Mammalian retinas display an astonishing diversity in the spatial arrangement of their spectral cone photoreceptors, probably in adaptation to different visual environments. Opsin expression patterns like the dorsoventral gradients of short-wave-sensitive (S) and middle-to long-wave-sensitive (M) cone opsin found in many species are established early in development and thought to be stable thereafter throughout life. In mouse early development, thyroid hormone (TH), through its receptor TR␤2, is an important regulator of cone spectral identity. However, the role of TH in the maintenance of the mature cone photoreceptor pattern is unclear. We here show that TH also controls adult cone opsin expression. Methimazole-induced suppression of serum TH in adult mice and rats yielded no changes in cone numbers but reversibly altered cone patterns by activating the expression of S-cone opsin and repressing the expression of M-cone opsin. Furthermore, treatment of athyroid Pax8 Ϫ/Ϫ mice with TH restored a wild-type pattern of cone opsin expression that reverted back to the mutant S-opsin-dominated pattern after termination of treatment. No evidence for cone death or the generation of new cones from retinal progenitors was found in retinas that shifted opsin expression patterns. Together, this suggests that opsin expression in terminally differentiated mammalian cones remains subject to control by TH, a finding that is in contradiction to previous work and challenges the current view that opsin identity in mature mammalian cones is fixed by permanent gene silencing.

OAT (organic anion transporter) 2 [human gene symbol SLC22A7 (SLC is solute carrier)] is a member of the SLC22 family of transport proteins. In the rat, the principal site of expression of OAT2 is the sinusoidal membrane domain of hepatocytes. The particular physiological function of OAT2 in liver has been unresolved so far. In the present paper, we have used the strategy of LC (liquid chromatography)-MS difference shading to search for specific and cross-species substrates of OAT2. Heterologous expression of human and rat OAT2 in HEK (human embryonic kidney)-293 cells stimulated accumulation of the zwitterion trigonelline; subsequently, orotic acid was identified as an excellent and specific substrate of OAT2 from the rat (clearance=106 μl·min⁻¹·mg of protein⁻¹) and human (46 μl·min⁻¹·mg of protein⁻¹). The force driving uptake of orotic acid was identified as glutamate antiport. Efficient transport of glutamate by OAT2 was directly demonstrated by uptake of [³H]glutamate. However, because of high intracellular glutamate, OAT2 operates as glutamate efflux transporter. Thus expression of OAT2 markedly increased the release of glutamate (measured by LC-MS) from cells, even without extracellular exchange substrate. Orotic acid strongly trans-stimulated efflux of glutamate. We thus propose that OAT2 physiologically functions as glutamate efflux transporter. OAT2 mRNA was detected, after laser capture microdissection of rat liver slices, equally in periportal and pericentral regions; previous reports of hepatic release of glutamate into blood can now be explained by OAT2 activity. A specific OAT2 inhibitor could, by lowering plasma glutamate and thus promoting brain-to-blood efflux of glutamate, alleviate glutamate exotoxicity in acute brain conditions.

A large body of evidence indicates that nitric oxide (NO) and cGMP contribute to central sensitization of pain pathways during inflammatory pain. Here, we investigated the distribution of cyclic nucleotide-gated (CNG) channels in the spinal cord, and identified the CNG channel subunit CNGA3 as a putative cGMP target in nociceptive processing. In situ hybridization revealed that CNGA3 is localized to inhibitory neurons of the dorsal horn of the spinal cord, whereas its distribution in dorsal root ganglia is restricted to non-neuronal cells. CNGA3 expression is upregulated in the superficial dorsal horn of the mouse spinal cord and in dorsal root ganglia following hindpaw inflammation evoked by zymosan. Mice lacking CNGA3 (CNGA3 Ϫ/Ϫ mice) exhibited an increased nociceptive behavior in models of inflammatory pain, whereas their behavior in models of acute or neuropathic pain was normal. Moreover, CNGA3 Ϫ/Ϫ mice developed an exaggerated pain hypersensitivity induced by intrathecal administration of cGMP analogs or NO donors. Our results provide evidence that CNGA3 contributes in an inhibitory manner to the central sensitization of pain pathways during inflammatory pain as a target of NO/cGMP signaling.

Background: The Global Terrorism Database (GTD) is an open-source database that includes information on terrorist incidents that have occurred around the world since 1970. It is maintained by the Center for Terrorism and Intelligence Studies and the University of Maryland National Consortium for the Study of Terrorism and Responses to Terrorism (START), a Department of Homeland Security Center of Excellence. Objective: To characterize chemical terrorism incidents reported to the GTD and understand more about the kinds of chemical agents used, the associated morbidity and mortality, the geography of incidents, and the intended targets. Methods: We searched the GTD database to identify all terrorism incidents categorized as “chemical” or with “chemical weapon” in the incident description; we excluded duplicate entries and those not involving a chemical agent. We reviewed each incident and assigned it to one of eight chemical agent categories. We analyzed the total number of chemical terrorism incidents between 1970 and 2015 by chemical agent category, injury and fatality volume, geographic region, and target. We determined injury and fatality counts and mean number of injuries and fatalities by chemical agent category. Results: During the study period, 156,772 terrorism incidents were reported to the GTD, of which 321 (0.2%) were reported as “chemical” or “chemical weapons” incidents. Of these, 292 (90.1%) met our inclusion criteria for analysis (duplicate reports and incidents that did not involve a chemical terrorism agent were excluded). The reported chemical agent categories were: unknown chemical (30.5%); corrosives (23.3%); tear gas/mace (12.3%); unspecified gas (11.6%); cyanide (8.2%); pesticides (5.5%); metals (6.5%); and nerve gas (2.1%). On average, chemical terrorism incidents in this dataset resulted in 51 injuries (mean range across agents: 2.5–1622) and 7 deaths (mean range across agents: 0.0–224.3) per incident. Nerve gas incidents (2.1%) had the highest reported mean number of fatalities (n=224) and injuries (n=1622) per incident. The highest number of reported chemical terrorism incidents occurred in South Asia (29.5%), Western Europe (16.8%), Middle East/North Africa (13%), and South America (9.3%). The most common targets were private citizens (19.5%). Conclusions: This is the first publication to characterize chemical terrorism incidents collected by the GTD. Data suggest that morbidity and mortality vary by chemical category and by region. Results may be helpful in developing and optimizing regional chemical terrorism preparedness activities.

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