Effects of a Nonwearable Digital Therapeutic Intervention on Preschoolers With Autism Spectrum Disorder in China: Open-Label Randomized Controlled Trial.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder that can cause difficulty with communication and social interactions as well as complicated family dynamics. Digital health interventions can reduce treatment costs and promote healthy lifestyle changes. These therapies can be adjunctive or replace traditional treatments. However, issues with cooperation and compliance prevent preschool patients with ASD from applying these tools. In this open-label, randomized controlled trial, we developed a nonwearable digital therapy called virtual reality-incorporated cognitive behavioral therapy (VR-CBT). OBJECTIVE: The aim of this study was to assess the adjunctive function of VR-CBT by comparing the effects of VR-CBT plus learning style profile (LSP) intervention with those of LSP-only intervention in preschool children with ASD. METHODS: This trial was performed in China on 78 preschool children (age 3-6 years, IQ>70) diagnosed with ASD who were randomized to receive a 20-week VR-CBT plus LSP intervention (intervention group, 39/78, 50%) or LSP intervention only (control group, 39/78, 50%). The primary outcome was the change of scores from baseline to week 20, assessed by using the parent-rated Autism Behavior Checklist (ABC). Secondary outcomes included the Childhood Autism Rating Scale (CARS), Attention-Deficit/Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV), and behavioral performance data (accuracy and reaction time) in go/no-go tasks. All primary and secondary outcomes were analyzed in the intention-to-treat population. RESULTS: After the intervention, there was an intervention effect on total ABC (ß=-5.528; P<.001) and CARS scores (ß=-1.365; P=.02). A similar trend was observed in the ABC subscales: sensory (ß=-1.133; P=.047), relating (ß=-1.512; P=.03), body and object use (ß=-1.211; P=.03), and social and self-help (ß=-1.593; P=.03). The intervention also showed statistically significant effects in improving behavioral performance (go/no-go task, accuracy, ß=2.923; P=.04). Moreover, a significant improvement of ADHD hyperactivity-impulsivity symptoms was observed in 53 children with comorbid ADHD based on ADHD-RS-IV (ß=-1.269; P=.02). No statistically significant intervention effect was detected in the language subscale of ABC (ß=-.080; P=.83). Intervention group girls had larger improvements in ABC subscales, that is, sensory and body and object use and in the CARS score and accuracy of go/no-go task (all P<.05) than the control group girls. Statistically significant intervention effects could be observed in hyperactivity-impulsivity symptoms in the intervention group boys with comorbid ADHD compared with those in the control group boys (ß=-1.333; P=.03). CONCLUSIONS: We found potentially positive effects of nonwearable digital therapy plus LSP on core symptoms associated with ASD, leading to a modest improvement in the function of sensory, motor, and response inhibition, while reducing impulsivity and hyperactivity in preschoolers with both ASD and ADHD. VR-CBT was found to be an effective and feasible adjunctive digital tool. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2100053165; http://www.chictr.org.cn/showproj.aspx?proj=137016.

Single-cell transcriptomics reveals lineage trajectory of human scalp hair follicle and informs mechanisms of hair graying.

Hair conditions, such as hair loss and graying, are prevalent human conditions. But they are often poorly controlled due to our insufficient understanding of human scalp hair follicle (hsHF) in health and disease. Here we describe a comprehensive single-cell RNA-seq (scRNA-seq) analysis on highly purified black and early-stage graying hsHFs. Based on these, a concise single-cell atlas for hsHF and its early graying changes is generated and verified using samples from multiple independent individuals. These data reveal the lineage trajectory of hsHF in unprecedented detail and uncover its multiple unexpected features not found in mouse HFs, including the presence of an innerbulge like compartment in the growing phase, lack of a discrete companion layer, and enrichment of EMT features in HF stem cells (HFSCs). Moreover, we demonstrate that besides melanocyte depletion, early-stage human hair graying is also associated with specific depletion of matrix hair progenitors but not HFSCs. The hair progenitors' depletion is accompanied by their P53 pathway activation whose pharmaceutical blockade can ameliorate hair graying in mice, enlightening a promising therapeutic avenue for this prevalent hair condition.

miR-24 controls the regenerative competence of hair follicle progenitors by targeting Plk3.

