Axially Chiral Nonbenzenoid Nanographene with Second Harmonic Generation Property.

Chiral nanographenes (NGs) have garnered significant interest as optoelectronic materials in recent years. While helically chiral NGs have been extensively studied, axially chiral NGs have only witnessed limited examples, with no prior reports of axially chiral nonbenzenoid NGs. Herein we report an axially chiral nonbenzenoid nanographene featuring six pentagons and four heptagons. This compound, denoted as 2, was efficiently synthesized via an efficient Pd-catalyzed aryl silane homocoupling reaction. The presence of two bulky 3,5-di-tert-butylphenyl groups around the axis connecting the two nonbenzenoid PAH (AHR) segments endows 2 with atropisomeric chirality and high racemization energy barrier, effectively preventing racemization of both R- and S-enantiomers at room temperature. Optically pure R-2 and S-2 were obtained by chiral HPLC separation, and they exhibit circular dichroism (CD) activity at wavelengths up to 660 nm, one of the longest wavelengths with CD responses reported for the chiral NGs. Interestingly, racemic 2 forms a homoconfiguration π-dimer in the crystal lattice, belonging to the I222 chiral space group. Consequently, this unique structure renders crystals of 2 with a second harmonic generation (SHG) response, distinguishing it from all the reported axially chiral benzenoid NGs. Moreover, R-2 and S-2 also exhibit SHG-CD properties.

Integrated analyses of metabolomics and transcriptomics reveal the potential regulatory roles of long non-coding RNAs in gingerol biosynthesis.

BACKGROUND: As the characteristic functional component in ginger, gingerols possess several health-promoting properties. Long non-coding RNAs (lncRNAs) act as crucial regulators of diverse biological processes. However, lncRNAs in ginger are not yet identified so far, and their potential roles in gingerol biosynthesis are still unknown. In this study, metabolomic and transcriptomic analyses were performed in three main ginger cultivars (leshanhuangjiang, tonglingbaijiang, and yujiang 1 hao) in China to understand the potential roles of the specific lncRNAs in gingerol accumulation. RESULTS: A total of 744 metabolites were monitored by metabolomics analysis, which were divided into eleven categories. Among them, the largest group phenolic acid category contained 143 metabolites, including 21 gingerol derivatives. Of which, three gingerol analogs, [8]-shogaol, [10]-gingerol, and [12]-shogaol, accumulated significantly. Moreover, 16,346 lncRNAs, including 2,513, 1,225, and 2,884 differentially expressed (DE) lncRNA genes (DELs), were identified in all three comparisons by transcriptomic analysis. Gene ontology enrichment (GO) analysis showed that the DELs mainly enriched in the secondary metabolite biosynthetic process, response to plant hormones, and phenol-containing compound metabolic process. Correlation analysis revealed that the expression levels of 11 DE gingerol biosynthesis enzyme genes (GBEGs) and 190 transcription factor genes (TF genes), such as MYB1, ERF100, WRKY40, etc. were strongly correlation coefficient with the contents of the three gingerol analogs. Furthermore, 7 and 111 upstream cis-acting lncRNAs, 1,200 and 2,225 upstream trans-acting lncRNAs corresponding to the GBEGs and TF genes were identified, respectively. Interestingly, 1,184 DELs might function as common upstream regulators to these GBEGs and TFs genes, such as LNC_008452, LNC_006109, LNC_004340, etc. Furthermore, protein-protein interaction networks (PPI) analysis indicated that three TF proteins, MYB4, MYB43, and WRKY70 might interact with four GBEG proteins (PAL1, PAL2, PAL3, and 4CL-4). CONCLUSION: Based on these findings, we for the first time worldwide proposed a putative regulatory cascade of lncRNAs, TFs genes, and GBEGs involved in controlling of gingerol biosynthesis. These results not only provide novel insights into the lncRNAs involved in gingerol metabolism, but also lay a foundation for future in-depth studies of the related molecular mechanism.

Clozapine Use for Bipolar Disorder: An Asian Psychotropic Prescription Patterns Consortium Study.

