Psychometric Properties of the Chinese Version of the Gilliam Autism Rating Scale-Third Edition (CV-GARS-3).

Gilliam Autism Rating Scale-Third Edition (GARS-3) serves as an effective screening tool for autism spectrum disorder (ASD) that is based on the latest and authoritative diagnostic criteria, however, there is a deficiency in adaptive research in China. We aimed to revise the Chinese version of GARS-3 (CV-GARS-3) and evaluate its psychometric characteristics, providing a theoretical basis for the improvement of ASD screening tools in China. This study developed CV-GARS-3 through translation and cultural adaptation of GARS-3. 362 ASD individuals, 126 typical development individuals, and 103 individuals with other disorders were recruited to analyze the psychometric characteristics of CV-GARS-3. The results showed that exploratory structural equation model demonstrated satisfactory goodness-of-fit. Within the non-verbal ASD samples, all items loaded on anticipated factors. Regarding verbal ASD samples, 3 items exhibited considerable cross-loadings and were categorized under unexpected factors. Meanwhile, acceptable criterion validity was reflected in the four subscales (r = 0.71) and the six subscales (r = 0.74). Satisfactory reliability was observed in the four subscales (Cronbach's α = 0.96, inter-rater consistency = 0.86, test-retest consistency = 0.87) and the six subscales (Cronbach's α = 0.94, inter-rater consistency = 0.81, test-retest consistency = 0.81). In addition, receiver operating characteristic analysis demonstrated that both the four subscales (sensitivity = 89%, specificity = 85%, accuracy = 88%) and the six subscales (sensitivity = 86%, specificity = 88%, accuracy = 86%) had outstanding screening effects. Therefore, the results suggested that the CV-GARS-3 is considered as a useful tool for the screening and auxiliary diagnosis of ASD. Notably, the expression of scale should be further improved to adapt the context of Chinese culture and achieve more precise diagnostic results.

Physical activity promotes brain development through serotonin during early childhood.

Early childhood serves as a critical period for neural development and skill acquisition when children are extremely susceptible to the external environment and experience. As a crucial experiential stimulus, physical activity is believed to produce a series of positive effects on brain development, such as cognitive function, social-emotional abilities, and psychological well-being. The World Health Organization recommends that children engage in sufficient daily physical activity, which has already been strongly advocated in the practice of preschool education. However, the mechanisms by which physical activity promotes brain development are still unclear. The role of neurotransmitters, especially serotonin, in promoting brain development through physical activity has received increasing attention. Physical activity has been shown to stimulate the secretion of serotonin by increasing the bioavailability of free tryptophan and enriching the diversity of gut microbiota. Due to its important role in modulating neuronal proliferation, differentiation, synaptic morphogenesis, and synaptic transmission, serotonin can regulate children's explicit cognitive and social interaction behavior in the early stages of life. Therefore, we hypothesized that serotonin emerges as a pivotal transmitter that mediates the relationship between physical activity and brain development during early childhood. Further systematic reviews and meta-analyses are needed to specifically explore whether the type, intensity, dosage, duration, and degree of voluntariness of PA may affect the role of serotonin in the relationship between physical activity and brain function. This review not only helps us understand the impact of exercise on development but also provides a solid theoretical basis for increasing physical activity during early childhood.

Impact of COVID-19 on emotional and behavioral problems among preschool children: a meta-analysis.

The impact of the Coronavirus Disease 2019 (COVID-19) on society is continuous, resulting in negative psychological consequences. Given the vulnerability and sensitivity to the environment among preschool children, their emotional and behavioral problems deserve more attention. The current study aimed to explore the impact of the epidemic on preschool children's mental health by determining the pooled prevalence of emotional and behavioral problems amidst the Coronavirus Disease 2019 pandemic and to reveal potential reasons for variations between studies. Published studies were searched in Embase, PubMed, ProQuest, PsycINFO, Web of Science, CNKI, and Wanfang. Based on the inclusion criteria outlined in this study, a total of 10 studies encompassing 38,059 participants were incorporated. Employing a random-effect model for estimating the prevalence of emotional and behavioral problems, the results revealed a pooled prevalence rate of 24.3% (95% CI, 0.15-0.38; I²=99.9%) among preschool children. This rate surpasses the pre-outbreak prevalence observed in different countries, signifying a detrimental influence of the epidemic on the mental well-being of preschoolers. Therefore, mental health care and recovery are essential for the vulnerable group during and after the public health crisis. Specific emotional and behavioral problems among preschool children are expected to be researched in the future to provide more targeted guidance for intervention.

