Early Gray Matter Structural Covariance Predicts Longitudinal Gain in Arithmetic Ability in Children.

Previous neuroimaging studies on arithmetic development have mainly focused on functional activation or functional connectivity between brain regions. It remains largely unknown how brain structures support arithmetic development. The present study investigated whether early gray matter structural covariance contributes to later gain in arithmetic ability in children. We used a public longitudinal sample comprising 63 typically developing children. The participants received structural magnetic resonance imaging scanning when they were 11 years old and were tested with a multiplication task at 11 years old (time 1) and 13 years old (time 2), respectively. Mean gray matter volumes were extracted from eight brain regions of interest to anchor salience network (SN), frontal-parietal network (FPN), motor network (MN), and default mode network (DMN) at time 1. We found that longitudinal gain in arithmetic ability was associated with stronger structural covariance of the SN seed with frontal and parietal regions and stronger structural covariance of the FPN seed with insula, but weaker structural covariance of the FPN seed with motor and temporal regions, weaker structural covariance of the MN seed with frontal and motor regions, and weaker structural covariance of the DMN seed with temporal region. However, we did not detect correlation between longitudinal gain in arithmetic ability and behavioral measure or regional gray matter volume at time 1. Our study provides novel evidence for a specific contribution of gray matter structural covariance to longitudinal gain in arithmetic ability in childhood.

Direct synthesis of phenanthrenyl triflates from 1-biphenylyl-2-diazo-2-aryl ketones and triflic anhydride.

A strategy for direct synthesis of phenanthrenyl triflates from 1-biphenylyl-2-diazo-2-aryl ketones and triflic anhydride is described. The reaction of 1-biphenylyl-2-diazo-2-aryl ketones with triflic anhydride proceeded smoothly in the presence of 2,6-di-tert-butylpyridine under mild conditions to produce phenanthrenyl triflates in high to excellent yields. The phenanthrenyl triflate products were demonstrated to be utilized as coupling partners in various coupling reactions. The proposed mechanism involves an intramolecular Friedel-Crafts reaction of a vinyl cation intermediate formed in situ.

MolLoG: A Molecular Level Interpretability Model Bridging Local to Global for Predicting Drug Target Interactions.

Developing new pharmaceuticals is a costly and time-consuming endeavor fraught with significant safety risks. A critical aspect of drug research and disease therapy is discerning the existence of interactions between drugs and proteins. The evolution of deep learning (DL) in computer science has been remarkably aided in this regard in recent years. Yet, two challenges remain: (i) balancing the extraction of profound, local cohesive characteristics while warding off gradient disappearance and (ii) globally representing and understanding the interactions between the drug and target local attributes, which is vital for delivering molecular level insights indispensable to drug development. In response to these challenges, we propose a DL network structure, MolLoG, primarily comprising two modules: local feature encoders (LFE) and global interactive learning (GIL). Within the LFE module, graph convolution networks and leap blocks capture the local features of drug and protein molecules, respectively. The GIL module enables the efficient amalgamation of feature information, facilitating the global learning of feature structural semantics and procuring multihead attention weights for abstract features stemming from two modalities, providing biologically pertinent explanations for black-box results. Finally, predictive outcomes are achieved by decoding the unified representation via a multilayer perceptron. Our experimental analysis reveals that MolLoG outperforms several cutting-edge baselines across four data sets, delivering superior overall performance and providing satisfactory results when elucidating various facets of drug-target interaction predictions.

Design, synthesis and biological evaluation of aloperine derivatives as potential anticancer agents.

Modifications at different positions on the aloperine molecule were performed to improve its anticancer activity and develop anticancer drugs. The in vitro anticancer activities of 44 synthesized compounds were evaluated. The effect of modification positions on anticancer activity was discussed and a structure-activity relationship analysis was established. A novel series of compounds with modifications at the N12 position showed much higher cytotoxicity than aloperine. Among them, compound 22 displayed promising in vitro anticancer activity against PC9 cells with a median inhibitory concentration (IC50) of 1.43 µM. The mechanism studies indicated that compound 22 induced cell apoptosis and cell cycle arrest in PC9 cells. These results demonstrate the potential of aloperine thiourea derivatives in anticancer activity.

