Injectable nanocomposite hydrogels with enhanced lubrication and antioxidant properties for the treatment of osteoarthritis.

Osteoarthritis (OA) is a chronic inflammatory joint disease characterized by progressive cartilage degeneration, synovitis, and osteoid formation. In order to effectively treat OA, it is important to block the harmful feedback caused by reactive oxygen species (ROS) produced during joint wear. To address this challenge, we have developed injectable nanocomposite hydrogels composed of polygallate-Mn (PGA-Mn) nanoparticles, oxidized sodium alginate, and gelatin. The inclusion of PGA-Mn not only enhances the mechanical strength of the biohydrogel through a Schiff base reaction with gelatin but also ensures efficient ROS scavenging ability. Importantly, the nanocomposite hydrogel exhibits excellent biocompatibility, allowing it to effectively remove ROS from chondrocytes and reduce the expression of inflammatory factors within the joint. Additionally, the hygroscopic properties of the hydrogel contribute to reduced intra-articular friction and promote the production of cartilage-related proteins, supporting cartilage synthesis. In vivo experiments involving the injection of nanocomposite hydrogels into rat knee joints with an OA model have demonstrated successful reduction of osteophyte formation and protection of cartilage from wear, highlighting the therapeutic potential of this approach for treating OA.

Mitochondrial-Targeted Metal-Phenolic Nanoparticles to Attenuate Intervertebral Disc Degeneration: Alleviating Oxidative Stress and Mitochondrial Dysfunction.

As intervertebral disc degeneration (IVDD) proceeds, the dysfunctional mitochondria disrupt the viability of nucleus pulposus cells, initiating the degradation of the extracellular matrix. To date, there is a lack of effective therapies targeting the mitochondria of nucleus pulposus cells. Here, we synthesized polygallic acid-manganese (PGA-Mn) nanoparticles via self-assembly polymerization of gallic acid in an aqueous medium and introduced a mitochondrial targeting peptide (TP04) onto the nanoparticles using a Schiff base linkage, resulting in PGA-Mn-TP04 nanoparticles. With a size smaller than 50 nm, PGA-Mn-TP04 possesses pH-buffering capacity, avoiding lysosomal confinement and selectively accumulating within mitochondria through electrostatic interactions. The rapid electron exchange between manganese ions and gallic acid enhances the redox capability of PGA-Mn-TP04, effectively reducing mitochondrial damage caused by mitochondrial reactive oxygen species. Moreover, PGA-Mn-TP04 restores mitochondrial function by facilitating the fusion of mitochondria and minimizing their fission, thereby sustaining the vitality of nucleus pulposus cells. In the rat IVDD model, PGA-Mn-TP04 maintained intervertebral disc height and nucleus pulposus tissue hydration. It offers a nonoperative treatment approach for IVDD and other skeletal muscle diseases resulting from mitochondrial dysfunction, presenting an alternative to traditional surgical interventions.

Up-regulation of RAN by MYBL2 maintains osteosarcoma cancer stem-like cells population during heterogeneous tumor generation.

Intratumor heterogeneity is one of the major features of cancers, leading to aggressive disease and treatment failure. Cancer stem-like cells (CSCs) are believed to give rise to the heterogeneous cell types within tumors. Hence, understanding the regulatory mechanism underlying the recurrence process of heterogeneous tumor by CSCs could facilitate the development of CSC-targeted therapies. Here, utilizing single-cell transcriptomics, we present the molecular profile of osteosarcoma CSCs-derived heterogeneous tumors consisting of CSC clusters, osteoprogenitor and differentiated cell types, such as pre-osteoblasts, osteoblasts and chondroblasts. Furthermore, by constructing the comprehensive map of modulated genes during CSCs self-renewal and differentiation, we identify RAN exhibiting specific peak expression in osteosarcoma CSCs clusters which is transcriptionally up-regulated by MYBL2. Functionality, MYBL2-RAN pathway promotes the CSCs self-renewal by enhancing the nuclear accumulation of MYC protein, which in turn boosts the overexpression of RAN as a positive feedback. Importantly, blockage of MYBL2-RAN pathway sensitizes CSCs to cisplatin treatment and synergistically enhanced the cisplatin-induced cytotoxicity. Both MYBL2 and RAN are highly expressed in clinical osteosarcoma tissues which indicate poor prognosis. Collectively, our study provides advanced insights into the regeneration process of heterogeneous tumor originating from CSCs and highlights the MYBL2-RAN pathway as a promising target for CSC-based therapy in osteosarcoma.

