Effects and Mechanisms of Sciadonic Acid on Colonic Transit Function through Regulating 5-HT4/cAMP/PKA/AQP4 Signaling Pathway in STC Model Mice.

Torreya grandis (T. grandis) oil has been reported to alleviate symptoms of slow transit constipation (STC). However, the impact of sciadonic acid (SA), a distinctive fatty acid found in T. grandis oil, on the pathological progression of STC remains unclear. This study aimed to evaluate the effect of SA on STC and uncover the underlying mechanisms. The STC model was established by feeding Balb/c mice with loperamide. After 2 weeks of intervention, SA significantly improved weight loss and intestinal motility decline induced by STC, along with enhancing plasma indices and reducing colon pathological damage. SA effectively reversed the STC-induced decrease in the 5-HT4/cAMP/PKA/AQP4 signaling pathway genes and expression. Furthermore, 16S rRNA analysis demonstrated that SA mitigated the imbalance of the intestinal microbiota induced by STC, by reducing the ratio of Firmicutes to Bacteroidetes (F/B) and increasing the abundance of beneficial bacteria such as Akkermansia. In conclusion, SA intervention alleviated colonic dysfunction in STC mice. The activation of the SA-mediated 5-HT4/cAMP/PKA/AQP4 signaling pathway may serve as a potential target for STC treatment. These findings suggest that SA holds promise as a treatment option for STC and could potentially be extended to other related gut diseases for further investigation.

A finite element analysis of periodontal ligament fluid mechanics response to occlusal loading based on hydro-mechanical coupling model.

OBJECTIVE: Considering fluid stimulation is one of the essential biomechanical signals for periodontal tissues, this study aims to characterizing fluid mechanics response during occlusal loading by a hydro-mechanical coupling model for periodontal ligament. DESIGN: Models simulating periodontium with normal bone height and with intraosseous defects were built with three mechanical modules: tooth, periodontal ligament and alveolar bone. Tooth was modeled as linear elastic, and periodontal ligament and alveolar bone as a hydro-mechanical coupling model. Transient analyses under dynamic occlusal loading were performed. Fluid dynamics within periodontal ligament space was simulated and visualized by post-processing module. RESULTS: Reciprocating oscillatory flow occurred within the periodontal ligament under occlusal loading. Higher pore pressure and fluid velocity were observed in furcation and apical regions compared to mid-root and cervical regions. Intraosseous defects increased pore pressure and fluid velocity within the periodontal ligament, most significantly near the defect. CONCLUSION: Based on the results of the hydro-mechanical coupling model, significant oscillatory fluid motion is observed within the periodontal ligament under occlusal loading. Particularly, higher fluid velocity is evident in the furcation and apical areas. Additionally, Intraosseous defects significantly enhance fluid motion within the periodontal ligament.

Discovery of potential components characteristic by conjugated enone from the branches and leaves of Croton lauioides with anti-neuroinflammatory activity via regulating the NF-κB pathway.

In this study, the chemical composition and pharmacological activity of Croton lauioides were investigated for the first time. The bioactive and HPLC-UV guided isolation led to the discovery of twenty-three conjugated enone-type components (1-23), including nine previously unknown sesquiterpenoid derivatives (1-4, 9-10, 12-14). Notably, compounds 1 and 12 are epoxides containing an endoperoxide bridge (1) or a unique dioxaspiro core (12), respectively. Compounds 2-7 are non-benzenoid aromatics featuring a tropone function, while 9-11 possess a rare rearranged scaffold with tropone shift into benzene. Extensive characterization was performed using NMR spectra, HRESIMS data, and electronic circular dichroism (ECD) calculations. Furthermore, we evaluated the bioactivities of all isolated compounds against neuroinflammation in LPS-stimulated BV-2 microglial cells. Remarkably, most sesquiterpenoid derivatives exhibited significant NO inhibit activities, and compound 5 showed the most potent effect with an IC50 value of 0.14 ± 0.04 µM. Structure-activity relationship (SAR) analysis revealed that sesquiterpenoids modified with endocyclic enone conjugation may serve as a key pharmacophore for NO inhibition, particularly involving aromatic tropone moiety. The qPCR and Western blot results demonstrated that 5 exerted an inhibitory effect on the mRNA levels of iNOS, TNF-α and COX-2 in a time-dependent manner, as well as suppressed the protein expression of iNOS, TNF-α, COX-2. In mechanism, 5 could prevented activation of NF-κB pathway by suppressing phosphorylation of p65 and IκB-α. These findings revealed C. lauioides might be a promising resource for drug candidate development targeting neuroinflammation.

