High Dense Gas Fraction in Intensely Star-forming Dusty Galaxies

We present ALMA and VLA detections of the dense molecular gas tracers HCN, HCO$^+$ and HNC in two lensed, high-redshift starbursts selected from the {\it Herschel}-ATLAS survey: {\it H}-ATLAS\,J090740.0$-$004200 (SDP.9, $z \sim 1.6$) and {\it H}-ATLAS\,J091043.1$-$000321 (SDP.11, $z \sim 1.8$). ALMA observed the $J = 3-2$ transitions in both sources, while the VLA observed the $J = 1-0$ transitions in SDP.9. We have detected all observed HCN and HCO$^+$ lines in SDP.9 and SDP.11, and also HNC(3--2) in SDP.9. The amplification factors for both galaxies have been determined from sub-arcsec resolution CO and dust emission observations carried out with NOEMA and the SMA. The HNC(1--0)/HCN(1--0) line ratio in SDP.9 suggests the presence of photon-dominated regions, as it happens to most local (U)LIRGs. The CO, HCN and HCO$^+$ SLEDs of SDP.9 are compatible to those found for many local, infrared (IR) bright galaxies, indicating that the molecular gas in local and high-redshift dusty starbursts can have similar excitation conditions. We obtain that the correlation between total IR ($L_{\rm IR}$) and dense line ($L_{\rm dense}$) luminosity in SDP.9 and SDP.11 and local star-forming galaxies can be represented by a single relation. The scatter of the $L_{\rm IR} - L_{\rm dense}$ correlation, together with the lack of sensitive dense molecular gas tracer observations for a homogeneous sample of high-redshift galaxies, prevents us from distinguishing differential trends with redshift. Our results suggest that the intense star formation found in some high-redshift dusty, luminous starbursts is associated with more massive dense molecular gas reservoirs and higher dense molecular gas fractions.Comment: Submitted to ApJ. Comments most welcom

Comparison of the Bioactivation Potential of the Antidepressant and Hepatotoxin Nefazodone with Aripiprazole, a Structural Analog and Marketed Drug

ABSTRACT: In vitro metabolism/bioactivation of structurally related central nervous system agents nefazodone (hepatotoxin) and aripiprazole (nonhepatotoxin) were undertaken in human liver microsomes in an attempt to understand the differences in toxicological profile. NADPH-supplemented microsomal incubations of nefazodone and glutathione generated conjugates derived from addition of thiol to quinonoid intermediates. Inclusion of cyanide afforded cyano conjugates to iminium ions derived from ␣-carbon oxidation of the piperazine ring in nefazodone and downstream metabolites. Although the arylpiperazine motif in aripiprazole did not succumb to bioactivation, the dihydroquinolinone group was bioactivated via an intermediate monohydroxy metabolite to a reactive species, which was trapped by glutathione. Studies with synthetic dehydroaripiprazole metabolite revealed an analogous glutathione conjugate with molecular weight 2 Da lower. Based on the proposed structure of the glutathione conjugate(s), a bioactivation sequence involving aromatic ortho-or para-hydroxylation on the quinolinone followed by oxidation to a quinone-imine was proposed. P4503A4 inactivation studies in microsomes indicated that, unlike nefazodone, aripiprazole was not a time-and concentration-dependent inactivator of the enzyme. Overall, these studies reinforce the notion that not all drugs that are bioactivated in vitro elicit a toxicological response in vivo. A likely explanation for the markedly improved safety profile of aripiprazole (versus nefazodone) despite the accompanying bioactivation liability is the vastly improved pharmacokinetics (enhanced oral bioavailability, longer elimination half-life) due to reduced P4503A4-mediated metabolism/bioactivation, which result in a lower daily dose (5-20 mg/day) compared with nefazodone (200-400 mg/day). This attribute probably reduces the total body burden to reactive metabolite exposure and may not exceed a threshold needed for toxicity

Food Restriction Alters Neuronal Morphology in the Hypothalamic Ventromedial Nucleus of Male Rats

Several lines of evidence have implicated the hypothalamic ventromedial nucleus (VMH) in the control of caloric homeostasis. For example, the activity of VMH neurons depends on energy availability. We tested the hypothesis that energy balance may involve the remodeling of the dendritic arbor of VMH neurons. We compared two groups of animals: one group had ad libitum access to food, and the other experienced 10-d restricted access to food. As expected, the food-deprived group lost body weight and had reduced levels of glucose, insulin, and leptin. VMH neurons were visualized after Golgi impregnation, and dendrite length was measured. Food deprivation had differential effects on VMH neurons. In particular, within the ventrolateral VMH, for neurons with long primary dendrites (LPDs) that extended in the lateral, but not medial, direction, the LPDs were 31% shorter. These same neurons exhibited a 32% reduction in the number of other dendrites without a change in soma size. In contrast, within the dorsomedial VMH, for neurons with medially, but not laterally, extended LPDs, the soma area was reduced by 28%. However, neurons in the dorsomedial VMH did not display a change in the length or number of dendrites, regardless of LPD direction. Thus, although structural changes during calorie depletion occur in both the dorsomedial and ventrolateral VMH, only the latter exhibits a remodeled dendritic arbor. These results also suggest that the direction of the LPD may be an important marker of neuronal function in the VMH