Autistic traits predict social avoidance and distress: The chain mediating role of perceived stress and interpersonal alienation.

Social avoidance and distress are the primary aspects of social anxiety. Nonautistic people with high levels of autistic traits are more likely to exhibit social avoidance and distress. However, research has yet to reveal how autistic traits induce social avoidance and distress. To fill this gap, the present study recruited 708 participants to complete the 25-item Autism Spectrum Quotient, Social Avoidance and Distress Scale, Chinese Perceived Stress Scale, and Interpersonal Alienation Subscale. The results indicated that autistic traits significantly predicted social avoidance and distress in nonautistic people. In addition, autistic traits induced social avoidance and distress through perceived stress and interpersonal alienation, respectively. Importantly, perceived stress and interpersonal alienation (including the subdimensions of interpersonal alienation: sense of loneliness, sense of social isolation, and alienation between family members) partially mediated the relationships between autistic traits and social avoidance and distress. Overall, autistic traits predict social avoidance and distress via perceived stress and interpersonal alienation. This finding extends the hypothetical model of clinical anxiety in autism spectrum disorders. Furthermore, reducing perceived stress and interpersonal alienation in nonautistic people with high levels of autistic traits may be a valid intervention method to prevent and eliminate their social avoidance and distress.

The impact of adolescent achievement goal orientation on learning anxiety: The mediation effect of peer interaction.

Learning anxiety is one of the most critical emotional disturbances, which also has a high incidence rate in adolescents. Peer interaction is critical and unique for adolescents. Although previous studies have found that achievement goal orientation has an important role in the development of learning anxiety, its mechanism has not been clarified. This study surveyed 470 adolescents (191 middle school students and 279 high school students; 211 boys) and established a structural equation model to explore the mediating role of peer interaction in the influence of achievement goal orientation on learning anxiety. Results showed that (1) there were significant gender differences in mastery-avoidance goal orientation, peer interaction, and learning anxiety, and there were grade differences in performance-approach goal and performance-avoidance goal orientations; (2) mastery-approach, mastery-avoidance, and performance-avoidance goal orientations directly predicted learning anxiety; and (3) social anxiety in peer interactions had a mediating effect on the influence of mastery-approach, mastery-avoidance, and performance-avoidance goal orientations on learning anxiety. The findings extend theoretical considerations by teasing out the process of peer interaction affecting the relationship between achievement goal orientation and learning anxiety. Additionally, the results have practical implications for the effective use of peer interaction to reduce learning anxiety.

Seed Priming with Fullerol Improves Seed Germination, Seedling Growth and Antioxidant Enzyme System of Two Winter Wheat Cultivars under Drought Stress.

The application of carbon-based nanomaterials (CBNMs) in plant science and agriculture is a very recent development. Many studies have been conducted to understand the interactions between CBNMs and plant responses, but how fullerol regulates wheat subjected to drought stress is still unclear. In this study, seeds of two wheat cultivars (CW131 and BM1) were pre-treated with different concentrations of fullerol to investigate seed germination and drought tolerance. Our results indicate that the application of fullerol at certain concentrations (25-200 mg L-1) significantly promoted seed germination in two wheat cultivars under drought stress; the most significant effective concentration was 50 mg L-1, which increased the final germination percentage by 13.7% and 9.7% compared to drought stress alone, respectively. Wheat plants exposed to drought stress induced a significant decrease in plant height and root growth, while reactive oxygen species (ROS) and malondialdehyde (MDA) contents increased significantly. Interestingly, wheat seedlings of both cultivars grown from 50 and 100 mg L-1 fullerol-treated seeds were promoted in seedling growth under water stress, which was associated with lower ROS and MDA contents, as well as higher antioxidant enzyme activities. In addition, modern cultivars (CW131) had better drought adaptation than old cultivars (BM1) did, while the effect of fullerol on wheat had no significant difference between the two cultivars. The study demonstrated the possibility of improving seed germination, seedling growth and antioxidant enzyme activities by using appropriate concentrations of fullerol under drought stress. The results are significant for understanding the application of fullerol in agriculture under stressful conditions.

