Active avoidance recruits the anterior cingulate cortex regardless of social context in male and female rats.

Actively avoiding danger is necessary for survival. Most research has focused on the behavioral and neurobiological processes when individuals avoid danger alone, under solitary conditions. Therefore, little is known about how social context affects active avoidance. Using a modified version of the platform-mediated avoidance task in rats, we investigated whether the presence of a social partner attenuates conditioned freezing and enhances avoidance learning compared to avoidance learned under solitary conditions. Rats spent a similar percentage of time avoiding during the tone under both conditions; however, rats trained under social conditions exhibited greater freezing during the tone as well as lower rates of darting and food seeking compared to solitary rats. Under solitary conditions, we observed higher levels of avoidance in females compared to males, which was not present in rats trained under social conditions. To gain greater mechanistic insight, we optogenetically inactivated glutamatergic projection neurons in the anterior cingulate cortex (ACC) following avoidance training. Photoinactivation of ACC neurons reduced expression of avoidance under social conditions both in the presence and absence of the partner. Under solitary conditions, photoinactivation of ACC delayed avoidance in males but blocked avoidance in females. Our findings suggest that avoidance is mediated by the ACC, regardless of social context, and may be dysfunctional in those suffering from trauma-related disorders. Furthermore, sex differences in prefrontal circuits mediating active avoidance warrant further investigation, given that females experience a higher risk of developing anxiety disorders.

Preparation of Methyltriazolo[1,4]benzodiazepine via Oxidative Activation of a Thiolactam for the Synthesis of BET Inhibitor Molibresib.

A novel oxidative activation of a thiolactam was developed for the preparation of methyltriazolo[1,4]benzodiazepine in a single step. A sulfenic acid (R-SOH) was proposed as the activated intermediate with the concurrent formation of acetylhydrazone from acethydrazide and cyclocondensation to the triazole. A version of the method with 35% peracetic acid was scaled up to 40 kg as a part of the new route for the synthesis of BET inhibitor molibresib (GSK525762). The thiolactam was prepared from commercially available (2-amino-5-methoxyphenyl)(4-chlorophenyl)methanone in two steps in 66% yield. The concise four-step synthesis delivered 52 kg of molibresib of >99.9% ee in an overall 41% yield from the ketone. The condition for the methyltriazole was mild and free of racemization of the sensitive stereocenter. The oxidative method, with several advantages to the known methods, should be applicable to the synthesis of alkyltriazoles from other thiolactams and acylhydrazines.

Convergent Synthesis of the NS5B Inhibitor GSK8175 Enabled by Transition Metal Catalysis.

A convergent eight-stage synthesis of the boron-containing NS5B inhibitor GSK8175 is described. The previous route involves 13 steps in a completely linear sequence, with an overall 10% yield. Key issues include a multiday SNAr arylation of a secondary sulfonamide using HMPA as solvent, multiple functional group interconversions after all of the carbon atoms are installed (including a Sandmeyer halogenation), use of carcinogenic chloromethyl methyl ether to install a protecting group late in the synthesis, and an unreliable Pd-catalyzed Miyaura borylation as the penultimate step. We have devised an orthogonal approach using a Chan-Lam coupling between a halogenated aryl pinacol boronate ester and an aryl methanesulfonamide. This reaction is performed using a cationic Cu(I) precatalyst, which can be easily generated in situ using KPF6 as a halide abstractor. High-throughput screening revealed a new Pd catalyst system to effect the penultimate borylation chemistry using simple monodentate phosphine ligands, with PCyPh2 identified as optimal. Reaction progress analysis of this borylation indicated likely mass-transfer rate limitations under standard conditions using KOAc as the base. We have devised a K2CO3/pivalic acid system as an alternative, which dramatically outperforms the standard conditions. This new synthesis proceeds in eight stages with a 20% overall yield.

Mother-Son Communication About Sex and Routine Human Immunodeficiency Virus Testing Among Younger Men of Color Who Have Sex With Men.