Cross-cultural adaptation and clinical application of the Perth Empathy Scale.

OBJECTIVE: Alterations of empathy have been observed in patients with various mental disorders. The Perth Empathy Scale (PES) was recently developed to measure a multidimensional construct of empathy across positive and negative emotions. However, its psychometric properties and clinical applications have not been examined in the Chinese context. METHODS: The Chinese version of the PES was developed and administered to a large Chinese sample (n = 1090). Factor structure, internal consistency, test-retest reliability, and convergent, discriminant, as well as concurrent validity were examined. Moreover, 50 patients with major depressive disorder (MDD) and 50 healthy controls were recruited to explore the clinical utility of the PES. RESULTS: Confirmatory factor analyses supported a theoretically congruent three-factor structure of empathy, namely Cognitive Empathy, Negative Affective Empathy and Positive Affective Empathy. The PES showed good to excellent internal consistency reliability, good convergent and discriminant validity, acceptable concurrent validity, and moderate to high test-retest reliability. Patients with MDD had significantly lower PES scores compared to healthy controls. Linear discriminant function comprised of the three factors correctly differentiated 71% of participants, which further verified the clinical utility of the PES. CONCLUSIONS: Our findings indicated that the Chinese version of the PES is a reliable and valid instrument to measure cognitive and affective empathy across negative and positive emotions, and could therefore be used in both research and clinical practice.

Catalytic (4+2) Annulation via Regio- and Enantioselective Interception of in-situ Generated Alkylgold Intermediate.

A regio- and stereoselective stepwise (4+2) annulation of N-propargylamides and α,ß-unsaturated imines/ketones has been accomplished with synergetic catalysis by a combination of a gold-complex and a chiral quinine-derived squaramide (QN-SQA), leading to highly functionalized chiral tetrahydropyridines/dihydropyrans in good to high yields with generally excellent enantioselectivity. Mechanistic studies and DFT calculations indicate that the in situ formed alkylgold species is the key intermediate in this transformation, and the amide group served as a traceless directing group in this highly selective transformation. This method complements the enantioselective (4+2) annulation of allene reagents, providing the formal internal C-C π-bond cycloaddition products, which is challenging and remains elusive.

DSCAM Deficiency Leads to Premature Spine Maturation and Autism-like Behaviors.

Mutations in some cell adhesion molecules (CAMs) cause abnormal synapse formation and maturation, and serve as one of the potential mechanisms of autism spectrum disorders (ASDs). Recently, DSCAM (Down syndrome cell adhesion molecule) was found to be a high-risk gene for autism. However, it is still unclear how DSCAM contributes to ASD. Here, we show that DSCAM expression was downregulated following synapse maturation, and that DSCAM deficiency caused accelerated dendritic spine maturation during early postnatal development. Mechanistically, the extracellular domain of DSCAM interacts with neuroligin1 (NLGN1) to block the NLGN1-neurexin1ß (NRXN1ß) interaction. DSCAM extracellular domain was able to rescue spine overmaturation in DSCAM knockdown neurons. Precocious spines in DSCAM-deficient mice showed increased glutamatergic transmission in the developing cortex and induced autism-like behaviors, such as social novelty deficits and repetitive behaviors. Thus, DSCAM might be a repressor that prevents premature spine maturation and excessive glutamatergic transmission, and its deficiency could lead to autism-like behaviors. Our study provides new insight into the potential pathophysiological mechanisms of ASDs.SIGNIFICANCE STATEMENTDSCAM is not only associated with Down syndrome but is also a strong autism risk gene based on large-scale sequencing analysis. However, it remains unknown exactly how DSCAM contributes to autism. In mice, either neuron- and astrocyte-specific or pyramidal neuron-specific DSCAM deficiencies resulted in autism-like behaviors and enhanced spatial memory. In addition, DSCAM knockout or knockdown in pyramidal neurons led to increased dendritic spine maturation. Mechanistically, the extracellular domain of DSCAM binds to NLGN1 and inhibits NLGN1-NRXN1ß interaction, which can rescue abnormal spine maturation induced by DSCAM deficiency. Our research demonstrates that DSCAM negatively modulates spine maturation, and that DSCAM deficiency leads to excessive spine maturation and autism-like behaviors, thus providing new insight into a potential pathophysiological mechanism of autism.