Schedule risk model of water intake tunnel construction considering mood factors and its application.

The mood index [Formula: see text] was used to describe evaluator attitudes regarding the progress of a project that formed the basis of a construction period prediction model. The degrees of pessimism [Formula: see text] and optimism [Formula: see text] were introduced, and an analysis model was established using [Formula: see text] and [Formula: see text] to predict the construction period and completion probability Firstly, the absolute construction period of each process of tunnel No. 2 can be obtained according to the measured daily average footage of each process of tunnel No. 1. Secondly, the probability of the stoppage caused by different factors can be obtained after the statistical analysis of the factors responsible for the stoppage of tunnel No. 1. Finally, the expected construction period and completion probability of tunnel No. 2 under different pessimism and optimism conditions are obtained by using the progress risk analysis theory of emotional models and the program evaluation and review technique method. An engineering application showed that the expected construction period increased, and the completion probability decreased considerably with increasing pessimism; the opposite trend occurred as optimism increased. During the process of risk management and control, the prediction model can be used to perform precise quantitative analysis of the expected construction period and completion probability, reduce the blindness of construction management, control decisions of complex giant tunnel projects, and provide a more accurate basis for decision makers to judge risks. The findings of this study can be applied to hydraulic tunnels and can provide a reference for traffic tunnels, railway tunnels, and other similar projects.

Enhanced Mitochondrial Targeting and Inhibition of Pyroptosis with Multifunctional Metallopolyphenol Nanoparticles in Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IVDD) is a significant contributor to low back pain, characterized by excessive reactive oxygen species generation and inflammation-induced pyroptosis. Unfortunately, there are currently no specific molecules or materials available to effectively delay IVDD. This study develops a multifunctional full name of PG@Cu nanoparticle network (PG@Cu). A designed pentapeptide, bonded on PG@Cu nanoparticles via a Schiff base bond, imparts multifunctionality to the metal polyphenol particles (PG@Cu-FP). PG@Cu-FP exhibits enhanced escape from lysosomal capture, enabling efficient targeting of mitochondria to scavenge excess reactive oxygen species. The scavenging activity against reactive oxygen species originates from the polyphenol-based structures within the nanoparticles. Furthermore, Pyroptosis is effectively blocked by inhibiting Gasdermin mediated pore formation and membrane rupture. PG@Cu-FP successfully reduces the activation of the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 inflammasome by inhibiting Gasdermin protein family (Gasdermin D, GSDMD) oligomerization, leading to reduced expression of Nod-like receptors. This multifaceted approach demonstrates higher efficiency in inhibiting Pyroptosis. Experimental results confirm that PG@Cu-FP preserves disc height, retains water content, and preserves tissue structure. These findings highlight the potential of PG@Cu-FP in improving IVDD and provide novel insights for future research in IVDD treatments.

Loss of keratin 23 enhances growth inhibitory effect of melatonin in gastric cancer.

To investigate the effect of keratin 23 (KRT23) on the anticancer activity of melatonin (MLT) against gastric cancer (GC) cells, microarray analysis was applied to screen differentially expressed genes in AGS GC cells following MLT treatment. Western blotting was used to detect the expression of KRT23 in GC cells and normal gastric epithelial cell line GES­1. KRT23 knockout was achieved by CRISPR/Cas9. Assays of cell viability, colony formation, cell cycle, electric cell­substrate impedance sensing and western blotting were conducted to reveal the biological functions of KRT23­knockout cells without or with MLT treatment. Genes downregulated by MLT were enriched in purine metabolism, pyrimidine metabolism, genetic information processing and cell cycle pathway. Expression levels of KRT23 were downregulated by MLT treatment. Expression levels of KRT23 in AGS and SNU­216 GC cell lines were significantly higher compared with normal gastric epithelial cell line GES­1. KRT23 knockout led to reduced phosphorylation of ERK1/2 and p38, arrest of the cell cycle and inhibition of GC cell proliferation. Moreover, KRT23 knockout further enhanced the inhibitory activity of MLT on the tumor cell proliferation by inhibiting the phosphorylation of p38/ERK. KRT23 knockout contributes to the antitumor effects of MLT in GC via suppressing p38/ERK phosphorylation. In the future, KRT23 might be a potential prognostic biomarker and a novel molecular target for GC.