BACKGROUND: Pharmacoepidemiological studies of clozapine use to treat bipolar disorder (BD), especially in Asia, are rare, although they can provide insights into associated clinical characteristics and support international comparisons of indications and drug dosing. METHODS: We examined the prevalence and clinical correlates of clozapine treatment for BD in 13 Asian countries and regions (China, Hong Kong SAR, India, Indonesia, Japan, Korea, Malaysia, Myanmar, Pakistan, Singapore, Sri Lanka, Taiwan, and Thailand) within an Asian Prescription Patterns Research Consortium. We compared BD patients treated with clozapine or not in initial bivariate comparisons followed by multivariable logistic regression modeling. RESULTS: Clozapine was given to 2.13% of BD patients overall, at a mean daily dose of 275 (confidence interval, 267-282) chlorpromazine-equivalent mg/day. Patients receiving clozapine were older, more likely males, hospitalized, currently manic, and given greater numbers of mood-stabilizing and antipsychotic drugs in addition to clozapine. Logistic regression revealed that older age, male sex, current mania, and greater number of other antipsychotics remained significantly associated with clozapine treatment. Clozapine use was not associated with depressed mood, remission of illness, suicidal risk, or electroconvulsive treatment within the previous 12 months. CONCLUSIONS: The identified associations of clozapine use with particular clinical features call for vigilance in personalized clinical monitoring so as to optimize clinical outcomes of BD patients and to limit risks of adverse effects of polytherapy.

Diazulenorubicene as a Non-benzenoid Isomer of peri-Tetracene with Two Sets of 5/7/5 Membered Rings Showing Good Semiconducting Properties.

Non-benzenoid polycyclic aromatic hydrocarbons (PAHs) have received a lot of attention because of their unique optical, electronic, and magnetic properties, but their synthesis remains challenging. Herein, we report a non-benzenoid isomer of peri-tetracene, diazulenorubicene (DAR), with two sets of 5/7/5 membered rings synthesized by a (3+2) annulation reaction. Compared with the precursor containing only 5/7 membered rings, the newly formed five membered rings switch the aromaticity of the original heptagon/pentagon from antiaromatic/aromatic to non-aromatic/antiaromatic respectively, modify the intermolecular packing modes, and lower the LUMO levels. Notably, compound 2 b (DAR-TMS) shows p-type semiconducting properties with a hole mobility up to 1.27 cm2  V-1 s-1 . Moreover, further extension to larger non-benzenoid PAHs with 19 rings was achieved through on-surface chemistry from the DAR derivative with one alkynyl group.

The miR-30 family: Versatile players in breast cancer.

The microRNA family, miR-30, plays diverse roles in regulating key aspects of neoplastic transformation, metastasis, and clinical outcomes in different types of tumors. Accumulating evidence proves that miR-30 family is pivotal in the breast cancer development by controlling critical signaling pathways and relevant oncogenes. Here, we review the roles of miR-30 family members in the tumorigenesis, metastasis, and drug resistance of breast cancer, and their application to predict the prognosis of breast cancer patients. We think miR-30 family members would be promising biomarkers for breast cancer and may bring a novel insight in molecular targeted therapy of breast cancer.

Research on the prediction of longevity from both individual and family perspectives.

Increasing human longevity is of global interest. The present study explored the prediction of longevity from both individual perspective and family perspective based on demographic and psychosocial factors. A total of 186 longevous family members and 237 ordinary elderly family members participated in a cross-sectional study, and a sample of 62 longevous elderly and 57 ordinary elderly were selected for comparative research. The results showed that it was three times more female than male in longevous elderly group. Up to 71.2% of longevous elderly had no experience in education, which was significantly lower than that of ordinary elderly. Due to such extreme age, more widowed (81.4%) elderly than those in married (18.6%). Less than one-seventh of the longevous elderly maintained the habit of smoking, and about one-third of them liked drinking, both were significantly lower than that of ordinary elderly. In terms of psychosocial factors, longevous elderly showed lower neuroticism and social support, while higher extraversion, compared with the ordinary elderly. However, there were no significant differences between the two family groups in demographic and psychosocial variables, except longevous families showing lower scores in neuroticism. Regression analysis found that neuroticism, social support and smoking habit had significant impact on individuals' life span, then, neuroticism and psychoticism were the key factor to predict families' longevity. We conclude that good emotional management, benign interpersonal support, and moderation of habits are important factors for individual longevity, and the intergenerational influence of personality is closely related to family longevity.

Identification of circRNA-miRNA networks for exploring an underlying prognosis strategy for breast cancer.

Aim: Circular RNAs (circRNAs) still have many potential functions in the process of tumor development that are not completely understood. The study aims to explore novel circRNAs and their mechanisms of action in breast cancer (BCa). Materials & methods: A combination strategy of RNA-sequencing (RNA-seq) technique, quantitative real-time PCR and bioinformatic analysis was employed to identify the potential mechanisms involving differentially expressed circRNAs in the serum exosomes and tissues of BCa patients. Results: The expression levels of hsa-circRNA-0005795 and hsa-circRNA-0088088 were significantly different both in serum exosomes and tissues and might function as competing endogenous RNAs and play vital roles in BCa development. Conclusion: We constructed two circRNA-miRNA networks and provided new insight into the prognosis and therapy of BCa using circRNAs from serum exosomes.

