[Clinical and Mechanism Research Progress in Amelioration of Mild Cognitive Impairment via Meditation].

Mild cognitive impairment(MCI)has a high risk of progressing to dementia,with no recommended therapies.Recent studies have shown that meditation has huge potential to improve the cognitive function,with low cost and high safety,being suitable to be applied in the treatment of neurological and psychotic disorders.This paper reviews the application and prospects of meditation in treating MCI from the concept,clinical efficacy,and mechanism of meditation,aiming to provide reference for future clinical studies.

A pH-regulated fluorescence covalent organic framework for quantitative water content detection in methanol.

In this paper, we designed and synthesized a two-dimensional fluorescent covalent organic framework (TAPB-DMTP-COF) for the precise determination of H2O content in methanol. The COF was synthesized using two typical monomers by grinding method, which significantly reduced the synthesis time. By adjusting the pH value of the COF suspension to 4.0, the portion of the COF material structure is disrupted, thereby mitigating π-π stacking and resolving the aggregation-caused quenching (ACQ) effect. Consequently, the non-fluorescent TAPB-DMTP-COF exhibited blue-purple fluorescence emission in methanol. At the same time, it is observed that in the presence of H2O, there is a red shift in the maximum fluorescence emission peak of TAPB-DMTP-COF, which correlates with the H2O content within a specific range. Notably, this redshift demonstrates a linear relationship with H2O content from 4% to 80% in methanol. Our work presents novel insights for efficient analysis and detection of H2O content in methanol and could be used for H2O detection in other organic solvents.

Impact of the COVID-19 kindergarten closure on overweight and obesity among 3- to 7-year-old children.

BACKGROUND: Knowledge on the impact of the temporary kindergarten closure policy under COVID-19 in 2020 on childhood overweight and obesity is inadequate. We aimed to examine differences in rates of overweight and obesity from 2018 to 2021 among kindergarten children aged 3-7 years. METHODS: Overweight was defined as body mass index (BMI) > 1 standard deviation (SD) for age and sex, and obesity was defined as BMI > 2 SD for age and sex. Generalized linear mixed modeling was used for analysis. RESULTS: A total of 44,884 children and 71,216 growth data points from all 57 public kindergartens in Jiading District, Shanghai, China were analyzed. The rates of obesity from 2018 to 2021 were 6.9%, 6.6%, 9.5%, and 7.3% in boys and 2.8%, 2.8%, 4.5%, and 3.1% in girls, respectively. The rates of overweight from 2018 to 2021 were 14.3%, 14.3%, 18.2%, and 15.3% in boys and 10.6%, 10.9%, 13.9%, and 11.6% in girls. The rates of obesity and overweight among kindergarten children in 2020 were significantly higher than those in 2018, 2019, and 2021. Compared to 2020, the odds ratios of the obesity rate in 2018, 2019, and 2021 were 0.67 [95% confidence interval (CI) = 0.58-0.77, P < 0.001], 0.72 (95% CI = 0.64-0.80, P < 0.001) and 0.81 (95% CI = 0.72-0.92, P = 0.001), respectively. The odds ratios of the overweight rate in 2018, 2019, and 2021 were 0.75 (95% CI = 0.69-0.82, P < 0.001), 0.78 (95% CI = 0.72-0.84, P < 0.001), and 0.89 (95% CI = 0.81-0.97, P = 0.008), respectively, compared to 2020. CONCLUSIONS: The rates of overweight and obesity significantly increased among kindergarten children in 2020 after the 5-month kindergarten closure. It was critical to provide guidance to caregivers on fostering a healthy lifestyle for children at home under public health emergencies.

Dissolved Heavy Metal Pollution and Assessment of a Karst Basin around a Mine, Southwest China.