MiR-146b-5p enriched bioinspired exosomes derived from fucoidan-directed induction mesenchymal stem cells protect chondrocytes in osteoarthritis by targeting TRAF6.

Osteoarthritis (OA) is a common degenerative joint disease characterized by progressive cartilage degradation and inflammation. In recent years, mesenchymal stem cells (MSCs) derived exosomes (MSCs-Exo) have attracted widespread attention for their potential role in modulating OA pathology. However, the unpredictable therapeutic effects of exosomes have been a significant barrier to their extensive clinical application. In this study, we investigated whether fucoidan-pretreated MSC-derived exosomes (F-MSCs-Exo) could better protect chondrocytes in osteoarthritic joints and elucidate its underlying mechanisms. In order to evaluate the role of F-MSCs-Exo in osteoarthritis, both in vitro and in vivo studies were conducted. MiRNA sequencing was employed to analyze MSCs-Exo and F-MSCs-Exo, enabling the identification of differentially expressed genes and the exploration of the underlying mechanisms behind the protective effects of F-MSCs-Exo in osteoarthritis. Compared to MSCs-Exo, F-MSCs-Exo demonstrated superior effectiveness in inhibiting inflammatory responses and extracellular matrix degradation in rat chondrocytes. Moreover, F-MSCs-Exo exhibited enhanced activation of autophagy in chondrocytes. MiRNA sequencing of both MSCs-Exo and F-MSCs-Exo revealed that miR-146b-5p emerged as a promising candidate mediator for the chondroprotective function of F-MSCs-Exo, with TRAF6 identified as its downstream target. In conclusion, our research results demonstrate that miR-146b-5p encapsulated in F-MSCs-Exo effectively inhibits TRAF6 activation, thereby suppressing inflammatory responses and extracellular matrix degradation, while promoting chondrocyte autophagy for the protection of osteoarthritic cartilage cells. Consequently, the development of a therapeutic approach combining fucoidan with MSC-derived exosomes provides a promising strategy for the clinical treatment of osteoarthritis.

Organocatalytic Asymmetric Vinylogous Michael Addition of Electron-Deficient Aryl Alkane Nucleophiles to Enals.

We report herein a protocol for an organocatalyzed asymmetric vinylogous Michael addition of aryl alkane nucleophiles with enals under base- and additive-free conditions. A series of allylic building blocks were obtained in 60%-93% yield and 88-99% ee with 20 mol % diphenylprolinol silyl ether as catalyst. This protocol has advantages such as excellent chemoselectivity and regioselectivity, good tolerance of functionalities, and simple reaction conditions.

The Protective Effect of Marsdenia tenacissima against Cisplatin-Induced Nephrotoxicity Mediated by Inhibiting Oxidative Stress, Inflammation, and Apoptosis.

Cisplatin (Cis) is considered to be one of the most effective drugs for killing cancer cells and remains a first-line chemotherapeutic agent. However, Cis's multiple toxicities (especially nephrotoxicity) have limited its clinical use. Marsdenia tenacissima (Roxb.) Wight et Arn. (MT), a traditional Chinese medicine (TCM) employed extensively in China, not only enhances the antitumor effect in combination with Cis, but is also used for its detoxifying effect, as it reduces the toxic side effects of chemotherapy drugs. The aim of this study was to explore the therapeutic effect of MT on Cis-induced nephrotoxicity, along with its underlying mechanisms. In this study, liquid-mass spectrometry was performed to identify the complex composition of the extracts of MT. In addition, we measured the renal function, antioxidant enzymes, and inflammatory cytokines in mice with Cis-induced nephrotoxicity and conducted renal histology evaluations to assess renal injury. The expressions of the proteins related to antioxidant, anti-inflammatory, and apoptotic markers in renal tissues was detected by Western blotting (WB). MT treatment improved the renal function, decreased the mRNA expression of the inflammatory factors, and increased the antioxidant enzyme activity in mice. A better renal histology was observed after MT treatment. Further, MT inhibited the expression of the phospho-NFκB p65 protein/NFκB p65 protein (p-p65)/p65, phospho-inhibitor of nuclear factor kappa B kinase beta subunit/inhibitor of nuclear factor kappa B kinase beta subunit (p-IKKß/IKKß), Bcl-2-associated X (Bax), and Cleaved Caspase 3/Caspase 3 proteins, while the expression of nuclear factor-erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), Recombinant NADH Dehydrogenase, Quinone 1 (NQO1), and B-cell lymphoma-2 (Bcl-2) was increased. The present study showed that MT ameliorated renal injury, which mainly occurs through the regulation of the Nrf2 pathway, the NF-κB pathway, and the suppression of renal tissue apoptosis. It also suggests that MT can be used as an adjuvant to mitigate the nephrotoxicity of Cis chemotherapy.