Microglia are involved in regulating histamine-dependent and non-dependent itch transmissions with distinguished signal pathways.

Although itch and pain have many similarities, they are completely different in perceptual experience and behavioral response. In recent years, we have a deep understanding of the neural pathways of itch sensation transmission. However, there are few reports on the role of non-neuronal cells in itch. Microglia are known to play a key role in chronic neuropathic pain and acute inflammatory pain. It is still unknown whether microglia are also involved in regulating the transmission of itch sensation. In the present study, we used several kinds of transgenic mice to specifically deplete CX3CR1+ microglia and peripheral macrophages together (whole depletion), or selectively deplete microglia alone (central depletion). We observed that the acute itch responses to histamine, compound 48/80 and chloroquine were all significantly reduced in mice with either whole or central depletion. Spinal c-fos mRNA assay and further studies revealed that histamine and compound 48/80, but not chloroquine elicited primary itch signal transmission from DRG to spinal Npr1- and somatostatin-positive neurons relied on microglial CX3CL1-CX3CR1 pathway. Our results suggested that microglia were involved in multiple types of acute chemical itch transmission, while the underlying mechanisms for histamine-dependent and non-dependent itch transmission were different that the former required the CX3CL1-CX3CR1 signal pathway.

Divergent Construction of N-Doped Polycyclic Aromatic Hydrocarbons with Indole as the Nitrogen Source Building Block.

An Ag/Au-catalyzed divergent cascade reaction of alkyne embedded diazoketones with indoles has been described. Preliminary mechanistic studies indicate that the reaction goes through a [4+2]-cycloaddition of an in situ formed isobenzopyrylium intermediate with indole, followed by a sequential retro-Michael addition/carbene N-H insertion process to give the benzo[i]phenanthridines products with gold catalysis; whereas a dearomatization/rearomatization sequence occurs favourably when the reaction is catalyzed by a silver catalyst, delivering benzo[b]carbazoles in generally high to excellent yields. Notably, this is a rare example of using indole as the dienophile for cycloaddition with the isobenzopyrylium species, providing a concise and practical approach for the selective construction of N-doped polycyclic aromatic hydrocarbons (PAHs) with structural diversity and broad functional-group compatibility.

Visible-Light-Promoted Mn-Catalyzed C(sp3)-H Amidation with Dioxazolones.

A visible-light-driven Mn-catalyzed C(sp3)-H amidation of diphenylmethane derivatives with dioxazolones was described. These reactions occur with an external photosensitizer-free process and feature satisfactory to good yields (up to 81%) under mild conditions. Mechanistic investigations revealed that the reaction proceeded via a Mn-acyl nitrene intermediate and that H-atom abstraction was the rate-determining step. Computational studies showed that the decarboxylation of dioxazolone depends on the conversion of ground sextet state dioxazolone-bounding Mn species to quartet spin state via visible-light irradiation.

Palladium-catalyzed C-H dimethylamination of 1-chloromethyl naphthalenes with N,N-dimethylformamide as the dimethyl amino source.

Palladium-catalyzed remote C-H dimethylamination of 1-chloromethylnaphthalenes using N,N-dimethylformamide as the dimethylamino source is described for the first time. The dimethylamination took place exclusively at the 4-position of 1-chloromethylnaphthalenes in 2-methyltetrahydrofuran under mild conditions to afford 1-(N,N-dimethylamino)-4-alkylnaphthalenes in good to high yields. The halogen atom remained intact during the dimethylamination of 1-chloromethylnaphthalenes. A P,N bidentate ligand was conveniently synthesized and successfully utilized as the ligand in the Kumada-Corriu reaction.

One-pot synthesis of multisubstituted propenylbenzenes from benzyl chlorides through relay catalysis of palladium.

