Dynamic Foraging Behavior Performance Is Not Affected by Scn2a Haploinsufficiency.

Dysfunction in the gene SCN2A, which encodes the voltage-gated sodium channel Nav1.2, is strongly associated with neurodevelopmental disorders including autism spectrum disorder and intellectual disability (ASD/ID). This dysfunction typically manifests in these disorders as a haploinsufficiency, where loss of one copy of a gene cannot be compensated for by the other allele. Scn2a haploinsufficiency affects a range of cells and circuits across the brain, including associative neocortical circuits that are important for cognitive flexibility and decision-making behaviors. Here, we tested whether Scn2a haploinsufficiency has any effect on a dynamic foraging task that engages such circuits. Scn2a +/- mice and wild-type (WT) littermates were trained on a choice behavior where the probability of reward between two options varied dynamically across trials and where the location of the high reward underwent uncued reversals. Despite impairments in Scn2a-related neuronal excitability, we found that both male and female Scn2a +/- mice performed these tasks as well as wild-type littermates, with no behavioral difference across genotypes in learning or performance parameters. Varying the number of trials between reversals or probabilities of receiving reward did not result in an observable behavioral difference, either. These data suggest that, despite heterozygous loss of Scn2a, mice can perform relatively complex foraging tasks that make use of higher-order neuronal circuits.

An open-source behavior controller for associative learning and memory (B-CALM).

Associative learning and memory, i.e., learning and remembering the associations between environmental stimuli, self-generated actions, and outcomes such as rewards or punishments, are critical for the well-being of animals. Hence, the neural mechanisms underlying these processes are extensively studied using behavioral tasks in laboratory animals. Traditionally, these tasks have been controlled using commercial hardware and software, which limits scalability and accessibility due to their cost. More recently, due to the revolution in microcontrollers or microcomputers, several general-purpose and open-source solutions have been advanced for controlling neuroscientific behavioral tasks. While these solutions have great strength due to their flexibility and general-purpose nature, for the same reasons, they suffer from some disadvantages including the need for considerable programming expertise, limited online visualization, or slower than optimal response latencies for any specific task. Here, to mitigate these concerns, we present an open-source behavior controller for associative learning and memory (B-CALM). B-CALM provides an integrated suite that can control a host of associative learning and memory behaviors. As proof of principle for its applicability, we show data from head-fixed mice learning Pavlovian conditioning, operant conditioning, discrimination learning, as well as a timing task and a choice task. These can be run directly from a user-friendly graphical user interface (GUI) written in MATLAB that controls many independently running Arduino Mega microcontrollers in parallel (one per behavior box). In sum, B-CALM will enable researchers to execute a wide variety of associative learning and memory tasks in a scalable, accurate, and user-friendly manner.

Asymmetric Synthesis of Vicinal Tetrasubstituted Diamines via Reductive Coupling of Ketimines Templated by Chiral Diborons.

We herein describe the chiral diboron-templated asymmetric homocoupling of aryl alkyl ketimines, providing for the first time a series of chiral vicinal tetrasubstituted diamines with excellent ee values and good to high yields. The powerful and efficient diboron-participated [3,3]-sigmatropic rearrangement is successfully demonstrated by the homocoupling of a variety of ketimines thanks to the rational design and engineering of chiral diborons. Systematic DFT studies suggest that two chiral diborons adopt different conformational assembling strategies to couple the diboron template with ketimine substrates in their tight concerted transition states to ensure the excellent enantioselectivities. The synthetic value of chiral vicinal tetrasubstituted diamines is demonstrated by the asymmetric α-bromination of aliphatic aldehydes by employing a chiral vicinal tetrasubstituted diamine-based organocatalyst.

Mesolimbic dopamine release conveys causal associations.

Learning to predict rewards based on environmental cues is essential for survival. It is believed that animals learn to predict rewards by updating predictions whenever the outcome deviates from expectations, and that such reward prediction errors (RPEs) are signaled by the mesolimbic dopamine system-a key controller of learning. However, instead of learning prospective predictions from RPEs, animals can infer predictions by learning the retrospective cause of rewards. Hence, whether mesolimbic dopamine instead conveys a causal associative signal that sometimes resembles RPE remains unknown. We developed an algorithm for retrospective causal learning and found that mesolimbic dopamine release conveys causal associations but not RPE, thereby challenging the dominant theory of reward learning. Our results reshape the conceptual and biological framework for associative learning.

