Novel biallelic SASS6 variants associated with primary microcephaly and fetal growth restriction.

Primary microcephaly is characterized by a head circumference prenatally or at birth that falls below three standard deviations from age-, ethnic-, and sex-specific norms. Genetic defects are one of the underlying causes of primary microcephaly. Since 2014, five variants of the SASS6 gene have been identified as the cause of MCPH 14 in three reported families. In this study, we present the genetic findings of members of a nonconsanguineous Chinese couple with a history of microcephaly and fetal growth restriction (FGR) during their first pregnancy. Utilizing trio whole-exome sequencing, we identified compound heterozygous variants involving a frameshift NM_194292.3:c.450_453del p.(Lys150AsnfsTer7) variant and a splice region NM_194292.3:c.1674+3A>G variant within the SASS6 gene in the affected fetus. Moreover, reverse transcriptase-polymerase chain reaction from RNA of the mother's peripheral blood leukocytes revealed that the c.1674+3A>G variant led to the skipping of exon 14 and an inframe deletion. To the best of our knowledge, the association between FGR and SASS6-related microcephaly has not been reported, and our findings confirm the pivotal role of SASS6 in microcephaly pathogenesis and reveal an expanded view of the phenotype and mutation spectrum associated with this gene.

Romboutsia lituseburensis JCM1404 supplementation ameliorated endothelial function via gut microbiota modulation and lipid metabolisms alterations in obese rats.

Our previous study revealed moderate-intensity exercise improved endothelial function associated with decreasing Romboutsia in rats on a high-fat diet. However, whether Romboutsia influences endothelial function remains unclear. The aim of this study was to determine the effects of Romboutsia lituseburensis JCM1404 on the vascular endothelium of rats under standard diet (SD) or high-fat diet (HFD). Romboutsia lituseburensis JCM1404 had a better improvement effect on endothelial function under HFD groups, while no significant effect on small-intestinal and blood vessel morphology. HFD significantly decreased villus height of small intestine and increased outer diameter and media thickness of the vascular tissue. After the treatments by R. lituseburensis JCM1404, the expression of claudin5 was increased in the HFD groups. Romboutsia lituseburensis JCM1404 was found to increase alpha diversity in the SD groups, with an increase in beta diversity in the HFD groups. The relative abundance of Romboutsia and Clostridium_sensu_stricto_1 was decreased significantly in both diet groups after R. lituseburensis JCM1404 intervention. The functions of human diseases and endocrine and metabolic diseases significantly downregulated in the HFD groups by Tax4Fun analysis. Furthermore, we found Romboutsia was significantly associated with bile acids, triglycerides, amino acids and derivatives and organic acids and derivatives in the SD groups, while Romboutsia was significantly associated with triglycerides and free fatty acid in the HFD groups. Romboutsia lituseburensis JCM1404 significantly upregulated several metabolism-related pathways by KEGG analysis in the HFD groups, including glycerolipid metabolism, cholesterol metabolism, regulation of lipolysis in adipocytes, insulin resistance, fat digestion and absorption, thermogenesis. Overall, R. lituseburensis JCM1404 supplementation ameliorated endothelial function via gut microbiota modulation and lipid metabolisms alterations in obese rats.

Case Report: Novel Biallelic Null Variants of SMPD4 Confirm Its Involvement in Neurodevelopmental Disorder With Microcephaly, Arthrogryposis, and Structural Brain Anomalies.

The SMPD4 gene encodes sphingomyelin phosphodiesterase 4, which preferentially hydrolyzes sphingomyelin over other phospholipids. The biallelic loss-of-function variants of SMPD4 have been identified in a group of children with neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies (NEDMABA). Here, we report a girl of Chinese ancestry with intrauterine growth restriction, microcephaly, postnatal developmental delay, arthrogryposis, hypertonicity, seizure, and hypomyelination on brain magnetic resonance imaging; biallelic null variants (c.1347C > G [p.Tyr449*]; Chr2 [GRCh37]: g.130877574_131221737del [whole-gene deletion]) were detected by whole-exome sequencing. Our case is the first report of NEDMABA of Chinese ancestry, confirming the involvement of SMPD4 in NEDMABA and expanding the mutation spectrum of this syndrome.

Moderate-Intensity Exercise Improves Endothelial Function by Altering Gut Microbiome Composition in Rats Fed a High-Fat Diet.