Promoting healthy sleep in Chinese kindergarteners through a family-based intervention: protocol of the "Healthy Sleep" randomised controlled trial.

BACKGROUND: Sleep is instrumental for growth and development in children, making it critical to establish healthy sleep habits from the earliest years of life. Many kindergarteners (3-6 years) in China have inadequate and poor sleep, necessitating targeted interventions. This research protocol details the "Healthy Sleep" intervention that was designed to promote healthy sleep among kindergarteners in China. METHODS: The "Healthy Sleep" intervention will be family-based and will support parents as change agents. The development of the intervention is based on evidence regarding correlates of sleep in young children and guided by Bandura's social cognitive theory. A 12-month randomised controlled trial will be conducted to examine the efficacy of the intervention for promoting healthy sleep in Chinese kindergarteners and the intervention's effects on child development outcomes. A targeted sample of 160 kindergarteners and their parents will be recruited through social media. The intervention group (n = 80) will receive monthly webinars for one year that include multiple intervention components - including educational training, goal setting and planning, as well as follow-up support sessions. The control group (n = 80) will receive videos of the recorded educational sessions after the study end. For primary outcomes, child sleep behaviours will be examined using the Child Sleep Health Questionnaire. For secondary outcomes, communication, fine motor, gross motor, personal-social, and problem-solving development will be examined using the Ages and Stages Questionnaire; executive functions will be examined using the Head, Toes, Knees, and Shoulders Revised tasks. Potential intervention mediators and covariates will be measured using a parental questionnaire. Mixed models will be conducted. DISCUSSION: This intervention targets sleep behaviours among kindergarteners in China. It has the potential to inform programs to support parents in helping their child establish healthy sleep habits from the earliest years of life. The study will provide high-quality experimental evidence on sleep behaviours in relation to development outcomes in kindergarteners. This evidence will inform family-based strategies to optimise early childhood development and inform national and international updates of the sleep recommendations for young children. TRIAL REGISTRATION: The trial was registered prospectively at Chinese Clinical Trial Registry (ID: ChiCTR2300072105) on 2 June 2023.

1,1,1,3,3,3-Hexafluoroisopropanol (HFIP) Promoted N-Alkylation of Quinazolinones through Nucleophilic Substitution of Benzyl Alcohols.

We describe here a protocol for alkylation of quinazolinones with a series of primary or secondary alcohols under metal-free conditions. A class of quinazolinone derivatives were obtained in 31%-97% yield with good functional group tolerance. This protocol provides chemists a direct and effective way to obtain bioactive quinazolinone derivatives.

Surfactant-Tunable Nanoparticle Assembly via a Template-Directed Strategy.

Nanoparticle (NP) self-assembly from suspension evaporation has been a topic of interest in recent times to fabricate a solid-state structure with diverse functions. We present a simple and facile evaporation-induced strategy for the formation of NP arrays on a flat substrate utilizing a template-directed sandwich system. The lithographic features assist the assembly of the typical nanoparticles (NPs), including SiO2, QDs@PS FMs, and QDs, on the top into circle, stripe, triangle, or square geometries with a fixed width of 2 µm. Additionally, an anionic surfactant, sodium dodecyl sulfonate (SDS), is incorporated into a negatively charged, hydrophilic SiO2 dispersion to govern the aggregation and self-assembly of NPs, fine tuning the morphologies of the residual structures on the substrate. SDS is attributed to modify the nature of SiO2 NPs to be hydrophobic, increase the hydrophobic attraction, dominating particle-particle and particle-interface interactions, and strengthen the particle-particle repulsive electrostatic force that results in the reduction of SiO2 NPs trapped in the separated colloidal suspension drop. Thus, using the SDS surfactant with the concentration ranging from 0 to 1 wt %, the obtained well-ordered SiO2 NP pattern packing on the substrate varies from six layers to one layer.