PURPOSE: The purposes of this study were to document the HIV testing behaviors and serostatus of younger men of color who have sex with men (YMSM) and to explore sociodemographic, behavioral, and maternal correlates of HIV testing in the past 6 months. METHODS: A total of 135 YMSM aged 16-19 years completed a close-ended survey on HIV testing and risk behaviors, mother-son communication, and sociodemographic characteristics. Youth were offered point-of-care HIV testing, with results provided at survey end. Multivariate logistic regression analyzed the sociodemographic, behavioral, and maternal factors associated with routine HIV testing. RESULTS: A total of 90.3% of YMSM had previously tested for HIV, and 70.9% had tested in the past 6 months. In total, 11.7% of youth reported being HIV positive, and 3.3% reported unknown serostatus. When offered an HIV test, 97.8% accepted. Of these, 14.7% had a positive oral test result, and 31.58% of HIV-positive YMSM (n = 6) were seropositive unaware. Logistic regression results indicated that maternal communication about sex with males was positively associated with routine testing (odds ratio = 2.36; 95% confidence interval = 1.13-4.94). Conversely, communication about puberty and general human sexuality was negatively associated (odds ratio = .45; 95% confidence interval = .24-.86). Condomless anal intercourse and positive sexually transmitted infection history were negatively associated with routine testing; however, frequency of alcohol use was positively associated. CONCLUSIONS: Despite high rates of testing, we found high rates of HIV infection, with 31.58% of HIV-positive YMSM being seropositive unaware. Mother-son communication about sex needs to address same-sex behavior as this appears to be more important than other topics. YMSM with known risk factors for HIV are not testing at the recommended time intervals.

Behavioral activation therapy for return to work in medication-responsive chronic depression with persistent psychosocial dysfunction.

OBJECTIVE: Chronic depression is associated with significant impairment in work functioning, relationships, and health. Such impairment often persists following medication-induced remission of depressive symptoms. We adapted and tested Behavioral Activation therapy with a goal of return to work (BA-W) in subjects with chronic depression who had responded to medication treatment but remained unemployed. METHOD: Sixteen adults aged 18-65 with DSM-IV diagnosed Dysthymic Disorder or chronic Major Depression were recruited from clinical trials taking place at the New York State Psychiatric Institute between 4/2009 and 12/2012 and enrolled in 12 weeks of individual manual-driven BA-W. Functioning was measured at intake, post-treatment and at 24 week follow-up. RESULTS: Eighty-seven percent (n=14) of subjects completed the full 12 weeks of BA-W. Hours of work related activity (p<.005, d=0.83), hours of paid work (p<.0003, d=0.54), and work productivity (p<.0004, d=-0.48) increased significantly over the study period. Earned income increased post-treatment (p=.068) with significant changes by 24 week follow-up (p=.011). Secondary outcomes including behavioral avoidance (p<.004, d=-0.56), and global functioning (p<.0003, d=1.42) were also significantly improved post-treatment. Effect sizes, including for outcomes with non-significant changes, were generally in the range of 0.5-0.8. CONCLUSIONS: This pilot study provides preliminary evidence of the efficacy of a work-targeted psychotherapy to remediate vocational impairment in subjects with chronic depression. Data suggests that further testing of BA-W using a randomized controlled trial is warranted and may represent a significant advance in treatment for the residual disability present after successful pharmacotherapy.

An efficient synthesis of a potent PPARpan agonist.

An efficient synthesis of 2-{4-[({4-{[4-(4-methoxyphenyl)piperazin-1-yl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)thio]phenoxy}-2-methylpropanoic acid (1), a potent PPARpan agonist, is described. The seven-step synthesis, which afforded 1 in 30% overall yield, includes a highly regioselective carbon-sulfur bond formation via coupling of a bishydroxymethylthiazole (3) with 4-hydroxythiophenol, displacement of the remaining alcohol through a three-step telescoped sequence involving an efficient cleavage of an aryl mesylate, and an efficient and practical method of introducing an isobutyric acid fragment.