BACKGROUND: Obesity changes gut microbial ecology and is related to endothelial dysfunction. Although the correlation between gut microbial ecology and endothelial dysfunction has been studied in obese persons, the underlying mechanisms by which exercise enhances endothelial function in this group remain unclear. This study investigated whether exercise improves endothelial function and alters gut microbiome composition in rats fed a high-fat diet (HFD). METHODS: Obesity was induced by an HFD for 11 weeks. Whole-body composition and endothelium-dependent relaxation of mesenteric arteries were measured. Blood biochemical tests were performed, and gut microbiomes were characterized by 16S rRNA gene sequencing on an Illumina HiSeq platform. RESULTS: Exercise training for 8 weeks improved body composition in HFD-fed rats. Furthermore, compared with the untrained/HFD group, aerobic exercise significantly increased acetylcholine-induced, endothelium-dependent relaxation in mesenteric arteries (P < 0.05) and circulating vascular endothelial growth factor levels (P < 0.01) and decreased circulating C-reactive protein levels (P < 0.05). In addition, exercise and HFD resulted in alterations in the composition of the gut microbiome; exercise reduced the relative abundance of Clostridiales and Romboutsia. Moreover, 12 species of bacteria, including Romboutsia, were significantly associated with parameters of endothelial function in the overall sample. CONCLUSIONS: These results suggest that aerobic exercise enhances endothelial function in HFD-fed rats by altering the composition of the gut microbiota. These findings provide new insights on the application of physical exercise for improving endothelial function in obese persons.

Effects of exercise and diet intervention on appetite-regulating hormones associated with miRNAs in obese children.

AIMS: This study investigated the effects of exercise and diet intervention on appetite-regulating hormones and subjective appetite changes in obese children and examined expressions of specific key microRNAs (miRNA, miR). METHODS: 16 obese children were included in a training program consisting of exercise and diet intervention for 6 weeks. Before and after the intervention, fasting blood was collected to determine appetite-regulating hormones (leptin, ghrelin, and orexin) and miRNA (miR-103a-3p and miR-200a-3p) levels; eating behavior of the children was reported using the Children Eating Behavior Questionnaire (CEBQ). RESULTS: The level of orexin was significantly decreased (P < 0.05), while ghrelin was significantly enhanced (P < 0.05) after 6 weeks. The scores of food responsiveness (FR) and enjoyment of food (EF) of the CEBQ were significantly decreased (P < 0.05) after intervention. The changes of leptin and that of SR were significantly correlated (r = - 0.455, P < 0.05), and the correlation between the alterations of orexin and that of EF was moderate with significance (r = 0.625, P < 0.05). miR-103a-3p expression was not statistically changed, while miR-200a-3p was significantly inhibited after 6-week intervention (P < 0.05). The correlation between relative changes of miR-103a-3p and that of leptin and orexin were both with significant difference (r = 0.413, P < 0.05; r = 0.409, P < 0.05), whereas the alterations of miR-200a-3p were not correlative with hormones or appetite sensation. CONCLUSION: Exercise combined with diet intervention for 6 weeks was effective in regulating appetite sensations and hormones in obese children, and miR-103a-3p and miR-200a-3p might provide a foundation for target biomarkers of appetite trait in modulating the energy balance control by exercise and dietary intervention. LEVEL OF EVIDENCE: Level III, case-control analytic study. TRIAL REGISTRATION: The trial was registered in ClinicalTrials.gov (NCT03762629).

Dysfunction of perivascular adipose tissue in mesenteric artery is restored by aerobic exercise in high-fat diet induced obesity.

This study investigated the function of perivascular adipose tissue (PVAT) on vascular contractility within resistant arteries in high-fat diet induced obese rats after long-term aerobic exercise. Male Sprague-Dawley rats were subjected to normal diet control group (N-CTRL), normal diet exercise group (N-EX), high-fat diet control group (H-CTRL), and high-fat diet exercise group (H-EX) (n = 8 in each group). After intervention, adipose tissues morphology was observed. Vasomotor function of mesenteric arteries with or without PVAT were assessed; mesenteric PVAT isolated from each group were transferred to chambers bath with untreated vessels (without PVAT) to evaluate the independent effect. Isolated PVAT was further pre-treated with inhibitor of cystathionine-γ-lyase (CSE), a key hydrogen sulphide (H2 S) enzyme. Results showed that the size of lipid droplet around mesenteric arteries from H-EX was significantly reduced (P < .05); uncoupling protein1 (UCP1) in PVAT from H-EX was enhanced. In N-CTRL, N-EX, and H-EX, vessels without PVAT showed higher sensitivity to serotonin (5-HT) than that with intact PVAT. Vascular tension by 5-HT was significantly reduced in H-EX than H-CTRL (P < .05) in vessels with PVAT. Transferred PVAT from H-EX compared with H-CTRL significantly reduced vascular sensitivity to 5-HT (P < .05), and this effect was eliminated through inhibiting CSE. In summary, the anti-contractile effect of PVAT on resistance artery was impaired in obesity but restored by long-term aerobic exercise. The function of PVAT modified by obesity or by exercise has an independent influence on vascular reactivity, and PVAT derived H2 S may participate in this process.