Associations between Social Adversities and Chronic Medical Conditions in a Statewide Sample of Individuals in Treatment for Mental Illnesses.

Individuals with mental illnesses experience disproportionately high rates of social adversities, chronic medical conditions, and early mortality. We analyzed a large, statewide dataset to explore associations between four social adversities and the presence of one or more, and then two or more, chronic medical conditions among individuals in treatment for mental illnesses in New York State. In Poisson regression models adjusting for multiple covariates (e.g., gender, age, smoking status, alcohol use), the presence of one or more adversities was associated with the presence of at least one medical condition (prevalence ratio (PR) = 1.21) or two or more medical conditions (PR = 1.46), and two or more adversities was associated with at least one medical condition (PR = 1.25) or two or more medical conditions (PR = 1.52) (all significant at p < .0001). Greater attention to primary, secondary, and tertiary prevention of chronic medical conditions is needed in mental health treatment settings, especially among those experiencing social adversities.

Salvianolic acid B promotes angiogenesis and inhibits cardiomyocyte apoptosis by regulating autophagy in myocardial ischemia.

BACKGROUND: Myocardial ischemia (MI) can cause angina, myocardial infarction, and even death. Angiogenesis is beneficial for ensuring oxygen and blood supply to ischemic tissue, promoting tissue repair, and reducing cell damage. In this study, we evaluated the effects of Salvianolic acid B (Sal B) against myocardial ischemia and explored its underlying mechanism on autophagy. METHODS: The anti-apoptosis effect of Sal B was conducted by staining Annexin V-FITC/PI and Hoechst as well as evaluating apoptosis bio-markers at protein level in H9c2 cells at glucose deprivation condition. HUVECs were co-cultured with H9c2, and the tube formation assay was used to monitor Sal B's impact on angiogenesis. The MI model of mice was induced by intraperitoneal injection of isoproterenol (ISO). The effect of Sal B on MI mice was evaluated by HE, Masson, immunohistochemistry, WB and kits. In addition, Atg5 siRNA was applied to verify whether the protective effect of Sal B was regulated to autophagy. RESULTS: In H9c2, Sal B reduced the levels of lactate dehydrogenase (LDH), malondialdehyde (MDA) and reactive oxygen species (ROS), improved the levels of superoxide dismutase (SOD) and mitochondrial membrane potential, downregulated the expressions of Bax and cleaved-Caspase3, upregulated the expression of Bcl-2. Therefore, Sal B could significantly inhibit the damage of H9c2 caused by glucose deprivation. In the co-culture system of H9c2 and HUVECs, vascular endothelial growth factor (VEGF) level in the supernatant was dramatically raised by Sal B. Sal B upregulated the expressions of VEGF, platelet derived growth factor (PDGF) and endothelial marker CD31. It implied that Sal B exerted a significant pro-angiogenic effect. Moreover, Sal B increased the expression of LC3, Atg5, and Beclin1, while reducing the level of P62. When the expression of Atg5 was inhibited, the protective effects of Sal B on apoptosis and angiogenesis was reversed. CONCLUSIONS: Sal B inhibited cardiomyocyte apoptosis and promoted angiogenesis by regulating autophagy, thereby improving MI.

Preference for Self-Resembling Male Faces in Gay Men in China.

Self-resemblance refers to couples with similar characteristics, also known as homogamy or positive assortative mating. Previous studies have indicated that heterosexual men and women prefer partners with similar facial features. In this study, we examined whether Chinese gay men preferred self-resemblance to faces. The participants (N = 70) completed a personal information questionnaire and preference selection task involving 10 pairs of self-resembling/control male faces. Ten pairs of self-resembling/control male faces of each participant were also rated by another gay man. The results revealed that the proportion of the participants who chose self-resembling faces was significantly higher than that of the control faces. However, the preference for "self-resembling" and control faces by other-rating was not significantly different. These findings indicate homogeneity in facial preferences among gay men.

Adaptation and Feasibility of the Mandarin Version of PEERS® for Autistic Adolescents.