The acute toxic effects of silver nanoparticles on myocardial transmembrane potential, INa and IK1 channels and heart rhythm in mice.

This study focused on the potential toxicity of silver nanoparticles (AgNPs) on cardiac electrophysiology which is rarely investigated. We found that AgNPs (10-9-10-6 g/ml) concentration-dependently depolarized the resting potential, diminished the action potential, and finally led to loss of excitability in mice cardiac papillary muscle cells in vitro. In cultured neonatal mice cardiomyocytes, AgNPs (10-9-10-7 g/ml) concentration-dependently decreased the Na+ currents (INa), accelerated the activation, and delayed the inactivation and recovery of Na+ channels from inactivation within 5 min. AgNPs at 10-8 g/ml also rapidly decreased the inwardly rectifying K+ currents (IK1) and delayed the activation of IK1 channels. Intravenous injection of AgNPs at 3 mg/kg only decreased the heart rate, while at ≥4 mg/kg sequentially induced sinus bradycardia, complete atrio-ventricular conduction block, and cardiac asystole. AgNPs at 10-10-10-6 g/ml did not increase reactive oxygen species (ROS) generation and only at 10-6 g/ml mildly induced lactate dehydrogenase (LDH) release in the cardiomyocytes within 5 min. Endocytosis of AgNPs by cardiomyocytes was not observed within 5 min, but was observed 1 h after exposing to AgNPs. Comparative Ag+ (≤0.02% of the AgNPs) could not induce above toxicities. We conclude that AgNPs exert rapid toxic effects on myocardial electrophysiology and induce lethal bradyarrhythmias. These acute toxicities are likely due to direct effects of AgNPs on ion channels at the nano-scale level, but not caused by Ag+, ROS, and membrane injury. These findings provide warning to the nanomedical practice using AgNPs.

A novel role of microRNA 17-5p in the modulation of circadian rhythm.

The circadian clock helps living organisms to adjust their physiology and behaviour to adapt environmental day-night cycles. The period length of circadian rhythm reflects the endogenous cycle transition rate and is modulated by environmental cues or internal molecules, and the latter are of substantial importance but remain poorly revealed. Here, we demonstrated that microRNA 17-5p (miR-17-5p), which has been associated with tumours, was an important factor in controlling the circadian period. MiR-17-5p was rhythmically expressed in synchronised fibroblasts and mouse master clock suprachiasmatic nuclei (SCN). MiR-17-5p and the gene Clock exhibited a reciprocal regulation: miR-17-5p inhibited the translation of Clock by targeting the 3'UTR (untranslated region) of Clock mRNA, whereas the CLOCK protein directly bound to the promoter of miR-17 and enhanced its transcription and production of miR-17-5p. In addition, miR-17-5p suppressed the expression of Npas2. At the cellular level, bidirectional changes in miR-17-5p or CLOCK resulted in CRY1 elevation. Accordingly, in vivo, both increase and decrease of miR-17-5p in the mouse SCN led to an increase in CRY1 level and shortening of the free-running period. We conclude that miR-17-5p has an important role in the inspection and stabilisation of the circadian-clock period by interacting with Clock and Npas2 and potentially via the output of CRY1.

High eosinophil cationic protein level in asthmatic patients with "heat" Zheng.

In traditional Chinese medicine (TCM), the imbalance of yin and yang is one of the basic pathogeneses of a disease. Preponderance of yang leads to "heat" manifestations including thirst, dryness of the throat, dark scanty urine and constipation. Treatment of asthma in TCM is based on the differentiation of "heat" Zheng according to the manifestations. Some of the patients with allergic asthma also present typical "heat" manifestations. To investigate the essence of "heat" manifestation in asthma, we measured the serum level of eosinophil cationic protein (ECP) in asthmatic patients. ECP usually represents the activation of eosinophils which are the main effectors in late allergic reactions. Our results demonstrated that asthmatic patients with "heat" manifestations had higher serum ECP levels, compared to those without "heat" manifestations (34.3 +/- 4 microg/l versus 15.3 +/- 3 microg/l). However, total immunoglobulin B (IgE), and the eosinophil count in peripheral blood did not show any difference between the "heat" and "non-heat" groups. Therefore, we conclude that ECP in asthmatic patients plays an important role in the development of "heat" manifestations as diagnosed by TCM.