Role of abscisic acid in modulating drought acclimation, agronomic characteristics and ß-N-oxalyl-L-α,ß-diaminopropionic acid (ß-ODAP) accumulation in grass pea (Lathyrus sativus L.).

BACKGROUND: ß-N-oxalyl-l-α,ß-diaminopropionic acid (ß-ODAP) is a physiological indicator in response to drying soil. However, how abscisic acid (ABA) modulates ß-ODAP accumulation and its related agronomic characteristics in drought stressed grass pea (Lathyrus sativus L.) continue to be unclear. The present study aimed to evaluate the effects of ABA addition on drought tolerance, agronomic characteristics and ß-ODAP content in grass pea under drought stress. RESULTS: Exogenous ABA significantly promoted ABA levels by 19.3% and 18.3% under moderate and severe drought stress, respectively, compared to CK (without ABA, used as control check treatment). ABA addition activated earlier trigger of non-hydraulic root-sourced signal at 69.1% field capacity (FC) (65.5% FC in CK) and accordingly prolonged its operation period to 45.6% FC (49.0% FC in CK). This phenomenon was mechanically associated with the physiological mediation of ABA, where its addition significantly promoted the activities of leaf superoxide dismutase, catalase and peroxidase enzymes and the biosynthesis of leaf proline, simultaneously lowering the accumulation of malondialdehyde and hydrogen peroxide under moderate and severe stresses. Interestingly, ABA application significantly increased seed ß-ODAP content by 21.7% and 21.3% under moderate and severe drought stress, but did not change leaf ß-ODAP content. Furthermore, ABA application produced similar shoot biomass and grain yield as control groups. CONCLUSION: Exogenous ABA improved the drought adaptability of grass pea and promoted the synthesis of ß-ODAP in seeds but not in leaves. Our findings provide novel insights into the agronomic role of ABA in relation to ß-ODAP enrichment in grass pea subjected to drought stress. © 2021 Society of Chemical Industry.

Novel 1-(prop-2-yn-1-ylamino)-2,3-dihydro-1H-indene-4-thiol derivatives as potent selective human monoamine oxidase B inhibitors: Design, SAR development, and biological evaluation.

Successes have been achieved in developing human monoamine oxidase B (hMAO-B) inhibitors as anti-Parkinson's disease (PD) drugs. However, low efficiency and unwanted side effects of the marketed hMAO-B inhibitors hamper their medical applications, therefore, novel potent selective hMAO-B inhibitors are still of great interest. Herein we report 1-(prop-2-yn-1-ylamino)-2,3-dihydro-1H-indene-4-thiol derivatives as hMAO-B inhibitors, which were designed by employing a fragment-based drug design strategy to link rasagiline to hydrophobic fragments. Among the synthesized 31 compounds, K8 and K24 demonstrated very encouraging hMAO-B inhibitory activities and selectivity over hMAO-A, better than rasagiline and safinamide. In vitro studies indicated that K8 and K24 are nontoxic to nervous tissue cells and they have considerable effects against ROS formation and potential neuroprotective activity. Further mice behavioral tests demonstrated these two compounds have good therapeutic effects on MPTP-induced PD model mice. All these experiment results suggest that compounds K8 and K24 can be promising candidates for further research for treatment of PD.

LncRNA MALAT1 Aggravates the Progression of Non-Small Cell Lung Cancer by Stimulating the Expression of COMMD8 via Targeting miR-613.