A Review on Autism Spectrum Disorder Screening by Artificial Intelligence Methods.

PURPOSE: With the increasing prevalence of autism spectrum disorders (ASD), the importance of early screening and diagnosis has been subject to considerable discussion. Given the subtle differences between ASD children and typically developing children during the early stages of development, it is imperative to investigate the utilization of automatic recognition methods powered by artificial intelligence. We aim to summarize the research work on this topic and sort out the markers that can be used for identification. METHODS: We searched the papers published in the Web of Science, PubMed, Scopus, Medline, SpringerLink, Wiley Online Library, and EBSCO databases from 1st January 2013 to 13th November 2023, and 43 articles were included. RESULTS: These articles mainly divided recognition markers into five categories: gaze behaviors, facial expressions, motor movements, voice features, and task performance. Based on the above markers, the accuracy of artificial intelligence screening ranged from 62.13 to 100%, the sensitivity ranged from 69.67 to 100%, the specificity ranged from 54 to 100%. CONCLUSION: Therefore, artificial intelligence recognition holds promise as a tool for identifying children with ASD. However, it still needs to continually enhance the screening model and improve accuracy through multimodal screening, thereby facilitating timely intervention and treatment.

Sequential annulation and isomerisation reaction of 3-acylmethylidene oxindoles with Huisgen zwitterions and synthesis of 5-(3-oxindolyl)oxazoles.

Herein, we report a facile synthesis of 5-(3-oxindolyl)oxazole derivatives via a sequential annulation and isomerisation reaction of 3-acylmethylidene oxindoles with in situ generated Huisgen zwitterions (HZs) from PPh3 and azodicarboxylates. This reaction exhibits good functional group tolerance with 30 examples of structurally diverse products prepared with moderate to good efficiencies (up to 88% yield), thus providing a generally applicable route to the biologically important 5-(3-indolyl)oxazole structural motifs. Key to the success of this sequential one-pot strategy is the utilization of DBU as a base to promote the isomerisation process of the corresponding intermediate annulation products.

Copper-Catalyzed Chemo- and Enantioselective Radical 1,2-Carbophosphonylation of Styrenes.

The copper-catalyzed enantioselective radical difunctionalization of alkenes from readily available alkyl halides and organophosphorus reagents possessing a P-H bond provides an appealing approach for the synthesis of α-chiral alkyl phosphorus compounds. The major challenge arises from the easy generation of a P-centered radical from the P-H-type reagent and its facile addition to the terminal side of alkenes, leading to reverse chemoselectivity. We herein disclose a radical 1,2-carbophosphonylation of styrenes in a highly chemo- and enantioselective manner. The key to the success lies in not only the implementation of dialkyl phosphites with a strong bond dissociation energy to promote the desired chemoselectivity but also the utilization of an anionic chiral N,N,N-ligand to forge the chiral C(sp3 )-P bond. The developed Cu/N,N,N-ligand catalyst has enriched our library of single-electron transfer catalysts in the enantioselective radical transformations.

Synthesis of α-Quaternary ß-Lactams via Copper-Catalyzed Enantioconvergent Radical C(sp3 )-C(sp2 ) Cross-Coupling with Organoboronate Esters.

The copper-catalyzed enantioconvergent radical C(sp3 )-C(sp2 ) cross-coupling of tertiary α-bromo-ß-lactams with organoboronate esters could provide the synthetically valuable α-quaternary ß-lactams. The challenge arises mainly from the construction of sterically congested quaternary stereocenters between the tertiary alkyl radicals and chiral copper(II) species. Herein, we describe our success in achieving such transformations through the utilization of a copper/hemilabile N,N,N-ligand catalyst to forge the sterically congested chiral C(sp3 )-C(sp2 ) bond via a single-electron reduction/transmetalation/bond formation catalytic cycle. The synthetic potential of this approach is shown in the straightforward conversion of the corresponding products into many valuable building blocks. We hope that the developed catalytic cycle would open up new vistas for more enantioconvergent cross-coupling reactions.

