Homicide and geographic access to gun dealers in the United States

<p>Abstract</p> <p>Background</p> <p>Firearms are the most commonly used weapon to commit homicide in the U.S. Virtually all firearms enter the public marketplace through a federal firearms licensee (FFL): a store or individual licensed by the federal government to sell firearms. Whether FFLs contribute to gun-related homicide in areas where they are located, in which case FFLs may be a homicide risk factor that can be modified, is not known.</p> <p>Methods</p> <p>Annual county-level data (1993–1999) on gun homicide rates and rates of FFLs per capita were analyzed using negative binomial regression controlling for socio-demographic characteristics. Models were run to evaluate whether the relation between rates of FFLs and rates of gun homicide varied over the study period and across counties according to their level of urbanism (defined by four groupings, as below). Also, rates of FFLs were compared against FS/S – which is the proportion of suicides committed by firearm and is thought to be a good proxy for firearm availability in a region – to help evaluate how well the FFL variable is serving as a way to proxy firearm availability in each of the county types of interest.</p> <p>Results</p> <p>In major cities, gun homicide rates were higher where FFLs were more prevalent (rate ratio [RR] = 1.70, 95% CI 1.03–2.81). This association increased (p < 0.01) from 1993 (RR = 1.69) to 1999 (RR = 12.72), due likely to federal reforms that eliminated low-volume dealers, making FFL prevalence a more accurate exposure measure over time. No association was found in small towns. In other cities and in suburbs, gun homicide rates were significantly lower where FFLs were more prevalent, with associations that did not change over the years of the study period. FFL prevalence was correlated strongly (positively) with FS/S in major cities only, suggesting that the findings for how FFL prevalence relates to gun homicide may be valid for the findings pertaining to major cities but not to counties of other types.</p> <p>Conclusion</p> <p>Modification of FFLs through federal, state, and local regulation may be a feasible intervention to reduce gun homicide in major cities.</p

CBX8, a component of the Polycomb PRC1 complex, modulates DOT1L-mediated gene expression through AF9/MLLT3

AbstractAF9 is known to interact with multiple proteins including activators and repressors of transcription. Our data indicate that other AF9 binding proteins compete with the histone methyltransferase DOT1L for AF9 binding thus diminishing its ability to methylate lysine 79 of histone 3. Specifically, we show that AF9 is part of a protein multimer containing members of Polycomb group (PcG) PRC1 complex, CBX8, RING1B, and BMI1. Interaction with CBX8 precludes AF9–DOT1L binding. Knockdown of CBX8 with short-hairpin RNA (shRNA) leads to decreased expression of the AF9 target gene ENaCα. In contrast, CBX8 overexpression results in increased ENaCα mRNA levels and this effect can be partially overcome by co-overexpression of AF9

Degree of Recruitment of DOT1L to MLL-AF9 Defines Level of H3K79 Di- and Tri-methylation on Target Genes and Transformation Potential

The MLL gene is a common target of chromosomal translocations found in human leukemia. MLL-fusion leukemia has a consistently poor outcome. One of the most common translocation partners is AF9 (MLLT3). MLL-AF9 recruits DOT1L, a histone 3 lysine 79 methyltransferase (H3K79me1/me2/me3), leading to aberrant gene transcription. We show that DOT1L has three AF9 binding sites and present the nuclear magnetic resonance (NMR) solution structure of a DOT1L-AF9 complex. We generate structure-guided point mutations and find that they have graded effects on recruitment of DOT1L to MLL-AF9. Chromatin immunoprecipitation sequencing (ChIP-seq) analyses of H3K79me2 and H3K79me3 show that graded reduction of the DOT1L interaction with MLL-AF9 results in differential loss of H3K79me2 and me3 at MLL-AF9 target genes. Furthermore, the degree of DOT1L recruitment is linked to the level of MLL-AF9 hematopoietic transformation

Reducing firearm violence: a research agenda

In the United States, firearms are involved in tens of thousands of deaths and injuries each year. The magnitude of this problem prompted the National Academy of Sciences (NAS) to issue a report in 2004 detailing the strengths and limitations of existing research on the relationship between firearms and violence. In response, a multidisciplinary group of experts in the field of firearms and violence formed the National Research Collaborative on Firearm Violence. The Collaborative met for 2 days in June 2005 to (1) critically review the main findings of the NAS report and (2) define a research agenda that could fill research and data gaps and inform policy that reduces gun‐related crime, deaths and injuries. This article summarizes the Collaborative's conclusions and identifies priorities for research and funding

Hsp90 Directly Modulates the Spatial Distribution of AF9/MLLT3 and Affects Target Gene Expression*

AF9/MLLT3 contributes to the regulation of the gene encoding the epithelial sodium channel α, ENaCα, in renal tubular cells. Specifically, increases in AF9 protein lead to a reduction in ENaCα expression and changes in AF9 activity appear to be an important component of aldosterone signaling in the kidney. Whereas AF9 is found in the nucleus where it interacts with the histone H3 lysine 79 methyltransferase, Dot1, AF9 is also present in the cytoplasm. Data presented in this report indicate that the heat shock protein Hsp90 directly and specifically interacts with AF9 as part of an Hsp90-Hsp70-p60/Hop chaperone complex. Experimental manipulation of Hsp90 function by the inhibitor novobiocin, but not 17-AAG, results in redistribution of AF9 from a primarily nuclear to cytoplasmic location. Knockdown of Hsp90 with siRNA mimics the effect elicited by novobiocin. As expected, a shift in AF9 from the nucleus to the cytoplasm in response to Hsp90 interference leads to increased ENaCα expression. This is accompanied by a decrease in AF9 occupancy at the ENaCα promoter. Our data suggest that the interaction of Hsp90, Hsp70, and p60/Hop with AF9 is necessary for the proper subnuclear localization and activity of AF9. AF9 is among a growing number of nuclear proteins recognized to rely on the Hsp90 complex for nuclear targeting