PURPOSE: The Program for the Education and Enrichment of Relational Skills (PEERS®) is a group-based social skills training program for adolescents on the autism spectrum. Although the program has been shown to be effective in improving social skills in autistic adolescents, evidence of its effectiveness from the Mandarin-speaking Chinese population is sparse. The present study used a non-randomized, pre- and post-intervention research design to investigate the feasibility and cultural validity of the program, as well as examine the moderators of intervention outcomes. METHODS: Thirty-three autistic adolescents with intelligence quotient above 70 (Mage = 13.57, SDage = 1.43; Male: Female 25:8) and their parents received 14 concurrent 90-minute sessions. Adolescents' autistic traits, challenging behaviors, emotional functioning, socio-cognitive process, social environment factors (school support), and caregivers' well-being were evaluated. RESULTS: The findings suggest that with minor adjustments, the Mandarin version of PEERS® was generally acceptable and feasible for autistic adolescents and their parents. PEERS® may improve the social skills knowledge, reciprocal communication abilities, and emotional well-being of autistic adolescents. Also, participants with a higher level of school support, and parents with lower perceived subjective well-being at baseline may gain more benefits from PEERS®. The cultural adaptation and acceptability of the Mandarin Version of PEERS® were discussed. CONCLUSION: This feasibility study (Chinese Clinical Trial Registry: ChiCTR2200061417, 2022-06-23, retrospectively registered) provides a basis for further randomized control trials of the Mandarin version of PEERS®.

The therapeutic effect of wasp venom (Vespa magnifica, Smith) and its effective part on rheumatoid arthritis fibroblast-like synoviocytes through modulating inflammation, redox homeostasis and ferroptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Rheumatoid arthritis (RA) is a chronic inflammatory disease that is related to the aberrant proliferation of fibroblast-like synoviocytes (FLS). Wasp venom (WV, Vespa magnifica, Smith), an insect secretion, has been used to treat RA in Chinese Jingpo national minority's ancient prescription. However, the potential mechanisms haven't been clarified. AIM OF THE STUDY: The purposes of this paper were two-fold. First, to investigate which was the best anti-RA effective part of WV-I (molecular weight less than 3 kDa), WV-II (molecular weight 3-10 kDa) and WV-III (molecular weight more than 10 kDa) that were separated from WV. Second, to explore the underlying molecular mechanism of WV and WV-II that was best effective part in RA. MATERIALS AND METHODS: The wasps were electrically stimulated and the secretions were collected. WV-I, WV-II and WV-III were acquired by ultracentrifuge method according to molecular weight. Next, WV, WV-I, WV-II and WV-III were identified by HPLC. Functional annotation and pathway analysis of WV used to bioinformatics analysis. RNA-seq analyses were constructed to identify differentially expressed genes (DEGs). GO and KEGG pathway analyses were performed by Metascape database. STRING was used to analyze the PPI network from DEGs. Next, PPI network was visualized using Cytoscape that based on MCODE. The pivotal genes of PPI network and MCODE analysis were verified by qRT-PCR. Subsequently, MH7A cells were performed by MTT assay to evaluate the ability of inhibiting cell proliferation. Luciferase activity assay was conducted in HepG2/STAT1 or HepG2/STAT3 cells to assess STAT1/3 sensitivity of WV, WV-I, WV-II and WV-III. Additionally, interleukin (IL)-1ß and IL-6 expression levels were detected by ELISA kits. Intracellular thioredoxin reductase (TrxR) enzyme was evaluated by TrxR activity assay kit. ROS levels, lipid ROS levels and Mitochondrial membrane potential (MMP) were assessed by fluorescence probe. Cell apoptosis and MMP were measured by using flow cytometry. Furthermore, the key proteins of JAK/STAT signaling pathway, protein levels of TrxR and glutathione peroxidase 4 axis (GPX4) were examined by Western blotting assay. RESULTS: RNA-sequencing analysis of WV displayed be related to oxidation-reduction, inflammation and apoptosis. The data displayed that WV, WV-II and WV-III inhibited significantly cells proliferation in human MH7A cell line compared to WV-I treatment group, but WV-III had no significant suppressive effect on luciferase activity of STAT3 compared with IL-6-induced group. Combined with earlier reports that WV-III contained major allergens, we selected WV and WV-II further to study the mechanism of anti-RA. In addition, WV and WV-II decreased the level of IL-1ß and IL-6 in TNF-α-induced MH7A cells via inactivating of JAK/STAT signaling pathway. On the other hand, WV and WV-II down-regulated the TrxR activity to produce ROS and induce cell apoptosis. Furthermore, WV and WV-II could accumulate lipid ROS to induce GPX4-mediated ferroptosis. CONCLUSIONS: Taken together, the experimental results revealed that WV and WV-II were potential therapeutic agents for RA through modulating JAK/STAT signaling pathways, redox homeostasis and ferroptosis in MH7A cells. Of note, WV-II was an effective part and the predominant active monomer in WV-II will be further explored in the future.