Engineered high-strength biohydrogel as a multifunctional platform to deliver nucleic acid for ameliorating intervertebral disc degeneration.

Intervertebral disc degeneration (IVDD) is a leading cause of low back pain. The strategy of using functional materials to deliver nucleic acids provides a powerful tool for ameliorating IVDD. However, the immunogenicity of nucleic acid vectors and the poor mechanical properties of functional materials greatly limit their effects. Herein, antagomir-204-3p (AM) shows low immunogenicity and effectively inhibits the apoptosis of nucleus pulposus cells. Moreover, a high-strength biohydrogel based on zinc-oxidized sodium alginate-gelatin (ZOG) is designed as a multifunctional nucleic acid delivery platform. ZOG loaded with AM (ZOGA) exhibits great hygroscopicity, antibacterial activity, biocompatibility, and biodegradability. Moreover, ZOGA can be cross-linked with nucleus pulposus tissue to form a high-strength collagen network that improves the mechanical properties of the intervertebral disc (IVD). In addition, ZOGA provides an advantageous microenvironment for genetic expression in which AM can play an efficient role in maintaining the metabolic balance of the extracellular matrix. The results of the radiological and histological analyses demonstrate that ZOGA restores the height of the IVD, retains moisture in the IVD, and maintains the tissue structure. The ZOGA platform shows the sustained release of nucleic acids and has the potential for application to ameliorate IVDD, opening a path for future studies related to IVD.

Melatonin enhances anti-tumor immunity by targeting macrophages PD-L1 via exosomes derived from gastric cancer cells.

Melatonin (MLT) is a hormone with potential anti-tumor properties, but the molecular mechanisms remain unclear. The present study aimed to explore the effect of MLT on exosomes derived from gastric cancer cells, with the goal of gaining insight into its anti-tumor activity. Results from in vitro experiments showed that MLT was able to enhance the anti-tumor activity of macrophages that had been suppressed by exosomes from gastric cancer cells. This effect was achieved through regulation of the levels of PD-L1 in macrophages via modulation of the associated microRNAs in the cancer-derived exosomes. Furthermore, MLT treatment increased the secretion of TNF-α and CXCL10 by the macrophages. Besides, MLT treatment of gastric cancer cells led to the production of exosomes that promoted the recruitment of CD8+ T cells to the tumor site, resulting in inhibition of tumor growth. Collectively, these results provide evidence for the modulation of the tumor immune microenvironment by MLT through regulation of exosomes derived from gastric cancer cells, suggesting a potential role for MLT in novel anti-tumor immunotherapies.

Characteristics of tummy time and dose-response relationships with development in infants.

This study aimed to examine change in tummy time patterns and preferences in the first 6 months of life, as well as dose-response relationships between tummy time duration and development at 2, 4, and 6 months. Participants were parents of infants from the Early Movers project in Edmonton, Canada (baseline: n = 411). At 2, 4, and 6 months, infant tummy time duration and preference (i.e., 1 = really likes to 5 = really dislikes) and development (i.e., Ages & Stages Questionnaire (ASQ-3) communication, fine motor, gross motor, problem-solving, personal-social) were measured by a parental questionnaire. In a subsample (n = 127), tummy time patterns (i.e., bout frequency, mean and median bout length) were measured using a 3-day time-use diary. Tummy time bout frequency, bout length, and preference significantly increased over time. Linear dose-response relationships between tummy time duration and development outcomes were observed at 4 (gross motor) and 6 months (all development outcomes). Moreover, at 2 months, 30-44 min/day of tummy time was associated with a higher total development score (vs. < 15 min/day; B = 11.14; 95%CI: 1.60, 20.68). At 6 months, 61-120 min/day (vs. < 30 min/day; B = 27.12; 95%CI: 11.93, 42.32) and > 120 min/day (vs. < 30 min/day; B = 33.80; 95%CI: 18.90, 48.70) of tummy time were associated with higher total development scores. Differences in threshold doses between some developmental outcomes were observed. Conclusion: In the first 6 months of life, increases were observed in tummy time preference as well as tummy time bout frequent and length. This finding may explain why the optimal amount of tummy time needed for more advanced development appeared to increase with age. What is Known: • Tummy time is a type of physical activity in infancy. International and national guidelines recommend at least 30 minutes of tummy time per day for infants who are not yet mobile. What is New: • In the first six months of life, preference for tummy time as well as tummy time bout frequency and length increased. • Tummy time duration had dose-response associations with several development outcomes, and the optimal amount of tummy time needed for more advanced development appeared to increase with age.

