Gangs, displaced, and group-based aggression

Many urban areas experienced an alarming growth of gang activity and violence during the end of the 20th and the beginning of the 21st centuries. Gang members, motivated by various factors, commit a variety of different types of violent acts towards rivals and other targets. Our focus involves instances of displaced aggression, which generally refers to situations in which aggression is targeted towards individuals who have either not themselves committed an offense against the aggressor (s), or who provide an offense that is too mild to justify the aggression levels that are expressed towards them. We discuss how social–psychological mechanisms and models of two types of displaced aggression might help explain some aspects of the retaliatory behavior that is expressed by members of street gangs. We also propose general techniques that have the potential to reduce such aggressive behavior

Fluorescent Risedronate Analogues Reveal Bisphosphonate Uptake by Bone Marrow Monocytes and Localization Around Osteocytes In Vivo

Bisphosphonates are effective antiresorptive agents owing to their bone-targeting property and ability to inhibit osteoclasts. It remains unclear, however, whether any non-osteoclast cells are directly affected by these drugs in vivo. Two fluorescent risedronate analogues, carboxyfluorescein-labeled risedronate (FAM-RIS) and Alexa Fluor 647–labeled risedronate (AF647-RIS), were used to address this question. Twenty-four hours after injection into 3-month-old mice, fluorescent risedronate analogues were bound to bone surfaces. More detailed analysis revealed labeling of vascular channel walls within cortical bone. Furthermore, fluorescent risedronate analogues were present in osteocytic lacunae in close proximity to vascular channels and localized to the lacunae of newly embedded osteocytes close to the bone surface. Following injection into newborn rabbits, intracellular uptake of fluorescently labeled risedronate was detected in osteoclasts, and the active analogue FAM-RIS caused accumulation of unprenylated Rap1A in these cells. In addition, CD14high bone marrow monocytes showed relatively high levels of uptake of fluorescently labeled risedronate, which correlated with selective accumulation of unprenylated Rap1A in CD14+ cells, as well as osteoclasts, following treatment with risedronate in vivo. Similar results were obtained when either rabbit or human bone marrow cells were treated with fluorescent risedronate analogues in vitro. These findings suggest that the capacity of different cell types to endocytose bisphosphonate is a major determinant for the degree of cellular drug uptake in vitro as well as in vivo. In conclusion, this study shows that in addition to bone-resorbing osteoclasts, bisphosphonates may exert direct effects on bone marrow monocytes in vivo. © 2010 American Society for Bone and Mineral Researc

Microwave-Accelerated McKenna Synthesis of Phosphonic Acids: An Investigation

Phosphonic acids represent one of the most important categories of organophosphorus compounds, with myriad examples found in chemical biology, medicine, materials, and other domains. Phosphonic acids are rapidly and conveniently prepared from their simple dialkyl esters by silyldealkylation with bromotrimethylsilane (BTMS), followed by desilylation upon contact with water or methanol. Introduced originally by McKenna, the BTMS route to phosphonic acids has long been a favored method due to its convenience, high yields, very mild conditions, and chemoselectivity. We systematically investigated microwave irradiation as a means to accelerate the BTMS silyldealkylations (MW-BTMS) of a series of dialkyl methylphosphonates with respect to solvent polarity (ACN, dioxane, neat BTMS, DMF, and sulfolane), alkyl group (Me, Et, and iPr), electron-withdrawing P-substitution, and phosphonate–carboxylate triester chemoselectivity. Control reactions were performed using conventional heating. We also applied MW-BTMS to the preparation of three acyclic nucleoside phosphonates (ANPs, an important class of antiviral and anticancer drugs), which were reported to undergo partial nucleoside degradation under MW hydrolysis with HCl at 130–140 °C (MW-HCl, a proposed alternative to BTMS). In all cases, MW-BTMS dramatically accelerated quantitative silyldealkylation compared to BTMS with conventional heating and was highly chemoselective, confirming it to be an important enhancement of the conventional BTMS method with significant advantages over the MW-HCl method

On the Observation of Discrete Fluorine NMR Spectra for Uridine 5′-β,γ-Fluoromethylenetriphosphate Diastereomers at Basic pH

Jakeman et al. recently reported the inability to distinguish the diastereomers of uridine 5′-β,γ-fluoromethylenetriphosphate (β,γ-CHF-UTP, <b>1</b>) by ¹⁹F NMR under conditions we previously prescribed for the resolution of the corresponding β,γ-CHF-dGTP spectra, stating further that <b>1</b> decomposed under these basic conditions. Here we show that the ¹⁹F NMR spectra of <b>1</b> (∼1:1 diastereomer mixture prepared by coupling of UMP-morpholidate with fluoro­methylene­bis­(phos­phonic acid)) in D₂O at pH 10 are indeed readily distinguishable. <b>1</b> in this solution was stable for 24 h at rt

5′-β,γ-CHF-ATP Diastereomers: Synthesis and Fluorine-Mediated Selective Binding by c‑Src Protein Kinase

The first preparation of the individual β,γ-CHF-ATP stereoisomers <b>12a</b> and <b>12b</b> is reported. Configurationally differing solely by the orientation of the C–F fluorine, <b>12a</b> and <b>12b</b> have discrete ³¹P (202 MHz, pH 10.9, Δδ_Pα 6 Hz, Δδ_Pβ 4 Hz) and ¹⁹F NMR (470 MHz, pH 9.8, Δδ_F 25 Hz) spectral signatures and exhibit a 6-fold difference in IC₅₀ values for c-Src kinase, attributed to a unique interaction of the (<i>S</i>)-fluorine of bound <b>12b</b> with R388 in the active site