A strategy for the synthesis of multisubstituted propenylbenzenes using benzyl chlorides as starting materials is described. The palladium-catalyzed allylative dearomatization and the subsequent Wagner-Meerwein rearrangement as well as the olefin isomerization proceeded smoothly under mild conditions to produce propenylation products in good yields with high regioselectivity. Control experiments and cyclic voltammetry analysis suggest that Bu3SnCl, a by-product generated in the first step of allylative dearomatization, plays an essential role in the third step of olefin isomerization in the presence of a Brønsted acid.

Cu-catalyzed convenient synthesis of 2-trifluoromethyl benzimidazoles via cyclization of o-phenylenediamines with hexafluoroacetylacetone.

An efficient and convenient method for the synthesis of 2-trifluoromethyl benzimidazoles is described in this paper. The cyclization reaction of various o-phenylenediamines with hexafluoroacetylacetone proceeded smoothly in the presence of Cu2O as the catalyst to produce 2-trifluoromethyl benzimidazoles in satisfactory to excellent yields (up to >99% yield). The CF3 source, hexafluoroacetylacetone, acted not only as cyclization partner, but also acted as a ligand for the Cu catalyst. Various synthetically useful functional groups, such as halogen atoms, cyano, and methoxycarbonyl groups, remained intact during the cyclization reactions. The reaction mechanism was thoroughly investigated and was determined to involve a seven-membered cyclic diimine intermediate.

Gold-catalyzed carbocyclization and imidization of alkyne-tethered diazo compounds with nitrosoarenes for the synthesis of nitrones and naphthalene derivatives.

A gold-catalyzed carbocyclization/imidization cascade reaction has been developed,leading a facile access to the synthesis of functionalized nitrones in moderate to good yields under mild conditions. The reaction initiated by a catalytic 6-endo-dig diazo-yne carbocyclization to form the key endocyclic vinyl carbene from alkyne-tethered diazo compounds, followed by addition with nitrosoarenes that features an imidization process. Notably, these resulting nitrone products could be smoothly converted into different substituted naphthalenol analogues, such as 4-aminonaphthalen-1-ol, naphthalene-1,4-dione, and naphthalene-1,4-diol derivatives, in high yields. Moreover, the generated products exhibited potential tumor suppression activity in tested cancer celllines; compound 3c (HCT116 cells, IC50 = 7.41 µM; MCF-7 cells, IC50 = 14.28 µM) exhibits higher anticancer potency than other tested compounds.

Synthesis of dihydrofuran-3-one and 9,10-phenanthrenequinone hybrid molecules and biological evaluation against colon cancer cells as selective Akt kinase inhibitors.

A series of dihydrofuran-3-one and 9,10-phenanthrenequinone hybrid compounds were synthetized through a one-pot gold-catalyzed oxidative cyclization and Aldol-type addition cascade reaction of homopropargylic alcohols with 9,10-phenanthrenequinone. The cytotoxicity of newly synthesized compounds was evaluated in CCK8 assay against different human cancer cells, showing significantly antiproliferative activity against tested tumor cell lines with a lowest IC50 value of 0.92 µM over HCT-116. Further investigation revealed that the treatment of HCT-116 cell line with the promising compound 4c induced cell death as a selective Akt inhibitor. In addition, controlled experiments and molecular docking study suggested that the significant antitumor activity might be attributed to the unique hybrid structure, which implied the promising potential of this dual heterocycle hybrid method in the discovery of novel bioactive molecules with structural diversity.

Negative emotion amplifies retrieval practice effect for both task-relevant and task-irrelevant information.

Selective retrieval of task-relevant information often facilitates memory retention of that information. However, it is still unclear if selective retrieval of task-relevant information can alter memory for task-irrelevant information, and the role of emotional arousal in it. In two experiments, we used emotional and neutral faces as stimuli, and participants were asked to memorise the name (who is this person?) and location (where does he/she come from?) associated with each face in initial study. Then, half of the studied faces were presented as cues, and participants were asked to retrieve the corresponding names (Experiment 1) or locations (Experiment 2). Finally, all the faces were presented and participants were asked to retrieve both the corresponding names and locations. The results of the final test showed that retrieval practice not only enhanced memory of task-relevant information but also enhanced memory of task-irrelevant information. More importantly, negative emotion amplified the retrieval practice effect overall, with a larger retrieval-induced benefit for the negative than neutral condition. These findings demonstrated an emotional arousal amplification effect on retrieval-induced enhancement effects, suggesting that the advantage of the retrieved memory representations can be amplified by emotional arousal even without explicit goals in a task setting.