Cascade Ring-Opening/Cyclization Reaction of Spiro(nitrocyclopropane)oxindoles with Huisgen Zwitterions and Synthesis of Pyrazolo[3,4-b]indoles.

Herein, we report a ring-opening/cyclization cascade reaction of spiro(nitrocyclopropane)oxindoles with in situ generated Huisgen zwitterions (HZs) from PPh3 and azodicarboxylates. This reaction provides an array of polyfunctionalized pyrazolo[3,4-b]indole derivatives in moderate-to-excellent yields and generally high stereoselectivities with a broad substrate scope. The annulation products obtained from di-tert-butyl azodicarboxylates can be readily transformed into aromatic-substituted pyrazolo[3,4-b]indoles in moderate yields upon treatment with trifluoroacetic acid, thus providing a new entry to this fused heterocycle skeleton. In terms of nitro-substituted donor-acceptor cyclopropane, this work significantly broadens the substrate scope for the annulation reaction of nitrocyclopropanes and HZs. The dual roles of the oxindole moiety in the ring opening of cyclopropane and a plausible mechanism for the cascade reaction are also discussed.

Mechanism-based ligand design for copper-catalysed enantioconvergent C(sp3)-C(sp) cross-coupling of tertiary electrophiles with alkynes.

In contrast with the well-established enantioconvergent radical C(sp3)-C cross-coupling of racemic secondary alkyl electrophiles, the corresponding coupling of tertiary electrophiles to forge all-carbon quaternary stereocentres remains underexplored. The major challenge arises from the steric hindrance and the difficult enantio-differentiation of three distinct carbon substituents of prochiral tertiary radicals. Here we demonstrate a general copper-catalysed enantioconvergent C(sp3)-C(sp) cross-coupling of diverse racemic tertiary alkyl halides with terminal alkynes (87 examples). Key to the success is the rational design of chiral anionic N,N,N-ligands tailor-made for the computationally predicted outer-sphere radical group transfer pathway. This protocol provides a practical platform for the construction of chiral C(sp3)-C(sp/sp2/sp3) bonds, allowing for expedient access to an array of synthetically challenging quaternary carbon building blocks of interest in organic synthesis and related areas.

Copper-Catalyzed Intermolecular Enantioselective Radical Oxidative C(sp3 )-H/C(sp)-H Cross-Coupling with Rationally Designed Oxazoline-Derived N,N,P(O)-Ligands.

The intermolecular asymmetric radical oxidative C(sp3 )-C(sp) cross-coupling of C(sp3 )-H bonds with readily available terminal alkynes is a promising method to forge chiral C(sp3 )-C(sp) bonds because of the high atom and step economy, but remains underexplored. Here, we report a copper-catalyzed asymmetric C(sp3 )-C(sp) cross-coupling of (hetero)benzylic and (cyclic)allylic C-H bonds with terminal alkynes that occurs with high to excellent enantioselectivity. Critical to the success is the rational design of chiral oxazoline-derived N,N,P(O)-ligands that not only tolerate the strong oxidative conditions which are requisite for intermolecular hydrogen atom abstraction (HAA) processes but also induce the challenging enantiocontrol. Direct access to a range of synthetically useful chiral benzylic alkynes and 1,4-enynes, high site-selectivity among similar C(sp3 )-H bonds, and facile synthesis of enantioenriched medicinally relevant compounds make this approach very attractive.

Design, synthesis and biological evaluation of novel 2-(4-(1H-indazol-6-yl)-1H-pyrazol-1-yl)acetamide derivatives as potent VEGFR-2 inhibitors.

Vascular endothelial growth factor-2 (VEGFR-2) plays a pivotal role in tumor angiogenesis. Herein, a library of novel 2-(4-(1H-indazol-6-yl)-1H-pyrazol -1-yl)acetamide derivatives were designed and synthesized as VEGFR-2 inhibitors based on scaffold hopping strategy. These compounds exhibited the excellent inhibitory in both VEGFR-2 and tumor cells proliferation. Especially, compound W13 possessed potent VEGFR-2 inhibition with IC50 = 1.6 nM and anti-proliferation against HGC-27 tumor cells with IC50 = 0.36 ± 0.11 µM, as well as less toxicity against normal GES-1 cells with IC50 = 187.46 ± 10.13 µM. Moreover, W13 obviously inhibited colony formation, migration and invasion of HGC-27 cells by adjusting the expression of MMP-9 and E-cadherin, and induced HGC-27 cells apoptosis by increasing ROS production and regulating the expression of apoptotic proteins. Furthermore, W13 blocked the PI3K-Akt-mTOR signaling pathway in HGC-27 cells. In addition, anti-angiogenesis of W13 was proved by inhibiting tube formation and the expression of p-VEGFR-2 in HUVEC cells. All the results demonstrated that W13 could be developing as a promising anticancer agent for gastric cancer therapy.