Six-Week Exercise Training With Dietary Restriction Improves Central Hemodynamics Associated With Altered Gut Microbiota in Adolescents With Obesity.

Purpose: Obesity in children and in adolescents can lead to adult cardiovascular diseases, and the gut microbiota plays a crucial role in obesity pathophysiology. Exercise and diet interventions are typical approaches to improve physical condition and to alter the gut microbiota in individuals with obesity. However, whether central hemodynamic parameters including subendocardial viability ratio, the augmentation index standardized to a heart rate of 75/min (AIx75), resting heart rate, and blood pressure, correlate with gut microbiota changes associated with exercise and diet is unclear. Methods: Adolescents (n = 24, 12.88 ± 0.41 years) with obesity completed our 6-week program of endurance and strength exercises along with dietary restriction. Blood and fecal samples were collected, and physical parameters were measured before and 24 h after the last session of the intervention program. Pulse wave analysis using applanation tonometry provided the subendocardial viability ratio, a surrogate measure of microvascular myocardial perfusion, and AIx75, a measure of arterial stiffness and peripheral arteriolar resistance. Correlation analysis detected any associations of anthropometric or central hemodynamic parameters with gut microbiome composition. Results: Exercise and diet interventions significantly reduced body weight, body mass index, body fat, and waist-to-hip ratio, and lowered levels of fasting blood glucose, serum triglycerides, and high-density lipoprotein cholesterol. AIx75 and resting heart rate were also significantly reduced after the intervention without changes to systolic or diastolic blood pressure. The ratio of intestinal microbiota Firmicutes to Bacteroidetes displayed a marked increase after intervention. Interventional changes in gut microbiota members were significantly associated with anthropometric and metabolic parameters. Microbial changes were also significantly correlated with central hemodynamic parameters, including subendocardial viability ratio, AIx75, and resting heart rate. Conclusion: Exercise and diet interventions significantly improved measures of central hemodynamics, including subendocardial viability ratio, AIx75, and resting heart rate, which were correlated with altered gut microbiota in adolescents with obesity. Our findings shed light on the effects and mechanisms underlying exercise and diet interventions on obesity and suggest this approach for treating patients with both cardiovascular disease and obesity.

Carbon source self-heating: ultrafast, energy-efficient and room temperature synthesis of highly fluorescent N, S-codoped carbon dots for quantitative detection of Fe(iii) ions in biological samples.

In recent years, photoluminescent (PL) carbon dots (CDs) have attracted enormous attention because of their many fascinating properties. However, the traditional synthesis routes of PL CDs usually suffer from relatively low quantum yields (QYs) and require complicated operation processes as well as lots of externally supplied energy. Herein, we report a room temperature, green, ultrafast and energy-efficient route for large scale synthesis of highly PL N, S-codoped CDs without any external energy supply. The N, S-codoped CDs are prepared through a novel carbon source self-heating strategy, using the sole precursor tetraethylenepentamine (TEPA) simultaneously as the carbon, nitrogen and heat source, triggered by the heat initiator sodium persulfate (Na2S2O8). The large amount of heat released from Na2S2O8-triggered oxidation of TEPA could effectively promote the spontaneous polymerization and carbonization of TEPA precursors themselves as well as the in situ co-doping of sulfur, which had marked synergistic effects on the fluorescence enhancement of CDs, eventually leading to the high-yield (58.0%) preparation of highly fluorescent N, S-codoped CDs (QY 26.4%) at room temperature within 2 min. Moreover, the fluorescence of N, S-codoped CDs could be selectively quenched by Fe3+ ions in the presence of EDTA, in an ultra-wide range of 0.2-600 µM, with a detection limit of 0.10 µM. Ultimately, the fluorescent nanoprobe was successfully used for the quantitative detection of Fe3+ in human serum samples, indicating its great potential for sensing and biomedical applications.