Pupil calibration for pyramid wavefront sensors based on a wavefront corrector.

The pyramid wavefront sensor (PWS) presents numerous advantages, such as high energy utilization, exceptional spatial resolution, and adjustability. Precise calibration of the pupil's position and size in advance is essential for accurately extracting wavefront slope information from the captured pupil image by the PWS. What we believe to be a novel calibration method is proposed using a wavefront corrector to enhance the sharpness of the pupil images in the PWS. An experimental setup using a crystal spatial light modulator (SLM) is established to validate this method. Both physical experiments and simulated results demonstrate that our proposed method can achieve accurate calibration of the pupil image with an error within 4 pixels for pupil size and not exceeding 3 pixels for position, meeting practical application requirements. The proposed PWS calibration method exhibits excellent repeatability and robustness, making it directly applicable in astronomical adaptive optics systems.

Associations between demographic and parental factors and infant sleep characteristics.

Although sleep problems are highly prevalent in infants, the intrinsic and extrinsic factors that influence sleep consolidation and regulation in this age group are not well understood. This study aimed to examine the cross-sectional associations of demographic and parental factors with infant sleep characteristics. Participants were 97 Canadian mother-infant dyads primarily from Edmonton, Alberta. Demographic factors (e.g., infant age), parenting practices (e.g., sleep position, sleep initiation methods), and infants sleep characteristics (e.g., the frequency of nighttime awakenings) were assessed using the Brief Infant Sleep Questionnaire. Maternal sleep characteristics (e.g., nighttime sleep duration) were assessed using Actigraph accelerometers. Infant age (mean = 4.24 ± 2.90) was associated with most infant sleep characteristics. In multiple regression models for infant nighttime sleep duration, after removing influential observations, a negative association for side (vs. prone) sleep position was, respectively, observed. In multiple regression models for the frequency of nighttime awakenings in infants, positive associations for infants falling asleep while feeding (vs. in bed alone) and side (vs. prone) sleep position were consistently observed after removing influential observations. Lower nighttime sleep efficiency (B = - 0.08, 95%CI: - 0.13, - 0.02) and longer nighttime wake after sleep onset (B = 1.03, 95%CI: 0.41, 1.65) in mothers were associated with more frequent nighttime awakenings in infants. After removing influential observations, more frequent nighttime awakenings (B = 0.35; 95%CI: 0.09, 0.61) and longer total sleep duration (B = 0.33, 95%CI: 0.11, 0.55) in mothers were also associated with more frequent nighttime awakenings in infants. Sleep initiation methods with less parental involvement, and more continuous and efficient maternal nighttime sleep, tended to be associated with less interrupted infant sleep.

Adherence to Canadian 24-Hour Movement Guidelines among infants and associations with development: a longitudinal study.