Base-Catalyzed Nucleophilic Addition Reaction of Indoles with Vinylene Carbonate: An Approach to Synthesize 4-Indolyl-1,3-dioxolanones.

The N-functionalized indole is a privileged structural framework in a wide range of bioactive molecules. The nucleophilic addition between indoles with vinylene carbonate proceeded smoothly in the presence of K2CO3 as the catalyst to produce novel indolyl-containing skeletons and 4-indolyl-1,3-dioxolanones in satisfactory to excellent yields (up to >97% yield). Various synthetically useful functional groups, such as halogen atoms, cyano, nitro, and methoxycarbonyl groups, remained intact during the regioselective N-H addition reactions. The developed catalytic system also could accommodate 2-naphthalenol to achieve the target O-H additive product in good yield.

Defluorinative Multi-Functionalization of Fluoroaryl Sulfoxides Enabled by Fluorine-Assisted Temporary Dearomatization.

Owing to its unique physical properties, fluorine is often used to open up new reaction channels. In this report, we establish a cooperation of [5,5]-rearrangement and fluorine-assisted temporary dearomatization for arene multi-functionalization. Specifically, the [5,5]-rearrangement of fluoroaryl sulfoxides with ß,γ-unsaturated nitriles generates an intriguing dearomatized sulfonium species which is short-lived but exhibits unusually high electrophilicity and thus can be instantly trapped by nucleophiles and dienes at a remarkably low temperature (-95 °C) to produce four types of valuable multi-functionalized benzenes, respectively, involving appealing processes of defluorination, desulfurization, and sulfur shift. Mechanistic studies indicate that the use of fluorine on arenes not only circumvents the generally inevitable [3,3]-rearrangement but also impedes the undesired rearomatization process, thus provides a precious space for constructing and elaborating the temporarily dearomatized fluorinated sulfonium species.

The longitudinal development of large-scale functional brain networks for arithmetic ability from childhood to adolescence.

Arithmetic ability is an important high-level cognitive function that requires interaction among multiple brain regions. Previous studies on arithmetic development have focused on task-induced activation in isolated brain regions or functional connectivity among particular seed regions. However, it remains largely unknown whether and how functional connectivity among large-scale brain modules contributes to arithmetic development. In the present study, we used a longitudinal sample of task-based functional magnetic resonance imaging (fMRI) data comprising 63 typically developing children, with two testing points being about 2 years apart. With graph theory, we examined the longitudinal development of large-scale brain modules for a multiplication task in younger (mean age 9.88 at time 1) and older children (mean age 12.34 at time 1), respectively. The results showed that the default-mode (DMN) and frontal-parietal networks (FPN) became increasingly segregated over time. Specifically, intra-connectivity within the DMN and FPN increased significantly with age, and inter-connectivity between the DMN and visual network decreased significantly with age. Such developmental changes were mainly observed in the younger children but not in the older children. Moreover, the change in network segregation of the DMN was positively correlated with longitudinal gain in arithmetic performance in the younger children, and individual difference in network segregation of the FPN was positively correlated with arithmetic performance at Time 2 in the older children. Taken together, the present results highlight the development of the functional architecture in large-scale brain networks from childhood to adolescence, which may provide insights into potential neural mechanisms underlying arithmetic development.

Spirocarbocycle Synthesis from Chloromethylarenes via Transition-Metal-Catalyzed Allylative Dearomatization and Ring Closure Metathesis.

A strategy for the synthesis of spirocarbocycles by using chloromethyl arenes as starting materials is described in this paper. The palladium-catalyzed allylative dearomatization and the subsequent ruthenium-catalyzed ring closure metathesis proceeded smoothly under mild conditions to produce the corresponding spirocarbocycle products with moderate to high yields. Benzene-ring-, naphthalene-ring-, and anthracene-ring-containing substrates can be easily transformed into spirocarbocycles by using the proposed method.