Effects Of Exercise Training With Dietary Restriction On Arterial Stiffness, Central Hemodynamic Parameters And Cardiac Autonomic Function In Obese Adolescents.

PURPOSE: This study aimed to assess the effects of exercise with dietary restriction on arterial stiffness, central hemodynamics, and cardiac autonomic function in obese adolescents. PATIENTS AND METHODS: Twenty-one obese adolescents completed a 6-week exercise and dietary program. Body composition and metabolic parameters were measured. Carotid-femoral pulse wave velocity (cfPWV) and brachial-ankle pulse wave velocity (baPWV) were used to assess central and systemic arterial stiffness, respectively. Using applanation tonometry, the analyses of central hemodynamic parameters [central blood pressure, heart rate (HR), augmentation index normalized at 75 bpm (AIx75), and subendocardial viability ratio (SEVR)] were performed. To determine cardiac autonomic function, heart rate variability (HRV) was analyzed by standard deviation of normal R-R intervals (SDNN), root mean square of successive R-R interval differences (RMSSD), percentage of successive R-R intervals that differed by >50 ms (pNN50), total power (TP), low-frequency (LF) and high-frequency (HF) power, and LF/HF ratio. RESULTS: Following the intervention, obese adolescents had reductions in body mass index, body fat percentage, brachial systolic and diastolic blood pressure, and HR; and they had shown improvements in lipid profiles. There were reductions in both cfPWV and baPWV following the intervention. Moreover, there were reductions in AIx75, aortic systolic and diastolic blood pressure and an augmentation in SEVR after intervention. The intervention increased cardiac autonomic function (determined by increased SDNN, RMSSD, pNN50, HF, and reduced LF/HF). Furthermore, we observed a correlation between increased cardiac autonomic function (SDNN, RMSSD, pNN50 and HF) and increased central hemodynamics, as measured by SEVR and AIx75. CONCLUSION: Obese adolescents had increased central hemodynamics and autonomic function with reduced arterial stiffness after exercise and dietary restriction. Moreover, a positive correlation between an enhancement of cardiac autonomic function and an augmentation in central hemodynamics was found after the intervention.

[The cardiovascular protection of irisin and its research progress in sports field].

Irisin is a circulating myokine induced by exercise, which is a cleaved version of fibronectin type III domain containing protein 5 (FNDC5). It can promote the browning of white fat tissue, increase energy consumption, and decrease weight. Irisin plays an important role in the regulation of various diseases, such as diabetes and coronary heart disease. Different types of exercise have different effects on irisin level in blood circulation, and moderate exercise can reduce cardiovascular symptoms. In this paper, the cardiovascular protective effect of irisin and its research progress in the field of exercise are reviewed, hoping to provide a new target for the prevention and treatment of cardiovascular diseases.

[Genetic analysis of 10 children with cerebral palsy].

OBJECTIVE: To explore the genetic basis of cerebral palsy (CP). METHODS: A pair of twins with cerebral palsy and different phenotypes were subjected to whole genome sequencing, and other 8 children with CP were subjected to whole exome sequencing. Genetic variations were screened by a self-designed filtration process in order to explore the CP-related biological pathways and genes. RESULTS: Three biological pathways related to CP were identified, which included axon guiding, transmission across chemical synapses and protein-protein interactions at synapses, and 25 susceptibility genes for CP were identified. CONCLUSION: The molecular mechanism of CP has been explored, which may provide clues for development of new treatment for CP.

Melanin-mimetic multicolor and low-toxicity hair dye.

Most commercial permanent hair dyeing technologies are based on the oxidative process of p-phenylenediamine and its derivative materials. However, concerns about their toxicological issues have been raised throughout the years. Herein, we report an innovative surface coloration strategy for fabricating melanin-mimetic multicolor and low-toxicity hair dyes through sodium periodate-induced rapid deposition of eumelanin-like polydopamine (PDA) and pheomelanin-like PDA/cysteine co-deposited coatings on the hair surface. The color and morphology of the resulting hair were characterized in detail by several spectroscopy methods and the possible mechanism for the multi-coloring effects and structural differences of the melanin-mimetic coating was proposed. Our strategy eliminates the use of toxic dye precursors or organic solvents, and the favorable safety of the PDA-based formulations is demonstrated. The fabricated dyes can be applied to hair simply by combing, resulting in uniform multi-coloring effects within a short time. Furthermore, the melanin-mimetic hair dyes have excellent durability and ultraviolet protection performance. This work provides a facile and versatile methodology to develop the next generation of safe, sustainable and multicolor hair dyes and pave new avenues for advancing the field of surface coloration, nanoreactors, nanogenerators, energy storage materials and biomimetic sensing devices.