Maintaining a suitable level of sensitivity to environmental cues is crucial for proper function of adult stem cells. Here, we explore how the intrinsic sensitivity of skin hair follicle (HF) progenitors to growth stimuli is dynamically regulated. We discover miR-24 is an miRNA whose expression in HF progenitors inversely correlates with their growth potency in vivo. We show that its upregulation in adult skin epithelium leads to blunted responses of HF progenitors to growth cues and retards hair regeneration, while its conditional ablation leads to hyper-sensitized growth responsiveness of HF progenitors and precocious hair regeneration. Mechanistically, we find that miR-24 limits the intrinsic growth competence of HF progenitor by directly targeting Plk3, whose downregulation leads to reduced expression of CCNE1, a key cyclin for cell-cycle entry. These findings reveal an miRNA-mediated dynamic and cell-intrinsic mechanism used by HF progenitors to adapt their regenerative competence for different physiological conditions.

Effects of Combing Group Executive Functioning and Online Parent Training on School-Aged Children With ADHD: A Randomized Controlled Trial.

OBJECTIVE: The acceptance of drug treatment for younger children with attention-deficit/hyperactivity disorder (ADHD) in China remains low. Here, we explored the clinical benefits of a non-pharmaceutical intervention method combining a group and executive function training and an online parent training program, termed group executive functioning and online parent training (GEF-OPT), for school-aged students with ADHD through a randomized controlled trial. METHOD: A total of 145 children (aged 6-8 years) were formally registered and randomized to the intervention group (n = 73) and waitlist group (n = 72). The enrolled children received eight sessions of GEF-OPT treatment, which consists of a hospital-based children executive function (EF) training program and an online parent training program. Treatment outcome was assessed by a parent/teacher report questionnaire and neurophysiological experiment. RESULTS: After eight sessions of intervention, children in the intervention group showed a significant improvement in inattentive symptom compared to the waitlist group (14.70 ± 4.35 vs. 16.03 ± 2.93; p = 0.024), but an insignificant difference in hyperactive-impulsivity (9.85 ± 5.30 vs. 10.69 ± 5.10; p = 0.913). Comorbid oppositional defiant disorder was significantly reduced in the intervention group (7.03 ± 4.39 vs. 8.53 ± 4.41; p = 0.035). Children in the intervention group had greater reduction in the scores of behavioral regulation index (inhibition, emotional control) and metacognition index (working memory, planning/organization, monitoring) in executive function than those in the waitlist group (p < 0.05). Significant effects were also found in learning problem of Weiss Functional Impairment Scale-Parent form and parental distress between two groups at post-treatment (p < 0.05). In line with this, the result of go/no-go task showed significant improvements in accuracy change (4.45 ± 5.50% vs. 1.76 ± 3.35%; p = 0.001) and reaction time change (47.45 ± 62.25 s vs. 16.19 ± 72.22 s; p = 0.007) in the intervention group compared with the waitlist group. CONCLUSION: We conclude that participants in the GEF-OPT program improved outcomes for inattentive symptom, executive function, learning problems, and parental distress. GEF-OPT is a promising non-pharmaceutical therapeutic option for younger children. TRIAL REGISTRATION: ChiCTR2100052803.

A stress-induced miR-31-CLOCK-ERK pathway is a key driver and therapeutic target for skin aging.

Regressive changes in epithelial stem cells underlie mammalian skin aging, but the driving mechanisms are not well understood. Here, we report that mouse skin hair follicle stem cell (HFSC) aging is initiated by their intrinsic upregulation of miR-31, a microRNA that can be induced by physical injury or genotoxic stress and is also strongly upregulated in aged human skin epithelium. Using transgenic and conditional knockout mouse models plus a lineage-tracing technique, we show that miR-31 acts as a key driver of HFSC aging by directly targeting Clock, a core circadian clock gene whose deregulation activates a MAPK/ERK cascade to induce HFSC depletion via transepidermal elimination. Notably, blocking this pathway by either conditional miR-31 ablation or clinically approved MAPK/ERK inhibitors provides safe and effective protection against skin aging, enlightening a promising therapeutic avenue for treating skin aging and other genotoxic stress-induced skin conditions such as radiodermatitis.