BACKGROUND: Non-small cell lung cancer (NSCLC) is a common malignant tumor in humans. Long non-coding RNA (lncRNA) involved in cancer progression has been reported frequently. The objective of this study was to investigate the role of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and explore a novel mechanism in NSCLC development. MATERIALS AND METHODS: The expression of MALAT1, copper metabolism MURR1 domain-containing 8 (COMMD8) and microRNA-613 (miR-613) was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The protein levels of COMMD8, Cyclin D1, Ki67, B cell lymphoma/leukemia-2 (Bcl-2), Bcl-2 associated X protein (Bax), lactate dehydrogenase A (LDHA), CD63 and CD81 were determined by Western blot. Cell proliferation, the number of colonies and cell apoptosis were assessed by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT), colony formation and flow cytometry assays, respectively. Glycolysis was distinguished based on glucose consumption, lactate production and LDHA activity. The role of MALAT1 in vivo was verified by animal experiments. The relationship between miR-613 and MALAT1 or COMMD8 was predicted by the bioinformatics tool starbase and verified by dual-luciferase reporter assay. The exosomes were isolated using the corresponding kit and identified by transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). RESULTS: MALAT1 and COMMD8 were aberrantly upregulated in NSCLC tissues and cells. MALAT1 or COMMD8 knockdown blocked cell proliferation, colony formation and glycolysis but accelerated cell apoptosis in vitro. Besides, MALAT1 knockdown reduced tumor growth in vivo. We found that miR-613 was a target of MALAT1, and miR-613 could bind to the 3' untranslated region (3'UTR) of COMMD8. MALAT1 regulated the expression of COMMD8 by absorbing miR-613. Moreover, the extracellular MALAT1 was transmitted by wrapping into exosomes. CONCLUSION: MALAT1 promoted malignant activities of NSCLC cells through targeting miR-613/COMMD8 axis, and exosome-mediated transfer of NSCLC might be a novel approach for NSCLC treatment.

Discovery and Development of Cyclin-Dependent Kinase 8 Inhibitors.

Cyclin-dependent Kinase 8 (CDK8), a member of the CDKs family, has been widely focused owing to investigations of its critical roles in transcription and oncogenesis in recent years. Selective inhibition of CDK8 and its paralog CDK19 offers a novel therapeutic strategy for the treatment of some cancers. Up to now, though many small molecules against CDK8 have been discovered, most of them are discontinued in the preclinical trials due to the low selectivity and poor physicochemical properties. This review mainly summarizes the design strategies of selective CDK8 inhibitors having different chemical scaffolds with the aim to improve the inhibitory activity, selectivity, metabolic stability and solubility. Their corresponding Structure-activity Relationships (SAR) are also reviewed. On the basis of the discussion in this review, we hope more effective, selective and drug-like CDK8 inhibitors will be developed and demonstrate therapeutic values in the near future.

Developments in inhibiting platelet aggregation based on different design strategies.

Platelet aggregation is the central event in hemostasis and thrombosis. Up to now, many agents inhibiting platelet aggregation have been approved for the treatment of thrombotic disorders. In this review, we mainly summarized the progress in the research of platelet aggregation inhibitors based on different design strategies. The advantage and challenge of corresponding targets are also discussed in this article. We hope more platelet aggregation inhibitors with efficacy and safety will be discovered in the future.

Discovery of novel 2,3-dihydro-1H-inden-1-amine derivatives as selective monoamine oxidase B inhibitors.

Inhibition of MAO-B has been an effective strategy for the treatment of Parkinson's disease. To find more potent and selective MAO-B inhibitors with novel chemical scaffold, we designed and synthesized a series of new 2,3-dihydro-1H-inden-1-amine derivatives on basis of our previous study. Furthermore, the corresponding structure-activity relationship (SAR) of these compounds is detailedly discussed. Compounds L4 (IC50 = 0.11 µM), L8 (IC50 = 0.18 µM), L16 (IC50 = 0.27 µM) and L17 (IC50 = 0.48 µM) showed similar MAO-B inhibitory activity as Selegiline. Moreover, L4, L16 and L17 also exhibited comparable selectivity with Selegiline, indicating that L4, L16 and L17 could be promising selective MAO-B inhibitors for further study.

Design, synthesis and biological evaluation of novel human monoamine oxidase B inhibitors based on a fragment in an X-ray crystal structure.