Examine sex differences in autism spectrum disorder in school-aged children and adolescents with fluent language.

There are noteworthy sex disparities in the prevalence of autism spectrum disorders (ASD), while findings regarding the sex differences in core symptoms are inconsistent. There are few relevant studies on sex differences in mainland China. This study was dedicated to a deeper understanding of the impact of sex differences on the clinical presentation of ASD with fluent language. We retrospectively studied 301 children with ASD (58 females) and utilized raw scores from the ADI-R and ADOS and the intelligence quotient (IQ) to measure symptomatology. Based on the Full-Scale IQ (FS-IQ), a binary split of average, above-average IQ (high-IQ), and below-average IQ (low IQ) occurs at 85. Across the entire sample, males and females are comparable in the FS-IQ, while males scored higher in the Perceptual Reasoning Index (PRI) (F = 7.812, p = 0.006). ADI-R did not find any statistically significant sex differences in the diagnostic cutoff score satisfaction or the raw domain scores. While a significant effect of sex on ADOS social affect domain scores was found in the total sample [λ = 0.970, partial η2 = 0.030, F (3,295) = 3.019, p = 0.030]. Tests of between-subjects effects revealed that males scored higher than females mainly in the ADOS reciprocal social interaction subcategory (partial η2 = 0.022, F = 6.563, p = 0.011). Stratified analysis revealed that the effect of sex on ADOS reciprocal social interaction subcategory scores only significant in the low-IQ children with ASD (partial η2 = 0.092, F = 10.088, p = 0.002). In general, overall cognitive functioning is similar across males and females with ASD, while males have a higher perceptual reasoning ability. Females with ASD are more likely to have comorbid intellectual impairment than males, and they could require additional intervention support. Autistic children with low IQs are more likely to exhibit sex differences in their core symptoms than children with high IQs. Intelligence plays a key role in sex-based differences in the core symptoms of ASD.

Identifying activity level related movement features of children with ASD based on ADOS videos.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects about 2% of children. Due to the shortage of clinicians, there is an urgent demand for a convenient and effective tool based on regular videos to assess the symptom. Computer-aided technologies have become widely used in clinical diagnosis, simplifying the diagnosis process while saving time and standardizing the procedure. In this study, we proposed a computer vision-based motion trajectory detection approach assisted with machine learning techniques, facilitating an objective and effective way to extract participants' movement features (MFs) to identify and evaluate children's activity levels that correspond to clinicians' professional ratings. The designed technique includes two key parts: (1) Extracting MFs of participants' different body key points in various activities segmented from autism diagnostic observation schedule (ADOS) videos, and (2) Identifying the most relevant MFs through established correlations with existing data sets of participants' activity level scores evaluated by clinicians. The research investigated two types of MFs, i.e., pixel distance (PD) and instantaneous pixel velocity (IPV), three participants' body key points, i.e., neck, right wrist, and middle hip, and five activities, including Table-play, Birthday-party, Joint-attention, Balloon-play, and Bubble-play segmented from ADOS videos. Among different combinations, the high correlations with the activity level scores evaluated by the clinicians (greater than 0.6 with p < 0.001) were found in Table-play activity for both the PD-based MFs of all three studied key points and the IPV-based MFs of the right wrist key point. These MFs were identified as the most relevant ones that could be utilized as an auxiliary means for automating the evaluation of activity levels in the ASD assessment.

A multimodal machine learning system in early screening for toddlers with autism spectrum disorders based on the response to name.