Redox modulation of polydopamine surface chemistry: a facile strategy to enhance the intrinsic fluorescence of polydopamine nanoparticles for sensitive and selective detection of Fe3.

In recent years, polydopamine (PDA) nanoparticles have attracted considerable attention in different research fields because of their many fascinating physicochemical properties. However, as an analogue of naturally occurring melanin, PDA nanoparticles (PDANPs) typically exhibit weak fluorescence properties. Herein, we report a facile one-pot method for synthesizing bright blue luminescent PDANPs through the redox modulation of PDA surface chemistry. The composition and morphology of the resultant NPs were systematically characterized by transmission electron microscopy and several spectroscopy methods, which verified the successful fabrication of PDANPs. More importantly, comparative chemical analysis of dopamine polymerization revealed the significant impacts of synthesis conditions and PDA surface chemistry on the luminescence properties of PDANPs. Remarkably, in addition to their excellent water-solubility, salt-tolerance and high photostability under extreme pH conditions, the as-prepared PDANPs possess the highest quantum yield (5.1%) among all the reported intrinsic fluorescent PDANPs. Moreover, based on the coordination interaction between phenolic hydroxyl groups of PDANPs and ferric ions (Fe3+), the synthesized PDANPs were successfully utilized as a turn-off sensing platform for sensitive and selective detection of Fe3+ without using any additional targeting molecules. Upon increasing the Fe3+ concentration in the range from 0.5 to 20 µM, the fluorescence intensity of PDANPs decreased linearly. The detection limit of Fe3+ was 0.15 µM. Finally, this fluorescent sensor was successfully used to determine Fe3+ in natural water samples, showing good prospects for practical applications and may pave the way for the development of new rational methodologies for further enhancing the intrinsic fluorescence of PDA and fabricating other novel fluorescent organic nanoparticles.

Identification of pathways and genes associated with cerebral palsy.

Cerebral palsy (CP) is a non-progressive neurological disease, of which susceptibility is linked to genetic and environmental risk factors. More and more studies have shown that CP might be caused by multiple genetic factors, similar to other neurodevelopmental disorders. Due to the high genetic heterogeneity of CP, we focused on investigating related molecular pathways. Ten children with CP were collected for whole-exome sequencing by next-generation sequencing (NGS) technology. Customized processes were used to identify potential pathogenic pathways and variants. Three pathways (axon guidance, transmission across chemical synapses, protein-protein interactions at synapses) with twenty-three genes were identified to be highly correlated with CP. This study showed that the three pathways associated with CP might be the molecular mechanism of pathogenesis. These findings could provide useful clues for developing pathway-based pharmacotherapies. Further studies are required to confirm potential roles for these pathways in the pathogenesis of CP.

Exercise training with dietary restriction enhances circulating irisin level associated with increasing endothelial progenitor cell number in obese adults: an intervention study.

OBJECTIVE: Circulating endothelial progenitor cells (EPCs) correlate negatively with obesity. Previous studies have shown that exercise significantly restores circulating EPC levels in obese people; however, the underlying mechanisms have not been elucidated. Recently, irisin has been reported to have a critical role in the regulation of EPCs. This exercise-induced myokine has been demonstrated to play a therapeutic role in obesity. In this study, we hypothesized that the increase in circulating irisin may form a link with increasing EPC levels in obese people after exercise. METHODS: Seventeen obese adults completed an 8-week program of combined exercise and dietary intervention. Clinical characteristics, blood biochemistry, and circulating irisin levels of subjects were measured before and after eight weeks of training. EPC levels were evaluated via flow cytometry, and EPC migratory and adhesive functions were also determined. RESULTS: Circulating irisin levels significantly increased following the 8-week training program (P < 0.05). We furthermore observed an improvement in EPC numbers (P < 0.05), and EPC migratory and adhesive functions (P < 0.001 and P < 0.05, respectively) after the intervention. Additionally, we detected a positive correlation between changes in irisin and changes in EPC number (r = 0.52, P < 0.05). DISCUSSION: For the first time, a positive correlation between increasing irisin levels and increasing EPC levels has been reported after an 8-week program, consisting of exercise and dietary intervention. This result suggests a novel effect of irisin on the regulation of EPC mobilization, which might contribute to improvement of endothelial function in obese people.