Herein we report our efforts of developing reversible selective hMAO-B inhibitors based on isatin, a fragment in an X-ray crystal structure. Five different scaffolds were designed and many compounds were synthesized. Among them, compound A3 demonstrated very high potency and isoform selectivity against hMAO-B, 11 and 13 times more potent (IC50 = 3 nM) and 23.64 and 6.8 times more selective than the marked drugs, selegiline and safinamide. However, the endeavors to modify the polar 3-one group of isatin, that is in a hydrophobic environment in the binding site of hMAO-B, to small nonpolar hydrophobic groups did not bring about improved hMAO-B inhibitors, which may challenge our understanding of molecular interactions and molecular recognition in biological systems.

Plant toxin ß-ODAP activates integrin ß1 and focal adhesion: A critical pathway to cause neurolathyrism.

Neurolathyrism is a unique neurodegeneration disease caused by ß-N-oxalyl-L-α, ß- diaminopropionic (ß-ODAP) present in grass pea seed (Lathyrus stativus L.) and its pathogenetic mechanism is unclear. This issue has become a critical restriction to take full advantage of drought-tolerant grass pea as an elite germplasm resource under climate change. We found that, in a human glioma cell line, ß-ODAP treatment decreased mitochondrial membrane potential, leading to outside release and overfall of Ca2+ from mitochondria to cellular matrix. Increased Ca2+ in cellular matrix activated the pathway of ECM, and brought about the overexpression of ß1 integrin on cytomembrane surface and the phosphorylation of focal adhesion kinase (FAK). The formation of high concentration of FA units on the cell microfilaments further induced overexpression of paxillin, and then inhibited cytoskeleton polymerization. This phenomenon turned to cause serious cell microfilaments distortion and ultimately cytoskeleton collapse. We also conducted qRT-PCR verification on RNA-sequence data using 8 randomly chosen genes of pathway enrichment, and confirmed that the data was statistically reliable. For the first time, we proposed a relatively complete signal pathway to neurolathyrism. This work would help open a new window to cure neurolathyrism, and fully utilize grass pea germplasm resource under climate change.

B vitamin supplementation improves cognitive function in the middle aged and elderly with hyperhomocysteinemia.

OBJECTIVE: An intervention study was performed to determine if supplement containing folic acid, vitamin B6, and vitamin B12 could improve cognitive function and lower homocysteine in middle-aged and elderly patients with hyperhomocysteinemia. METHODS: One hundred and four participants with hyperhomocysteinemia were recruited in Tianjin, China, aged 55-94 years old. Fifty-seven individuals with hyperhomocysteinemia were included in the intervention group (vitamin B group, which received 800 µg/day of folate, with 10 mg of vitamin B6 and 25 µg of vitamin B12) and 47 patients in the placebo group. The endpoint was the improvement in cognitive function as evaluated by Basic Cognitive Aptitude Tests (BCATs). All parameters were measured before and after the treatment period of 14 weeks. RESULTS: The BCAT total score and four sub-tests scores (digit copy, Chinese character rotation, digital working memory, and recognition of meaningless figure) of BCAT at 14 weeks significantly increased only for the vitamin B group. Serum total homocysteine (tHcy) levels significantly decreased in the intervention group, while serum concentrations of folate, vitamin B6, and vitamin B12 significantly increased in the intervention group. CONCLUSION: The results demonstrated that supplement containing folate, vitamin B6, and vitamin B12 in middle-aged and elderly patients with hyperhomocysteinemia could improve their cognitive function partly and reduce serum tHcy levels.

Genotypic Variation in the Concentration of ß-N-Oxalyl-L-α,ß-diaminopropionic Acid (ß-ODAP) in Grass Pea (Lathyrus sativus L.) Seeds Is Associated with an Accumulation of Leaf and Pod ß-ODAP during Vegetative and Reproductive Stages at Three Levels of Water Stress.