Background: Reduced or absence of the response to name (RTN) has been widely reported as an early specific indicator for autism spectrum disorder (ASD), while few studies have quantified the RTN of toddlers with ASD in an automatic way. The present study aims to apply a multimodal machine learning system (MMLS) in early screening for toddlers with ASD based on the RTN. Methods: A total of 125 toddlers were recruited, including ASD (n = 61), developmental delay (DD, n = 31), and typical developmental (TD, n = 33). Procedures of RTN were, respectively, performed by the evaluator and caregiver. Behavioral data were collected by eight-definition tripod-mounted cameras and coded by the MMLS. Response score, response time, and response duration time were accurately calculated to evaluate RTN. Results: Total accuracy of RTN scores rated by computers was 0.92. In both evaluator and caregiver procedures, toddlers with ASD had significant differences in response score, response time, and response duration time, compared to toddlers with DD and TD (all P-values < 0.05). The area under the curve (AUC) was 0.81 for the computer-rated results, and the AUC was 0.91 for the human-rated results. The accuracy in the identification of ASD based on the computer- and human-rated results was, respectively, 74.8 and 82.9%. There was a significant difference between the AUC of the human-rated results and computer-rated results (Z = 2.71, P-value = 0.007). Conclusion: The multimodal machine learning system can accurately quantify behaviors in RTN procedures and may effectively distinguish toddlers with ASD from the non-ASD group. This novel system may provide a low-cost approach to early screening and identifying toddlers with ASD. However, machine learning is not as accurate as a human observer, and the detection of a single symptom like RTN is not sufficient enough to detect ASD.

The role of caregiver gestures and gesture-related responses of toddlers with autism spectrum disorder.

Autism spectrum disorder (ASD) is characterized by social communicative abnormalities. Deficits and delays in gestural communication are among the early deficits of ASD and also a major social modality in early caregiver-toddler interaction. Caregiver gestures have an important role in the cognitive and social development of children with ASD. Thus, it is urgent to further explore the role of caregiver gestures in early caregiver-toddler interaction. In this cross-sectional study, we observed the caregivers' gestures and responses of toddlers aged between 18 and 24 months during play (ASD = 44, TD = 29) and dining activities (ASD = 34, TD = 27). By observing the different frequencies and patterns of gestures by the caregiver-child interaction and the different proportions of children's responses to the caregiver's gestures, we found that, compared to caregivers of typically developing toddlers, caregivers of toddlers with ASD had fewer synchronized gestures and more unsynchronized gestures in the play activity and more supplementary gestures in dining activity. Toddlers with ASD produced more social responses to caregivers' synchronized gestures, whereas the use of synchronized gestures by the caregivers in caregiver-toddler interaction had a positive influence on social responses to toddlers with ASD. The findings suggest that effective use of gestures by caregivers during caregiver-toddler activities can improve children's social responses.

Adenylation domains of nonribosomal peptide synthetase: A potential biocatalyst for synthesis of dipeptides and their derivatives.

Dipeptides and their derivatives are important functional compounds that can be applied to fields such as medicine and food. As biological macromolecules, the adenylation domains of nonribosomal peptide synthetase (NRPS) can recognize and activate various building blocks, such as amino acids, for the biosynthesis of nonribosomal peptides. In this way, the amide bond formation can be achieved through a nucleophilic reaction where the adenylation domain serves as a biocatalyst and is further used to conduct dipeptide synthesis. In this study, the adenylation domains (BAA2, BBA2, and BCA4) of bacitracin synthetase were predicted and expressed. The substrate evaluation results showed that adenylation domains displayed broad substrate selectivity for amino acids in vitro. Furthermore, the use of dipeptide synthesis in adenylation domains suggested that the polarity of amino acids could have an influence on nucleophilic reactions. Finally, L-alanyl-L-glutamine and aspartame were successfully synthesized through catalysis by the adenylation domains BAA2 and BCA4, respectively. This study expands on approaches to the synthesis of functional dipeptides and their derivatives based on the chemoenzymatic process.

Design of composite nanosupports and applications thereof in enzyme immobilization: A review.

Enzyme immobilization techniques have developed dramatically over the past several decades. Support materials are key in shaping the function of a specific immobilized enzyme. Although they have large specific surface areas and functional active sites, single-component nanomaterials and their surface chemical modification derivatives struggle to meet increasing demand. Thus, composite materials, compounds of two or more materials, have been developed and applied in efficient immobilization through advances in materials science. More methods have been developed and employed to design composite nanomaterials in recent years. These novel composite nanomaterials often show superior physical, chemical, and biological performance as supports in enzyme immobilization, among other applications. In this review, immobilization techniques and their supports are stated first and methods to design and fabricate composite nanomaterials as nanosupports are also shown in the following section. Applications of composite nanosupports in laccase immobilization are discussed as models in the later sections of the paper. This review is intended to help readers gain insight into the design principles of composite nanomaterials for immobilization supports.

Preparation of Fucoidan-Based Electrospun Nanofibers and Their Interaction With Endothelial Cells.