Copper-Catalyzed Enantioconvergent Cross-Coupling of Racemic Alkyl Bromides with Azole C(sp2 )-H Bonds.

The development of enantioconvergent cross-coupling of racemic alkyl halides directly with heteroarene C(sp2 )-H bonds has been impeded by the use of a base at elevated temperature that leads to racemization. We herein report a copper(I)/cinchona-alkaloid-derived N,N,P-ligand catalytic system that enables oxidative addition with racemic alkyl bromides under mild conditions. Thus, coupling with azole C(sp2 )-H bonds has been achieved in high enantioselectivity, affording a number of potentially useful α-chiral alkylated azoles, such as 1,3,4-oxadiazoles, oxazoles, and benzo[d]oxazoles as well as 1,3,4-triazoles, for drug discovery. Mechanistic experiments indicated facile deprotonation of an azole C(sp2 )-H bond and the involvement of alkyl radical species under the reaction conditions.

The pro-inflammatory cytokines, salivary cortisol and alpha-amylase are associated with generalized anxiety disorder (GAD) in patients with asthma.

Generalized anxiety disorder (GAD) is common in patients with asthma. High levels of GAD may lead both to exacerbation of the condition and poor management. However, the physiological mechanisms of GAD in asthma patient is unclear. This study investigated the associations between the diurnal rhythm of sputum cytokines, salivary cortisol, α-amylase and GAD in asthma patients. Patients with co-morbid GAD and asthma showed higher sputum IL-1 AUC, sputum IL-6 AUC and sAA AUC. And there were positive correlations between Hamilton anxiety scale (HAMA) scores and sputum IL-1 AUC concentrations (r=0.37, P=0.002), HAMA scores and sputum IL-6 AUC (r=0.56, P<0.001), HAMA scores and sAA AUC (r=0.75, P<0.001). Also, there were positive correlations between Sputum IL-1 AUC and sAA AUC (r=0.40, P<0.001), between Sputum IL-6 AUC and sAA AUC. Stepwise multiple regression analyses showed the combination of sputum sAA AUC, IL-1 AUC, IL-6 AUC and cortisol AUC was the best predictor of HAMA scores (ΔR2=0.439, F(4,63)=14.086, p<0.001). Therefore, pro-inflammatory cytokines, salivary cortisol and alpha-amylase may all be involved in the occurrence of GAD in asthma patients.

A comparison of ultrasound-augmented and conventional leaching of silver from sintering dust using acidic thiourea.

In the process of steel manufacture, up to ten millions of tons of sintering dust (SD) are produced annually in China, which contain noble metals such as Ag. Therefore, recovery of silver (Ag) from SD could be a potential economic and environmental activity. The purpose of this article is to generate information about reaction kinetics of silver leaching with thiourea from SD, comparing the conventional and ultrasonic-augment leaching. The effects of various control parameters such as the ultrasound power, particle size, leaching temperature and thiourea concentration on leaching rate of silver were studied. The results showed 89% silver recovery for conventional process against 95% for ultrasound assisted leaching. The ultrasonic wave increased the leaching rate and shorten the reaction time. The rate controlling step was analyzed using shrinking core model and the rate controlling step is identified to be the diffusion through the product layer in both conventional and ultrasonic-augment leaching processes. The activation energies were estimated to be 28.01kJ/mol and 18.19kJ/mol, and the reaction order were 0.89 and 0.71, respectively.

Association of pro-inflammatory cytokines, cortisol and depression in patients with chronic obstructive pulmonary disease.