BACKGROUND: To examine: 1) longitudinal adherence to the Canadian 24-Hour Movement Guidelines in a sample of infants and 2) associations between adherence to the guidelines over time and development. METHODS: Participants were 250 parent-infant dyads from the Early Movers project in Edmonton, Alberta. At 2, 4, and 6 months of age, physical activity, sedentary behaviour, sleep, and development were measured with a parental questionnaire that included items from the Ages & Stages Questionnaire (ASQ-3). Parents also reported the dates six major gross motor milestones were acquired during the first 18 months of life according to World Health Organization criteria. In a sub-sample (n = 93), movement behaviours were also measured with a time-use diary at 2, 4, and 6 months and gross motor development was measured by a physiotherapist using the Alberta Infant Motor Scale (AIMS) at 6 months. Guideline adherence was defined as: 1) ≥ 30 min/day of tummy time, 2) no screen time, some reading time, no restrained bouts > 1 h (time-use diary only), and 3) 14-17 h (2 months) or 12-16 h (4 and 6 months) of sleep per 24-h period. Generalized estimating equations were conducted as well as linear mixed models and linear regression models that adjusted for demographic characteristics. RESULTS: Few infants met the guidelines at all time-points (questionnaire: 2%; time-use diary: 0%). Infants that met a recommendation at 2 months, compared to those that did not, were 1.8-8.2 times more likely to meet that recommendation at subsequent time-points. Meeting more recommendations across time-points, according to both measures, was associated with a higher mean ASQ-3 gross motor score. Each additional time-point of tummy time recommendation adherence (questionnaire-measured) was associated with a 5-11-day earlier acquisition of independent sitting, crawling, and independent standing milestones. In the sub-sample, each additional time-point of guideline adherence was associated with a 16% higher AIMS score at 6 months. CONCLUSIONS: Guideline adherence was low across the first 6 months of infancy. Overall, meeting more recommendations over this period appeared important for gross motor development. Parents and caregivers should be targeted as early as possible with guideline dissemination and activation strategies to promote healthy infant development.

Nontargeted metabolomics study and pharmacodynamic evaluation of bidirectional fermentation for Ganoderma lucidum with Marsdenia tenacissima.

Lung cancer is one of the malignant tumors with the fastest incidence rate and mortality growth and the greatest threat to human health and life. Marsdenia tenacissima is an antitumor of Chinese medicine. However, Marsdenia tenacissima has low bioavailability in the human body and most of its main active substances are aglycones, such as Tenacigenin A, Tenacigenin B. This study aims to produce biotransformation products rich in pungent saponins by using Marsdenia tenacissima as a fermentation medium of Ganoderma lucidum. Non-targeted metabolomics analysis was carried out on the fermentation products after the optimization process. A total of 249 differential metabolites were detected, and the content of saponins increased from 0.1% to 0.41% and most of them were tenacigenin. Furthermore, the biotransformation of C21 steroidal glycosides in Marsdenia tenacissima was the central reaction in this fermentation process. Pharmacodynamics resewed that the anticancer effect of Marsdenia tenacissima was significantly enhanced after fermentation, mainly through inhibiting the growth and apoptosis of cancer cells.

RNA-Seq approach to investigate the effects of melatonin on bone marrow-derived dendritic cells from dextran sodium sulfate-induced colitis mice.

Melatonin (MLT) was reported to have therapeutic effects on inflammatory bowel disease (IBD) such as ulcerative colitis (UC) and Crohn's disease (CD) due to its anti-inflammatory and immunomodulatory properties. However, whether the beneficial effects of melatonin on colitis are through altering the immune response of bone marrow-derived dendritic cells (BMDCs) has not been well characterized. Here, we propose that MLT alleviates dextran sulfate sodium (DSS)-induced colitis in mice through its regulation of the immune response of BMDCs, in which some lncRNA, circRNA, miRNA, and mRNA may be involved. We at first established a DSS-induced colitis mouse model and found that the concentration of MLT in the serum of DSS-induced colitis mice was significantly lower than that in the control mice. Supplementation with MLT alleviated DSS-induced colitis in mice, which was reflected by preventing mouse body weight loss, colon length shortening, inflammation, and epithelial tissue destruction and abscission in the colon. We then isolated and cultured BMDCs and found that MLT could inhibit the activation of BMDCs from the colitis mice, which was reflected by reducing the phagocytotic ability of the cells, inhibiting their migration, and decreasing their secretion of pro-inflammatory cytokines. RNA sequencing results showed that MLT promoted the transformation of BMDCs into immune tolerant phenotypes in DSS-induced colitis mice through affecting non-coding RNAs (ncRNAs). Among them, lncRNA ENSMUST00000226323, circRNA-0520, and circRNA-2243 were predicted to interact with miRNA-709, and mRNAs of Ywhaz and Ccl9 were the targets of miRNA-709, all of which were involved in MLT-induced alteration of BMDCs functions in DSS-induced colitis mice via PI3K-Akt pathway. Our findings may provide some clues for understanding MLT inhibiting inflammatory response in DSS-induced colitis, which may be through alteration of BMDCs function.