Discovery of novel pyrazolopyrimidine derivatives as potent mTOR/HDAC bi-functional inhibitors via pharmacophore-merging strategy.

The mTOR and HDAC dual suppression is meaningful for counteracting drug resistance resulted from kinase mutation and bypass mechanisms. Herein, we communicate our recent discovery of a novel structural series of mTOR/HDAC bi-functional inhibitors featuring the pyrazolopyrimidine core via pharmacophore-merging strategy. More than half of them exerted potent dual-target inhibitory activities. In particular, compound 50 exhibited IC50 values of 0.49 and 0.91 nM against mTOR and HDAC1, respectively, along with remarkably enhanced anti-proliferative activity (IC50 = 1.74 µM) against MV4-11 cell line than mTOR inhibitor MLN-0128 (IC50 = 5.84 µM) and HDAC inhibitor SAHA (IC50 = 8.44 µM). Its intracellular intervention of both mTOR signaling and HDAC was validated by the Western blot analysis. Moreover, as the first disclosed mTOR/HDAC dual inhibitor with selectivity for some specific HDAC subtypes, it has the potential to alleviate the adverse effects resulted from pan-HDAC inhibition. Attributed to its favorable in vitro performance, compound 50 is valuable for further functional investigation as a polypharmacological anti-cancer agent.

Enantioselective Reductive Coupling of Imines Templated by Chiral Diboron.

We herein report a general, practical, and highly efficient method for asymmetric synthesis of a wide range of chiral vicinal diamines via reductive coupling of imines templated by chiral diboron. The protocol features high enantioselectivity and stereospecificity, mild reaction conditions, simple operating procedures, use of readily available starting materials, and a broad substrate scope. The method signifies the generality of diboron-enabled [3,3]-sigmatropic rearrangement.

Photoluminescence characterization of Ca10Na(PO4)7:Eu3+ red-emitting phosphor.

Eu3+-doped Ca10Na(PO4)7 phosphors were successfully synthesized by solid-state reaction techniques. Their structures and photoluminescence characteristics were carefully studied. An efficient red emission under near-ultraviolet excitation is observed. The maximum intensity of luminescence was observed at the Eu3+ concentration around 9 mol%. The quadrupole-quadrupole interaction between Eu3+ ions is the dominant mechanism for concentration quenching of fluorescence emission from Eu3+ ions in Ca10-xNa(PO4)7:xEu3+. Due to the excitation spectrum is well coupled with near UV light, Ca10-xNa(PO4)7:xEu3+ phosphors have potential application as red phosphors in near UV chip-based white light emitting diodes.

Mechanism of the chiral SHG activity of bacteriorhodopsin films.

The nonlinear optical activity of bacteriorhodopsin (bR) Langmuir-Blodgett (LB) films were investigated computationally and experimentally. The second harmonic generation optical rotary dispersion (SHG-ORD) response was calculated directly from the known structure and orientation of the PSB retinal chromophore within bR with no adjustable parameters. The predicted results agree remarkably well in sign, magnitude, and trend with the experimental SHG-ORD measurements. The calculations indicated negligible chirality with the tensor for the PSB retinal chromophore, but significant chiral-specific activity for the thin film through a relatively simple orientational mechanism.

Inhibition of membrane-associated methyltransferases by a cholesterol-based metal chelator.

We have designed, synthesized, and characterized a metal chelating compound that is based on the structure of cholesterol and contains the high affinity metal chelating group, lysine nitrilotriacetic acid (Lys-NTA). Using the enzyme isoprenylcysteine carboxylmethyltransferase (Icmt) from yeast as a model integral membrane metalloenzyme, we find that this agent potently inhibits Icmt activity with an IC(50) value between 35 and 75 microM, which is at least 40 times more potent than the best known Icmt metal chelating inhibitor, Zincon. We propose that the rigid hydrophobic cholesterol moiety promotes partitioning into the membrane, enabling the metal-binding NTA group(s) to inactivate the enzyme by metal chelation. Because this compound is based on a naturally occurring membrane lipid and appears to chelate metals buried deeply within water insoluble environments, this agent may also be useful as a general tool for identifying previously unappreciated metal dependencies of other classes of membrane proteins.