Karst water quality is one of the most important environmental issues in karst areas. The study's purpose was to investigate dissolved heavy metal pollution and health risk assessment in karst water basins around mines. River water and groundwater samples were analyzed by principal component analysis, correlation analysis, water quality index, hazard quotient, and hazard index. Median concentrations of dissolved heavy metals in the Sidi River were similar to the world average with a slightly alkaline characteristic. The concentrations of most dissolved heavy metals in river water were higher than those in groundwater. The concentrations of Zn, Pb, and Cd around the mine exceeded the limits of drinking water indicators. The poor water quality samples with high water quality index values were distributed around the mine. Lead (Pb), Zn, As, Cd, and Cr were potentially threatening metals in the study area. The pollution level of dissolved heavy metals in the Sidi River was at a medium level compared with other rivers worldwide. Principal component analysis and correlation analysis showed that Cu, Pb, Zn, Cd, Mn, Fe, As, and Sr mainly came from mine drainage; Ca2+, Mg2+, and Cr mainly came from the contribution of carbonate rocks; Na+ and K+ were related to local human agricultural activities. The concentrations of dissolved heavy metals in groundwater were affected by karst aquifers. The results of this study can provide a data reference for water resources prevention and human health protection in the Sidi River's karst basin and similar karst basins.

A novel ABCD1 G1202A mutation in a Chinese patient with pure adrenomyeloneuropathy and literature review.

Adrenomyeloneuropathy (AMN) is a kind of varied disease caused by ABCD1 gene mutation and characterized by very-long-chain fatty acids (VLCFA) accumulation. It is diagnosed by clinical features, high VLCFAs levels and ABCD1 gene mutation. AMN is rarely reported in Chinese population. In this study, we report the genetic and clinical features of a Chinese pure AMN patient. Meanwhile, we conducted a literature review of AMN cases to summarize the characteristics of AMN. We report a rare Chinese pure AMN case with slowly progressive weakness of the lower extremities, caused by a novel c.1202G > A mutation in ABCD1 gene. The literature review indicates that spastic paraplegia is the mainly clinical manifestation in patients with AMN. VLCFAs and ABCD1 gene test should be performed in patients with spastic paraplegia of the lower limbs to diagnose AMN.

Highly selective and rapid detection of silver ions by using a "turn on" non-fluorescent cysteine stabilized gold nanocluster probe.

Cysteine is widely used as a stabilizer for the preparation of fluorescent gold nanoclusters (Au NCs) with different fluorescence properties. Herein, by using cysteine as a stabilizer and controlling the synthesis conditions, a new non-fluorescent cysteine stabilized gold nanocluster (Cys-Au NCs) probe was prepared and a new strategy for "turning on" the fluorescence of the Cys-Au NCs was studied for rapid and selective detection of silver ions. In this strategy, the addition of silver ions to non-fluorescent Cys-Au NCs solution could quickly induce a visible fluorescence "turn on" phenomenon in 30 s. Further studies indicated that this fluorescence "turn on" phenomenon is specific for silver ions and the "turn on" fluorescence intensity has a linear relationship with the amount of silver ions in the range from 3.0 to 30.0 µM. Therefore, the non-fluorescent Cys-Au NCs were applied to the detection of silver ions in environmental water samples and a limit of detection (LOD) of 0.26 µM was obtained. This research sheds light on new applications of Au NCs and proposes a simple, rapid, sensitive, and visual method for the detection of metal ions.

Glutathione stabilized green-emission gold nanoclusters for selective detection of cobalt ion.

A glutathione stabilized Au nanoclusters (GSH-Au NCs) was synthesized here and used to selective detection of cobalt ion. The as-prepared GSH-Au NCs had strong green light emission around 500 nm, and the features of the NCs have been systematically characterized by UV-vis absorption, X-ray photoelectronic spectroscopic, Fourier transform infrared spectroscopy and transmission electron microscope characterization. The interactions between the GSH-Au NCs and metal ions was studied, and the results indicated that the fluorescence of the GSH-Au NCs could be quenched in the presence of Co2+ ion at pH of 6.0. The quenching ratio was linear with the concentration of Co2+ ions, and the calibration curve was I0/I = 0.1187cco + 0.6085 in the Co2+ concentration ranges from 2.0 to 50.0 µM with correlation coefficient (R2) of 0.9950 and the limit of detection (LOD, 3σ) of 0.124 µM. In addition, we collected environmental water samples to test the reliability of the method and demonstrated this method is simple, rapid, and selective.