Brain Development in Infants of Mothers With Gestational Diabetes Mellitus: A Diffusion Tensor Imaging Study.

OBJECTIVE: The objective of this study was to investigate clinical neurocognitive performance and microstructural white matter (WM) alterations in infants of mothers with gestational diabetes mellitus (GDM) using diffusion tensor imaging. MATERIALS AND METHODS: Infants (corrected gestational age, 33.42-36.00 weeks) of mothers with GDM (n = 31) and gestational age- and sex-matched unexposed controls (n = 31) accomplished 3-T diffusion tensor imaging scans and neurocognitive tests. Diffusion tensor imaging measures, mainly referring to fractional anisotropy (FA) values, were compared between 2 groups, and within-group analysis of correlation between FA values and neurocognitive testing outcomes in GDM-exposed infants was conducted subsequently. RESULTS: Fractional anisotropy was significantly decreased in the splenium of corpus callosum, posterior limb of internal capsule, thalamus in infants of mothers with GDM when compared with controls (P < 0.05), reflecting microstructural WM abnormalities in the GDM group. Decreased FA was associated with worse neurocognitive performance in the exposed group (P < 0.05). CONCLUSIONS: Individuals of mothers with GDM showed microstructural WM abnormalities in different brain regions, which were significantly related to worse neurocognitive performance. This might reveal that GDM directly insults the brain development of the offspring.

Influence of ignited sediments on external phosphorus adsorption and sedimentary phosphorus forms.

Phosphorus (P) adsorpted by sediments, when covered by and mixed with ignited sediments from Meiliang Bay in Tai Lake, was analyzed in the laboratory. Potassium dihydrogen phosphate (KH2PO4) was added to the parallel experimental units to simulate periodic external P input. Based on the Langmuir model, the sediments after ignition had a greater Smax (maximum P adsorption), a lower equilibrium phosphorus concentration at zero adsorption (EPC0), and a lower degree of phosphorus saturation in comparison with sediments without ignition. This was confirmed by the variation in the dissolved inorganic phosphorus in the overlying water. When sediments were mixed with or covered by the ignited sediments, 5.985 and 5.978 mg of input P disappeared from the overlying water, respectively. However, when the sediments were mixed with the ignited sediments, 84.18% of the input P was converted to HCl-P, whereas when they were covered by the ignited sediments, sedimentary P was released, mainly from Fe/Al-P (up to 87.50%). This was attributed to differences in the microenvironments where less-intense anaerobic conditions were formed in the mixed sediments than in the sediments covered by the ignited sediments. This suggests that the injection of ignited sediments into existing sediments enhances their P adsorption and retention. It is favor of the control of the eutrophication with a simple technology.

Efficient Generation of diRNAs Requires Components in the Posttranscriptional Gene Silencing Pathway.

It has been reported that double-stranded break (DSB)-induced small RNAs (diRNAs) are generated via the RNA-directed DNA methylation pathway and function in DSB repair in Arabidposis. However, important questions remain regarding the biogenesis and function of diRNAs. Here, we used CRISPR/Cas9- or TALEN-triggered DSBs to characterize diRNAs in Arabidopsis and rice. We found that 21-nt diRNAs were generated from a 35S promoter::GU-US reporter transgene targeted by CRISPR/Cas9. Unexpectedly, Pol II transcription of the transgene was required for efficient diRNA production and the level of diRNA accumulation correlated with the expression level of the transgene. diRNAs were not detected from CRISPR/Cas9- or TALEN-induced DSBs within the examined endogenous genes in Arabidopsis or rice. We also found that DCL4 and RDR6 that are known to be involved in posttranscriptional gene silencing were required to generate diRNAs. Our results suggest that DSBs are necessary but not sufficient for efficient diRNA generation and a high level of diRNAs is not necessary for DSB repair.

[Effect of Different Adding Means of Ignited Water Purification Sludge on Phosphorus Adsorption and Forms].