Grass pea (Lathyrus sativus L.) cultivation is limited because of the presence in seeds and tissues of the nonprotein amino acid ß-N-oxalyl-L-α,ß-diaminopropionic acid (ß-ODAP), a neurotoxin that can cause lathyrism in humans. Seven grass pea genotypes differing in seed ß-ODAP concentration were grown in pots at three levels of water availability to follow changes in the concentration and amount of ß-ODAP in leaves and pods and seeds. The concentration and amount of ß-ODAP decreased in leaves in early reproductive development and in pods as they matured, while water stress increased ß-ODAP concentration in leaves and pods at these stages. The net amount of ß-ODAP in leaves and pods at early podding was positively associated with seed ß-ODAP concentration at maturity. We conclude that variation among genotypes in seed ß-ODAP concentration results from variation in net accumulation of ß-ODAP in leaves and pods during vegetative and early reproductive development.

Dryland wheat domestication changed the development of aboveground architecture for a well-structured canopy.

We examined three different-ploidy wheat species to elucidate the development of aboveground architecture and its domesticated mechanism under environment-controlled field conditions. Architecture parameters including leaf, stem, spike and canopy morphology were measured together with biomass allocation, leaf net photosynthetic rate and instantaneous water use efficiency (WUE(i)). Canopy biomass density was decreased from diploid to tetraploid wheat, but increased to maximum in hexaploid wheat. Population yield in hexaploid wheat was higher than in diploid wheat, but the population fitness and individual competition ability was higher in diploid wheats. Plant architecture was modified from a compact type in diploid wheats to an incompact type in tetraploid wheats, and then to a more compact type of hexaploid wheats. Biomass accumulation, population yield, harvest index and the seed to leaf ratio increased from diploid to tetraploid and hexaploid, associated with heavier specific internode weight and greater canopy biomass density in hexaploid and tetraploid than in diploid wheat. Leaf photosynthetic rate and WUEi were decreased from diploid to tetraploid and increased from tetraploid to hexaploid due to more compact leaf type in hexaploid and diploid than in tetraploid. Grain yield formation and WUEi were closely associated with spatial stance of leaves and stems. We conclude that the ideotype of dryland wheats could be based on spatial reconstruction of leaf type and further exertion of leaf photosynthetic rate.

[Ecological function and application of toxin beta-ODAP in grass pea (Lathyrus sativus)].

Grass pea (Lathyrus sativus) is a legume with various adverse adaptability and rich nutrition. However, it can lead to the human and animal neurotoxicity after long-term consumption due to its neurotoxin, beta-N-oxalyl-L-alpha, beta-diaminopropionic acid (beta-ODAP), limiting its utilization. This paper summarized the influences of beta-ODAP on osmotic adjustment and growth regulation in grass pea under drought stress, the research progress in analysis methods, toxicological mechanisms and practical utility of beta-ODAP, and the breeding strategies for low- and zero-beta-ODAP. Beta-ODAP synthesis was found to be abundant in grass pea under drought stress and its content was enhanced gradually with the increasing extent of drought stress. beta-ODAP could supply nitrogen for plant growth and seed development, scavenge reactive oxygen species (ROS), involve in osmotic adjustment as a soluble amino acid, transport zinc-ions as a carrier molecule, and impact nodule development. However, increasing the content of sulfur-containing amino acids (methionine and cysteine) could decrease the level of toxicity of grass pea. There were a lot of investigations on collecting genetic resources, cross breeding, tissue culture, and gene manipulation for low- and zero-toxin in grass pea in recent years. Although beta-ODAP could induce excitotoxicity by damaging intracellular Ca2+ homeostasis and as glutamate analogues, it has medicinal value on hemostasis and anti-tumor.

Variational iteration method for Bratu-like equation arising in electrospinning.

This paper points out that the so called enhanced variational iteration method (Colantoni & Boubaker, 2014) for a nonlinear equation arising in electrospinning and vibration-electrospinning process is the standard variational iteration method. An effective algorithm using the variational iteration algorithm-II is suggested for Bratu-like equation arising in electrospinning. A suitable choice of initial guess results in a relatively accurate solution by one or few iteration.

Differential expression and regulation of prohibitin during curcumin-induced apoptosis of immortalized human epidermal HaCaT cells.