Simultaneous Monitoring and Comparison of Multiple Product Quality Attributes for Cell Culture Processes at Different Scales Using a LC/MS/MS Based Multi-Attribute Method.

In response to the FDA's call for applying Quality by Design (QbD) to the manufacturing process, the biopharmaceutical industry has invested extensively into the monitoring and controlling of product quality attributes for bioprocesses. To assure the safety and efficacy of the drug product, defining critical quality attributes (CQA) and understanding their correlation with critical process parameters (CPP) becomes vitally important. In this work, a liquid chromatography-mass spectrometry based multi-attribute method (MAM) has been applied to the monitoring and trending of multiple CQAs of a monoclonal antibody product. To the best of our knowledge, this is the first demonstration of applying MAM to both a 3-liter development mini-bioreactor (3 L bioreactor) and a 2000-liter GMP single use bioreactor (2000L SUB). MAM was proven not only to be a great analytical tool for monitoring product quality attributes throughout the time course of the cell culture process, it could also provide critical product quality information in order to understand any potential process performance differences during scale-up and/or technology transfer. The successful monitoring and trending of the multiple CQAs throughout the 17-day cell culture process lays a solid foundation for possible real time in-process control and release of biotherapeutics using MAM in the future.

Rapid synthesis of cesium lead halide perovskite nanocrystals by l-lysine assisted solid-phase reaction at room temperature.

Nowadays, there are many ways to obtain cesium lead halide perovskite nanocrystals. In addition to the synthesis methods carried out in solution, the solid-phase synthesis was reported involving grinding and milling. In this paper, we synthesized luminescent CsPbBr3/Cs4PbBr6 perovskite nanocrystals (PNCs) by three solid-phase synthesis methods (grinding, knocking, stirring) using l-lysine as a ligand. This is the first attempt to use an amino acid for assisting the solid phase synthesis of perovskite and to study the difference in the products obtained by the three solid phase synthesis methods. The results show that the productivity of the solid-phase synthesis methods can be greatly improved by adding l-lysine and the perovskites obtained by the methods are more resistant to water due to the addition of l-lysine. The simplicity of the synthesis process expanded the use of solid-phase synthesis to obtain more perovskites and provided potential applications of perovskite in analytical detection and sensing in aqueous solution.

Fluorescent carbon quantum dots synthesized using phenylalanine and citric acid for selective detection of Fe3+ ions.

A facile, economical and one-step hydrothermal method was used to synthesize fluorescent carbon dots by utilizing citric acid as carbon source and phenylalanine to provide nitrogen. The as-prepared fluorescence carbon dots had strong blue light emission around 440 nm. As confirmed by UVvis absorption, X-ray photoelectron spectroscopic, Fourier transform infrared spectroscopy and transmission electron microscope characterization, the carbon dots were small and very stable in water for using as a fluorescent probe. It was also found that the fluorescence of the carbon dots could be quenched in the presence of Fe3+ ions, and the quenching rate was linear with the concentration of Fe3+ ions. We here proposed a static quenching mechanism about the fluorescence of the Phe-CDs could be selectively quenched by Fe3+ ions, which was because these Fe3+ ions could easily combine with the hydroxyl or carboxyl groups on the surface of Phe-CDs and induced aggregation. In addition, the pH had little effect on the fluorescence intensity of the Phe-CDs and maintained excellent fluorescence intensity even under extreme pH value conditions and could be used for the detection of Fe3+ ions. We have demonstrated that the method using the carbon dots for Fe3+ ions detection was rapid, reliable, and selective with a detection limit as low as 0.720 µM and a dynamic range from 5.0 to 500.0 µM. Moreover, the results of determination Fe3+ ions in tap water samples indicated that the presented method has potential for practical application in environmental metal analysis.