The adsorption of external phosphorus (P) and the distribution of dissolved inorganic P (DIP) in the sediment interstitial water and sedimentary P forms were researched under the ignited water purification sludge (IWPS) addition (mixing and capping). The results showed that the adsorption ability of the IWPS increased obviously, compared with the water purification sludge (WPS). It indicated that the Smax increased by 43.7%, the EPC0 decreased by 69.1% and the DPS decreased by 54.4%. The contribution of P disappearance in the overlying water had almost no difference between the mixing and capping with IWPS, but it was obviously higher than the control in both cases. Under the mixing condition, the adsorption of external P by unit IWPS was 2.3 times of that under the capping condition, if the contacting probability between the IWPS and the overlying water was considered. Under the capping condition, the DIP in the sediment interstitial water (1-2 cm) was 33.17 times (average) of that under the mixing condition. It was attributed to the decrease of the dissolved oxygen penetration due to capping. Under the mixing condition, the external P tended to form Ca-P, while the percentages of NH4Cl-P and Fe/Al-P to Tot-P were bigger under the capping condition. It was suggested that the improvement of the sedimentary microenvironment by mixing with the IWPS was favorable for the adsorption of the external P and the immobilization of the internal P.

[Distribution of Phosphorus Forms in the Overlying Water Under Disturbance with the Addition of Algae].

Distribution of different phosphorus (P) forms in the overlying water and the contribution of different algae to the P disappearance were investigated under disturbance with the addition of algae (Microcystis aeruginosa and Selenastrum capricornutum, respectively). The sediments and overlying water were taken from Meiliang Bay in Taihu Lake. The results showed that the concentrations of total P (TP), dissolved total P (DTP), dissolved inorganic P (DIP) and biavailable P (BAP) decreased with and without disturbance. The uptake of DTP and DIP by Microcystis aeruginosa was better than that of Selenastrum capricornutum under the disturbance, but it was the opposite without the disturbance. The disappearance of P in the overlying water was attributed completely to the physico-chemical adsorption of the suspended solids and the uptake of algae. But the contribution of suspended solids and algae depended on the disturbance. The contribution of Microcystis aeruginosa and Selenastrum capricornutum to DTP and DIP absorption was about 60% without disturbance. However, the value was reduced to 40% (Microcystis aeruginosa) and 25% ( Selenastrum capricornutum) under the disturbance. Under the disturbance and the action of algae, the distribution of sedimentary P forms changed. NH4 Cl-P and Ca-P release and Fe/Al-P increase were observed with and without disturbance. The decrease of NH4 Cl-P and Ca-P and the increase of Fe/Al-P were more obvious with disturbance than without disturbance. Selenastrum capricornutum was favor of the release of Ca-P and the formation of Fe/Al-P.

[Sedimentary Phosphorus Forms Under Disturbances and Algae in Taihu Lake].

Sedimentary phosphorus forms were investigated to clarify the release of sedimentary phosphorus forms under the repeated disturbance with the addition of algae at different initial concentrations. The sediments and overlying water were taken from the Meiliang Bay in Taihu Lake. The results showed that the concentrations of NH4 Cl-P and Res-P decreased, while the content of Fe/Al-P and Ca-P increased without disturbance. In addition, the Ca-P increased with the increase of the initial concentration of algae and the net increase of Ca-P increased by 48% (30 µg · L⁻¹), 66% (60 µg · L⁻¹), 74% (120 µg · L⁻¹), respectively. However, under the disturbance, the NH4Cl-P and Res-P were significantly reduced, the Fe/Al-P increased significantly. The percentage of Fe/Al-P to Tot-P was up to 66. 2% (average of the 3 experiments with the addition of algae of 30 µg · L⁻¹, 60 µg · L⁻¹ and 120 µg L-¹), it was higher than the value (53.%, average of the 3 experiments) without the disturbance. Moreover, under the disturbance, the percentage of Ca-P to Tot-P was 24.1% (average of the 3 experiments with the addition of algae of 30 µg · L⁻¹, 60 µg⁻¹ and 120 µg · L⁻¹) and it was slightly lower than that (33.0%, average of the 3 experiments) without the disturbance. It is suggested that the coexistence of disturbance and algae facilitated the formation of Fe/Al-P, but the algae accelerated the formation of Ca-P without disturbance.