Evidence suggests that pro-inflammatory cytokines and cortisol play a crucial role in the etiology of chronic obstructive pulmonary disease (COPD) and depression. Depression occurs commonly among COPD patients and an earlier diagnosis would be beneficial. This study investigated the associations between depression, sputum cytokines and salivary cortisol in COPD patients. The diurnal rhythms of sputum IL-1, IL-6, TNF-α and salivary cortisol were measured in COPD patients with depression compared to those only with depression, or COPD and healthy controls. The area under the diurnal variation curves (AUC) over the 24h time course and relative diurnal variation (VAR) were calculated while correlation and regression analysis were performed. Patients with co-morbid depression and COPD showed an increasing sputum IL-1, sputum TNF-α AUC and a decreasing salivary cortisol VAR (P<0.001). The combination of sputum TNF-α AUC, sputum IL-1 AUC, sputum IL-6 AUC and salivary cortisol VAR performed best as a potential biomarker in the diagnosis of depression in COPD patients, with a sensitivity of 94.74% and a specificity of 96.67%. Positive correlations were found between sputum IL-1 AUC and sputum TNF-α AUC versus depressive symptoms, respectively a negative correlation was found between salivary cortisol VAR and depression. They were independently associated with depression in logistic regression models. Depression in COPD is associated with higher 24-h overall levels of sputum IL-1, TNF-α and flattened diurnal salivary cortisol. These non-invasive sputum and salivary biomarkers may serve as a simple clinical tool for the early diagnosis of depression in COPD patients.

Clomipramine reverses hypoalgesia/hypoesthesia and improved depressive-like behaviors induced by inescapable shock in rats.

An increased vulnerability to pain complaints, along with a simultaneous increase in experimental pain thresholds, shows the paradoxical phenomenon of pain perception in depressive patients. Clomipramine, a tricyclic antidepressant, could also ameliorate syndromes in chronic pain patients. However, few studies have focused on the effect of antidepressants on experimental pain thresholds. By using a rat model, the learned helplessness paradigm, the present study explored the effect of clomipramine on behavioral deficits and experimental pain thresholds to different stimuli in "helpless" rats. Helpless rats were administered clomipramine (10mg/kg, i.p, b.i.d.) for 5 consecutive days. The depressive-like and anxiety-like behaviors were detected by shuttle box, open field and elevated plus maze test before and after inescapable shock and after medication. The sensitivity to the thermal and mechanical stimuli was also measured by the von Frey hair and Hargreaves test at the indicated time points. Helpless rats displayed shorter total travel distance and fewer rearing times in the open field test and decreased percentage of time spent in the open arms in the elevated plus maze test. In addition, they exhibited significant hypoalgesia/hypoesthesia to mechanical and thermal stimuli. Clomipramine alleviate depressive-like and anxiety-like behaviors and increased the sensitivity to von Frey filament stimuli with no effect on the sensitivity to radiant heat stimuli in helpless rats. These suggested that clomipramine could reverse mechanical but not thermal hypoalgesia/hypoesthesia and simultaneously improved behavioral deficits.

Activation of c-jun N-terminal kinase in spinal cord contributes to breast cancer induced bone pain in rats.

BACKGROUND: The most frequent pain in patients with metastatic breast and prostate cancer is bone pain, which can be severe and difficult to treat. The mechanisms underlying this pain remain unclear. Here we investigated the role of c-jun N-terminal kinase (JNK) pathway in the spinal cord in cancer-induced bone pain (CIBP). RESULTS: In this study, we used an established rat CIBP model to investigate the possible role of JNK activation in the spinal cord. After intra-tibial inoculation with Walker 256 rat mammary gland carcinoma cells, the rats displayed mechanical allodynia on day 5, which lasted to day 16. The activation of JNK in neurons and astrocytes in the spinal cord was found on day 12 and day 16 after intra-tibial inoculation with carcinoma cells. A single intrathecal injection with JNK inhibitor SP600125 by lumbar puncture attenuated mechanical allodynia on day 12, and repeated intrathecal injection of SP600126 from day 10 to day 14 had a cumulative analgesic effect on CIBP. CONCLUSIONS: Taken together, our results demonstrated for the first time that JNK activation in the spinal cord is required in the maintenance of CIBP. Inhibition of the spinal JNK pathway may provide a new therapy for CIBP management.

Robust spinal neuroinflammation mediates mechanical allodynia in Walker 256 induced bone cancer rats.