Prohibitin (PHB), also known as inhibin, is important in cell proliferation, differentiation and apoptosis. This protein localizes to the inner membrane of mitochondria, where it acts as a chaperone protein, and is also found in the nucleus, where it negatively regulates transcription. The tumor-suppressive role of PHB in cell proliferation appears to be contradictory. In this study, we investigated the existence, localization and alterations in the expression of PHB in the whole cell and nuclear matrix and analyzed its co-localization with the expression products of related genes. The western blot analysis results revealed that PHB exists in the composition of nuclear matrix proteins and that the expression level of PHB is significantly increased in the whole cell and markedly decreased in the nuclear matrix after curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) treatment. The laser confocal scanning microscope results demonstrated the co-localization of PHB with p53, c-Myc, Bax, and Fas in HaCaT cells, and this co-localization region was transferred as a result of curcumin treatment. In addition, the results of the GST pull-down assay demonstrated the direct interaction of PHB with p53, c-Myc and Bax but not Fas in vitro. Results of the present study confirmed that the expression and distribution of PHB, which is a nuclear matrix protein, affect the apoptosis of HaCaT cells and its co-localization with specific gene products connected with cell apoptosis.

Novel, chimeric, cancer-specific, and radiation-inducible gene promoters for suicide gene therapy of cancer.

BACKGROUND: Although the promoter of the human telomerase reverse transcriptase (hTERT) gene has been widely used in gene therapy for targeted cancer cells, it has some limitations for clinical use because of its low activity and potential toxicity to certain normal cells. To overcome these defects, the authors generated novel chimeric hTERT promoters that contained the radiation-inducible sequence CC(A/T)(6) GG (known as CArG elements). METHODS: Chimeric hTERT promoters were synthesized that contained different numbers of CArG elements, and the activity of chimeric promoters was assessed in different cancer cell lines and normal cells. The potential of selected promoters to successfully control horseradish peroxidase (HRP) and prodrug indole-3-acetic acid (IAA) suicide gene therapy was tested in vitro and in vivo. RESULTS: The promoter activity assays indicated that the synthetic promoter that contained 6 repeating CArG units had the best radiation inducibility than any other promoters that contained different numbers of CArG units, and the chimeric promoters retained their cancer-specific characteristics. The chimeric promoter was better at driving radiation-inducible gene therapy than the control promoters. The sensitizer enhancement ratio of the chimeric promoter system determined by clonogenic assay was higher, and the chimeric promoter system resulted in a significantly higher apoptotic level compared with other promoter systems. The combination of chimeric/promoter-mediated gene therapy and radiotherapy significantly inhibited tumor volume in a xenograft mouse model and resulted in a significant prolongation of survival in mice. CONCLUSIONS: The current results indicated that a combinational cancer-specific promoter system that is responsive to irradiation has great potential for improving the efficacy of cancer treatment.

Co-expression of interleukin 12 enhances antitumor effects of a novel chimeric promoter-mediated suicide gene therapy in an immunocompetent mouse model.

The human telomerase reverse transcriptase (hTERT) promoter has been widely used in target gene therapy of cancer. However, low transcriptional activity limited its clinical application. Here, we designed a novel dual radiation-inducible and tumor-specific promoter system consisting of CArG elements and the hTERT promoter, resulting in increased expression of reporter genes after gamma-irradiation. Therapeutic and side effects of adenovirus-mediated horseradish peroxidase (HRP)/indole-3-acetic (IAA) system downstream of the chimeric promoter were evaluated in mice bearing Lewis lung carcinoma, combining with or without adenovirus-mediated interleukin 12 (IL12) gene driven by the cytomegalovirus promoter. The combination treatment showed more effective suppression of tumor growth than those with single agent alone, being associated with pronounced intratumoral T-lymphocyte infiltration and minor side effects. Our results suggest that the combination treatment with HRP/IAA system driven by the novel chimeric promoter and the co-expression of IL12 might be an effective and safe target gene therapy strategy of cancer.