.
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One half to three quarters of persons currently infected with HCV have not received a diagnosis and are untreated; many will have progression to decompensated cirrhosis, hepatocellular carcinoma, and other liver complications.
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,
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Early diagnosis and treatment are essential to improve long-term health outcomes in this population. New guidelines from the Centers for Disease Control and Prevention . . .
The Pd-catalysed asymmetric allylic alkylation (Pd-AAA) of prochiral enamide anions derived from 5
H
-oxathiazole 2,2-dioxides has been developed. Various 4,5-disubstituted and 4-substituted cyclic ...sulfamidate imines have participated in the transformation with a range of allyl carbonates-as well as 2-vinyl oxirane, 2-vinyl-
N
-tosylaziridine, and 2-vinyl-1,1-cyclopropane dicarboxylate-to furnish the desired
C
-allylated products in moderate to high yields, with high regioselectivites and generally high enantioselectivities. Conversion between
N
- and
C
-allyl products was observed, with the
N
-allylated products converting to the
C
-allylated products over time. The resulting high-value allylated heterocyclic products all bear a tetrasubstituted stereogenic centre and can be reduced to an allylated chiral sulfamidate or an amino alcohol.
The Pd-catalysed asymmetric allylic alkylation (Pd-AAA) of prochiral enamide anions derived from 5
H
-oxathiazole 2,2-dioxides has been developed.
A two-step Pd-catalyzed (3 + 2) cycloaddition/HNO2 elimination reaction sequence has been developed to give novel cyclic 1,3-dien-5-yne systems from Pd-stabilized zwitterionic 1,3-dipoles and ...2-nitro-1,3-enyne substrates. The process is highly atom-efficient and tolerates the reaction of 2-vinyloxirane, 1-tosyl-2-vinylaziridine, and diethyl 2-vinylcyclopropane-1,1-dicarboxylate derived 1,3-dipoles with a variety of 2-nitro-1,3-enyne substrates. The stereochemistry of the intermediate (3 + 2) cycloadducts was determined by single crystal X-ray analysis. Furthermore, a selective kinetic elimination of the cycloadduct with an antiperiplanar relationship between the NO2 group and the participating hydrogen was demonstrated, allowing for efficient isolation of a single diastereoisomer of the cycloadduct.
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