It has been reported that remarkable and sustained activation of astrocytes and/or microglia occurs in cancer induced pain (CIP), which is different from neuropathic and inflammatory pain. The present study was designed to investigate the role of spinal Toll-like receptor 4 (TLR4) induced glial neuroinflammation in cancer induced pain using a modified rat model of bone cancer. The rat model of CIP consisted of unilateral intra-tibial injection with Walker 256 mammary gland carcinoma. Nine days after Walker 256 inoculation, a robust activation of both astrocytes and microglia in bilateral spinal dorsal horn was observed together with significant bilateral mechanical allodynia. This neuroinflammation was characterized by enhanced immunostaining of both glial fibrillary acidic protein (GFAP, astrocyte marker) and OX-42 (microglia marker), and an elevated level of IL-1ß, IL-6 and TNF-α mRNA. I.t. administration of fluorocitrate (an inhibitor of glial metabolism, 1 nmol) or minocycline (an inhibitor of microglia, 100 µg) has significant anti-allodynic effects on day 12 after Walker 256 inoculation. Naloxone (a nonstereoselective TLR4 signaling blocker, 60 µg, i.t.) also significantly alleviated mechanical allodynia and simultaneously blocked the increased inflammatory cytokine mRNA. The results suggested that spinal TLR4 might play an important role in the sustained glial activation that critically contributed to the robust and sustained spinal neuroinflammation in CIP. This result could potentially help clinicians and researchers to better understand the mechanism of complicated cancer pain.

A practical model of osteomyelitis-induced bone pain by intra-tibial injection of Staphylococcus aureus in rats.

Osteomyelitis is an acute or chronic inflammatory process of bone accompanied with mild to severe pain. Generally, mild to moderate pain induced by osteomyelitis can be relieved, yet severe pain cannot. Therefore, a further investigation into the mechanism of severe pain induced by osteomyelitis is needed. In this study, a traditional rat model of osteomyelitis was induced by intra-tibial injection of Staphylococcus aureus. Then, a series of tests including bone histology, blood analysis, mechanical allodynia, thermal hyperalgesia, and immunohistochemistry were performed. Four days after an intra-tibial bacterial injection, acute inflammation was observed in the bone marrow, which developed into chronic inflammation 12 days after the procedure. The results from the blood analysis confirmed the existence of bone inflammation. Significant mechanical allodynia and thermal hyperalgesia developed shortly after the injection. This osteomyelitis-induced pain behavior was reversed by Celecoxib, a selective COX-2 inhibitor. Furthermore, significant increase of both microglia and astrocytes was observed in the spinal cord. Our results suggest that osteomyelitis-induced rats display pain related behaviors and associated neurochemical changes. This study thus provides a novel practical rat model of bone inflammation induced pain.

Involvement of spinal neurotrophin-3 in electroacupuncture analgesia and inhibition of spinal glial activation in rat model of monoarthritis.

UNLABELLED: Although electroacupuncture (EA) has been proven to effectively relieve pain associated with arthritis, the underlying mechanism of EA analgesia requires further investigation. Here, the involvement of spinal neurotrophin-3 (NT-3) in EA's analgesic effects on complete Freund's adjuvant (CFA)-induced inflammatory pain was examined. The present study demonstrated that: 1) repeated EA stimulation of ipsilateral GB30 and GB34 acupoints remarkably suppressed CFA-induced hyperalgesia; 2) EA treatment markedly enhanced the upregulation of spinal NT-3 mRNA and protein levels following CFA injection; 3) antisense oligodeoxynucleotides (ODN) specifically against NT-3 intrathecally administered during EA treatment for 7 days significantly attenuated the EA analgesia; and 4) the suppressed expression of spinal GFAP (astrocytic marker), OX-42 (microglial marker) as well as proinflammatory cytokines, interleukin (IL)-1ß, IL-6 and tumor necrosis factor (TNF)-α by EA treatment was significantly attenuated following NT-3 antisense ODN delivery. These results suggested that endogenous NT-3 may be involved in the analgesic effect of EA on inflammatory pain in rats, mediated through the inhibition of spinal glial activity as well as proinflammatory cytokine production. PERSPECTIVE: The present study may initiate a discussion on the possible roles of NT-3/glia/cytokines in the therapeutic effects of acupuncture and provide insight on the mechanism underlie the analgesic effects of acupuncture on pain associated with arthritis.