Sulfated polysaccharide fucoidan (FD) is widely applied in biomedical applications owing to its outstanding bioactivities. In addition to the biochemical features, the architecture of biomaterials plays a critical role in tissue repair and regeneration. Particularly, nanofibers have elicited great interest due to their extracellular matrix-like structure, high specific surface area, and favorable biological properties. Herein, chitosan-modified FD/ultra-high molecular weight polyethylene oxide (UHMWPEO) nanofibers are developed via green electrospinning and electrostatic interaction for studying their interaction with endothelial cells. The appropriate solvent is screened to dissolve FD. The electrospinnability of FD/UHMWPEO aqueous solutions is greatly dependent on the weight ratios of FD/UHMWPEO. The incorporation of UHMWPEO significantly improves the electrospinnability of solution and thermo-stability of nanofibers. Also, it is found that there is good miscibility or no phase separation in FD/UHMWPEO solutions. In vitro biological experiments show that the chitosan-modified FD/UHMWPEO nanofibers greatly facilitate the adhesion of endothelial cells and inhibit the attachment of monocytes. Thus, the designed FD-based nanofibers are promising bio-scaffolds in building tissue-engineered blood vessels.

The Gestures in 2-4-Year-Old Children With Autism Spectrum Disorder.

Deficits in gestures act as early signs of impairment in social interaction (SI) and communication in children with autism spectrum disorder (ASD). However, the pieces of literature on atypical gesture patterns in ASD children are contradictory. This investigation aimed to explore the atypical gesture pattern of ASD children from the dimensions of quantity, communicative function, and integration ability; and its relationship with social ability and adaptive behavior. We used a semi-structured interactive play to evaluate gestures of 33 ASD children (24-48 months old) and 24 typically developing (TD) children (12-36 months old). And we evaluated the social ability, adaptive behavior, and productive language of ASD and TD children by using the Adaptive Behavior Assessment System version II (ABAS-II) and Chinese Communication Development Inventory (CCDI). No matter the total score of CCDI was corrected or not, the relative frequency of total gestures, behavior regulation (BR) gestures, SI gestures, and joint attention (JA) gestures of ASD children were lower than that of TD children, as well as the proportion of JA gestures. However, there was no significant group difference in the proportion of BR and SI gestures. Before adjusting for the total score of CCDI, the relative frequency of gestures without vocalization/verbalization integration and vocalization/verbalization-integrated gestures in ASD children was lower than that in TD children. However, after matching the total score of CCDI, only the relative frequency of gestures without vocalization/verbalization integration was lower. Regardless of the fact that the total score of CCDI was corrected or not, the relative frequency and the proportion of eye-gaze-integrated gestures in ASD children were lower than that in TD children. And the proportion of gestures without eye-gaze integration in ASD children was higher than that in TD children. For ASD children, the social skills score in ABAS-II was positively correlated with the relative frequency of SI gesture and eye-gaze-integrated gestures; the total score of ABAS-II was positively correlated with the relative frequency of total gestures and eye-gaze-integrated gestures. In conclusion, ASD children produce fewer gestures and have deficits in JA gestures. The deficiency of integrating eye gaze and gesture is the core deficit of ASD children's gesture communication. Relatively, ASD children might be capable of integrating vocalization/verbalization into gestures. SI gestures and the ability to integrate gesture and eye gaze are related to social ability. The quantity of gestures and the ability to integrate gesture with eye gaze are related to adaptive behavior. Clinical Trial Registration: www.ClinicalTrials.gov, identifier ChiCTR1800019679.

The Development of Brain Network in Males with Autism Spectrum Disorders from Childhood to Adolescence: Evidence from fNIRS Study.

In the current study, functional near-infrared spectroscopy (fNIRS) was used to collect resting-state signals from 77 males with autism spectrum disorders (ASD, age: 6~16.25) and 40 typically developing (TD) males (age: 6~16.58) in the theory-of-mind (ToM) network. The graph theory analysis was used to obtain the brain network properties in ToM network, and the multiple regression analysis demonstrated that males with ASD showed a comparable global network topology, and a similar age-related decrease in the medial prefrontal cortex area (mPFC) compared to TD individuals. Nevertheless, participants with ASD showed U-shaped trajectories of nodal metrics of right temporo-parietal junction (TPJ), and an age-related decrease in the left middle frontal gyrus (MFG), while trajectories of TD participants were opposite. The nodal metrics of the right TPJ was negatively associated with the social deficits of ASD, while the nodal metrics of the left MFG was negatively associated with the communication deficits of ASD. Current findings suggested a distinct developmental trajectory of the ToM network in males with ASD from childhood to adolescence.

