C−C Bond Formation via Double C−H Functionalization: Aerobic Oxidative Coupling as a Method for Synthesizing Heterocoupled Biaryls

The aerobic oxidative coupling of arenes such as benzofuran and N-substituted indoles with benzene and derivatives thereof is described. The reaction is shown to take place in both inter- and intramolecular scenarios

CTLA4 Message Reflects Pathway Disruption in Monogenic Disorders and Under Therapeutic Blockade

CTLA-4 is essential for immune tolerance. Heterozygous CTLA4 mutations cause immune dysregulation evident in defective regulatory T cells with low levels of CTLA-4 expression. Biallelic mutations in LRBA also result in immune dysregulation with low levels of CTLA-4 and clinical presentation indistinguishable from CTLA-4 haploinsufficiency. CTLA-4 has become an immunotherapy target whereby its blockade with a monoclonal antibody has resulted in improved survival in advanced melanoma patients, amongst other malignancies. However, this therapeutic manipulation can result in autoimmune/inflammatory complications reminiscent of those seen in genetic defects affecting the CTLA-4 pathway. Despite efforts made to understand and establish disease genotype/phenotype correlations in CTLA-4-haploinsufficiency and LRBA-deficiency, such relationships remain elusive. There is currently no specific immunological marker to assess the degree of CTLA-4 pathway disruption or its relationship with clinical manifestations. Here we compare three different patient groups with disturbances in the CTLA-4 pathway—CTLA-4-haploinsufficiency, LRBA-deficiency, and ipilimumab-treated melanoma patients. Assessment of CTLA4 mRNA expression in these patient groups demonstrated an inverse correlation between the CTLA4 message and degree of CTLA-4 pathway disruption. CTLA4 mRNA levels from melanoma patients under therapeutic CTLA-4 blockade (ipilimumab) were increased compared to patients with either CTLA4 or LRBA mutations that were clinically stable with abatacept treatment. In summary, we show that increased CTLA4 mRNA levels correlate with the degree of CTLA-4 pathway disruption, suggesting that CTLA4 mRNA levels may be a quantifiable surrogate for altered CTLA-4 expression

Spike-Timing Precision and Neuronal Synchrony Are Enhanced by an Interaction between Synaptic Inhibition and Membrane Oscillations in the Amygdala

The basolateral complex of the amygdala (BLA) is a critical component of the neural circuit regulating fear learning. During fear learning and recall, the amygdala and other brain regions, including the hippocampus and prefrontal cortex, exhibit phase-locked oscillations in the high delta/low theta frequency band (∼2–6 Hz) that have been shown to contribute to the learning process. Network oscillations are commonly generated by inhibitory synaptic input that coordinates action potentials in groups of neurons. In the rat BLA, principal neurons spontaneously receive synchronized, inhibitory input in the form of compound, rhythmic, inhibitory postsynaptic potentials (IPSPs), likely originating from burst-firing parvalbumin interneurons. Here we investigated the role of compound IPSPs in the rat and rhesus macaque BLA in regulating action potential synchrony and spike-timing precision. Furthermore, because principal neurons exhibit intrinsic oscillatory properties and resonance between 4 and 5 Hz, in the same frequency band observed during fear, we investigated whether compound IPSPs and intrinsic oscillations interact to promote rhythmic activity in the BLA at this frequency. Using whole-cell patch clamp in brain slices, we demonstrate that compound IPSPs, which occur spontaneously and are synchronized across principal neurons in both the rat and primate BLA, significantly improve spike-timing precision in BLA principal neurons for a window of ∼300 ms following each IPSP. We also show that compound IPSPs coordinate the firing of pairs of BLA principal neurons, and significantly improve spike synchrony for a window of ∼130 ms. Compound IPSPs enhance a 5 Hz calcium-dependent membrane potential oscillation (MPO) in these neurons, likely contributing to the improvement in spike-timing precision and synchronization of spiking. Activation of the cAMP-PKA signaling cascade enhanced the MPO, and inhibition of this cascade blocked the MPO. We discuss these results in the context of spike-timing dependent plasticity and modulation by neurotransmitters important for fear learning, such as dopamine

Increased timing variability in schizophrenia and bipolar disorder.

Theoretical and empirical evidence suggests that impaired time perception and the neural circuitry underlying internal timing mechanisms may contribute to severe psychiatric disorders, including psychotic and mood disorders. The degree to which alterations in temporal perceptions reflect deficits that exist across psychosis-related phenotypes and the extent to which mood symptoms contribute to these deficits is currently unknown. In addition, compared to schizophrenia, where timing deficits have been more extensively investigated, sub-second timing has been studied relatively infrequently in bipolar disorder. The present study compared sub-second duration estimates of schizophrenia (SZ), schizoaffective disorder (SA), non-psychotic bipolar disorder (BDNP), bipolar disorder with psychotic features (BDP), and healthy non-psychiatric controls (HC) on a well-established time perception task using sub-second durations. Participants included 66 SZ, 37 BDNP, 34 BDP, 31 SA, and 73 HC who participated in a temporal bisection task that required temporal judgements about auditory durations ranging from 300 to 600 milliseconds. Timing variability was significantly higher in SZ, BDP, and BDNP groups compared to healthy controls. The bisection point did not differ across groups. These findings suggest that both psychotic and mood symptoms may be associated with disruptions in internal timing mechanisms. Yet unexpected findings emerged. Specifically, the BDNP group had significantly increased variability compared to controls, but the SA group did not. In addition, these deficits appeared to exist independent of current symptom status. The absence of between group differences in bisection point suggests that increased variability in the SZ and bipolar disorder groups are due to alterations in perceptual timing in the sub-second range, possibly mediated by the cerebellum, rather than cognitive deficits

Numbers and percentages of major psychotropic medications prescribed across groups.

<p>*No control participants were taking psychotropic medication. Medication information was not available for 2 BDP, 2 SZ, and 1 SA.</p

Psychometric response curves for each group composed of the proportion of long responses as a function of signal duration.

<p>Smaller insets to the right show each clinical group individually as compared to the control group.</p

Means and standard deviations for each group for the bisection point (left panel), difference limen, (center panel) and Weber Fraction (right panel).

<p>No differences existed between groups on bisection point, although for all groups the perceived bisection point occurred earlier than the mathematical bisection point. SZ, BDP, and BDNP had increased temporal variability on both the difference limen and the Weber Fraction compared to controls. The SA group was not significantly different from controls.</p