The dopamine (DA) transporter DAT1 is a major target bound by cocaine in brain. We examined the influence of functional genetic variants in DAT1 on cocaine addiction. Repeat polymorphisms, including a 30-bp variable-number tandem repeat (VNTR) in intron 8 (Int8 VNTR) with two common alleles, were genotyped in cocaine-dependent abusers (n ؍ 699) and in controls with no past history of drug abuse (n ؍ 866) from Sã o Paulo, Brazil. Positive association was observed with allele 3 of the Int8 VNTR and cocaine abuse (allele odds ratio ؍ 1.2, 95% confidence interval ؍ 1.01-1.37, P ؍ 0.036; 3͞3 homozygote odds ratio ؍ 1.45, 95% confidence interval ؍ 1.18 -1.78, P ؍ 0.0008). Population stratification was assessed and did not affect the results. Haplotypic analyses using additional polymorphisms indicated that the Int8 VNTR is responsible for the observed association. Functional analyses in reportergene constructs, demonstrated that allele 3 mediates significant (P < 0.05) but small reduced expression compared with the ''protective'' allele 2. This difference increased when 1 and 10 M cocaine was added to the cell culture (Ϸ40% reduction of the 3 allele expression versus the 2 allele). The 3 allele also demonstrated Ϸ3-fold-increased expression over the 2 allele in response to KCl plus forskolin challenge. We demonstrate a robust association between cocaine dependence and a VNTR allele in SLC6A3, conferring a small but detectible effect, and we show that this VNTR may be functional. This study suggests that DAT1 gene variation may play a role in cocaine dependence etiology.addiction ͉ genetics ͉ SLC6A3
A novel coronavirus, SARS‐CoV‐2, has recently emerged in China and spread internationally, posing a health emergency to the global community. COVID‐19 caused by SARS‐CoV‐2 is associated with an acute respiratory illness that varies from mild to the life‐threatening acute respiratory distress syndrome (ARDS). The complement system is part of the innate immune arsenal against pathogens, in which many viruses can evade or employ to mediate cell entry. The immunopathology and acute lung injury orchestrated through the influx of pro‐inflammatory macrophages and neutrophils can be directly activated by complement components to prime an overzealous cytokine storm. The manifestations of severe COVID‐19 such as the ARDS, sepsis and multiorgan failure have an established relationship with activation of the complement cascade. We have collected evidence from all the current studies we are aware of on SARS‐CoV‐2 immunopathogenesis and the preceding literature on SARS‐CoV‐1 and MERS‐CoV infection linking severe COVID‐19 disease directly with dysfunction of the complement pathways. This information lends support for a therapeutic anti‐inflammatory strategy against complement, where a number of clinically ready potential therapeutic agents are available.
Pregnancy is a state of high metabolic demand. Fasting diverts metabolism to fatty acid oxidation, and the fasted response occurs much more rapidly in pregnant women than in the non-pregnant state. The product of the imprinted Delta-like homologue 1 gene (DLK1) is an endocrine signaling molecule that reaches a high concentration in the maternal circulation during late pregnancy. By utilising murine models with deleted Dlk1 we show that the fetus is the source of maternal circulating DLK1. In the absence of fetally-derived DLK1, the maternal fasting response is impaired. Furthermore, we found that maternal circulating DLK1 levels predict embryonic mass in mice and can differentiate healthy small for gestational age (SGA) from pathologically small infants in a human cohort. Therefore measurement of DLK1 in maternal blood may be a valuable method for diagnosing human disorders associated with impaired DLK1 expression, and to predict poor intrauterine growth and complications of pregnancy.
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