Computer Simulations on a pH-Responsive Anticancer Drug Delivery System Using Zwitterion-Grafted Polyamidoamine Dendrimer Unimolecular Micelles.

Unimolecular micelles have attracted wide attention in the field of drug delivery because of their thermodynamic stability and uniform size distribution. However, their drug loading/release mechanisms at the molecular level have been poorly understood. In this work, the stability and drug loading/release behaviors of unimolecular micelles formed using generation-5 polyamidoamine-graft-poly(carboxybetaine methacrylate) (PAMAM(G5)-PCBMA) were studied by dissipative particle dynamics simulations. In addition, the unimolecular micelles formed using generation-5 polyamidoamine-graft-poly(ethyleneglycol methacrylate) (PAMAM(G5)-PEGMA) were used as a comparison. The simulation results showed that PAMAM(G5)-PCBMA can spontaneously form core-shell unimolecular micelles. The PAMAM(G5) dendrimer constitutes a hydrophobic core to load the doxorubicin (DOX), while the zwitterionic PCBMA serves as a protective shell to improve the stability of the unimolecular micelle. The DOX can be encapsulated into the cavity of PAMAM(G5) at the physiological pH 7.4. The drug loading efficiency and drug loading content showed some regularities with the increase in the drug concentration. At the acidic pH 5.0, the loaded DOX can be released gradually from the hydrophobic core. The comparison of DOX-loaded morphologies between the PAMAM(G5)-PCBMA system and PAMAM(G5)-PEGMA system showed that the former has better monodisperse stability. This work could offer theoretical guidance for the design and development of promising unimolecular micelles for drug delivery.

Selective Covalent Targeting of Anti-apoptotic BFL-1 by a Sulfonium-Tethered Peptide.

Anti-apoptotic B cell lymphoma 2 (BCL-2) family proteins are proven targets for human cancers. Targeting the BH3-binding pockets of these anti-apoptotic proteins could reactivate apoptosis in BCL-2-depedent cancers. BFL-1 is a BCL-2 family protein overexpressed in various chemoresistant cancers. A unique cysteine at the binding interface of the BH3 and BFL-1 was previously proven to be an intriguing targeting site to irreversibly inhibit BFL-1 functions with stabilized cyclic peptide bearing a covalent warhead. Recently, we developed a sulfonium-tethered peptide cyclization strategy to construct peptide ligands that could selectively and efficiently react with the cysteine(s) of target proteins near the interacting interface. Using this method, we constructed a BFL-1 peptide inhibitor, B4-MC, that could selectively conjugate with BFL-1 both in vitro and in cell. B4-MC showed good cellular uptake, colocalized with BFL-1 on mitochondria, and showed obvious growth inhibition of BFL-1 over-expressed cancer cell lines.

Effects of Picrasma quassioides and its active constituents on Alzheimer's disease in vitro and in vivo.

Alzheimer disease (AD), a prevalent neurodegenerative disorder, is one of the leading causes of dementia. However, there is no effective drug for this disease to date. Picrasma quassioides (D.Don) Benn, a Chinese traditional medicine, was used mainly for the treatment of inflammation, fever, microbial infection and dysentery. In this paper, we reported that the EtOAc extract of Picrasma quassioides stems showed potential neuroprotective activities in l-glutamate-stimulated PC12 and Aß25-35-stimulated SH-SY5Y cell models, as well as improved memory and cognitive abilities in AD mice induced by amyloid-ß peptide. Moreover, it was revealed that the anti-AD mechanism was related to suppressing neuroinflammatory and reducing Aß1-42 deposition using ELISA assay kits. To clarify the active components of the EtOAc extract of Picrasma quassioides stems, a systematic phytochemistry study led to isolate and identify six ß-carboline alkaloids (1-6), seven canthin-6-one alkaloids (7-13), and five quassinoids (14-18). Among them, four ß-carbolines (1-3, and 6) and six canthin-6-ones (7-11, and 13) exhibited potential neuroprotective activities in vitro. Based on these date, the structure-activity relationships of alkaloids were discussed. Furthermore, molecular docking experiments showed that compounds 2 and 3 have high affinity for both of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYPKIA) and butyrylcholinesterase (BuChE).