A Randomized, 8-Week Study of the Effects of Extended-Release Paliperidone and Olanzapine on Heart Rate Variability in Patients With Schizophrenia.

PURPOSE: This study aimed to explore the effect of extended-release paliperidone (paliperidone ER) and olanzapine on heart rate variability (HRV) in patients with schizophrenia. METHODS: A total of 106 patients with schizophrenia diagnosed by the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) were randomly divided into the paliperidone ER group or the olanzapine group for an 8-week clinical trial, with 53 patients in each group. The time domain and frequency domain analyses including the SD of all the R-R intervals in 24 hours (SDNN), the SD of the mean value of all the normal R-R intervals in every 5-minute interval within 24 hours (SDANN index), the mean value of the SD of all the normal R-R intervals in every 5-minute interval within 24 hours (SDNN index), the root mean square of successive R-R differences, the percentage of adjacent R-R intervals that differ by more than 50 milliseconds, high-frequency power (HF), low-frequency power (LF), and LF/HF were adopted to assess the HRV of patients at baseline and after treatment for 8 weeks in each group. The Positive and Negative Symptom Scale was used to evaluate the clinical efficacy. The incidence rates of adverse reactions were also calculated. RESULTS: In total, 48 patients in the paliperidone ER group and 45 patients in the olanzapine group completed the entire 8-week treatment. The SDNN, SDNN index, and SDANN index in the olanzapine group were significantly lower than those in the paliperidone ER group (P < 0.05) after treatment for 8 weeks, whereas their mean LF level was higher than that in the paliperidone ER group (P < 0.05) after completion of treatment. Patients in the olanzapine group showed a significant decrease in the SDNN, SDANN index, and SDNN index as well as a statistical increase in the LF and LF/HF in comparison with the pretreatment values (P < 0.05), whereas patients in the paliperidone ER group showed a decrease in the SDANN index and a statistical increase in the LF in comparison with the pretreatment values (P < 0.05). CONCLUSION: The HRV of patients with schizophrenia changes when they are administered with paliperidone ER or olanzapine, and more attention should be paid to their cardiac autonomic function when using these 2 antipsychotics.

Clinical evaluation of endoscopic anti-reflux mucosectomy for gastroesophageal reflux disease / 中华消化内镜杂志

Objective@#To assess the efficacy and safety of the endoscopic anti-reflux mucosectomy for gastroesophageal reflux disease.@*Methods@#Data of 18 patients with gastroesophageal reflux disease who underwent endoscopic anti-reflux mucosectomy at the First Affiliated Hospital of ZhengZhou University from December 2015 to July 2018 were retrospectively studied. The therapeutic effects (improvement of heartburn and reflux symptoms, 24 h esophageal pH monitoring) and complications were analyzed.@*Results@#Anti-reflux mucosectomy was performed successfully in all patients with successful rate of 100%. ESD was performed in 8 cases and EMR in 10 cases.24 h esophageal pH monitoring results showed that the Demeester score, the time percentage of pH < 4, total reflux events and reflux times of pH < 4 with time longer than 5 minutes after treatment were significantly lower than those before treatment (20.16±9.12 VS 74.16±20.03, (2.70±0.88)% VS (6.42±1.37)%, 43.78±19.68 VS 156.56±41.22, 2.89±1.68 VS 9.89±2.95, all P<0.05). No bleeding, perforation or infection was observed after the procedure. During a follow-up period of 3-34 months, symptom relief rate was 89% (16/18). A tightened cardiac was noted in 18 cases and recovery of mucosal damage was found in 16 patients.@*Conclusion@#Anti-reflux mucosectomy is safe, effective and easy to operate for gastroesophageal reflux disease.

Clinical evaluation of endoscopic anti-reflux mucosectomy for gastroesophageal reflux disease / 中华消化内镜杂志

Objective To assess the efficacy and safety of the endoscopic anti-reflux mucosectomy for gastroesophageal reflux disease. Methods Data of 18 patients with gastroesophageal reflux disease who underwent endoscopic anti-reflux mucosectomy at the First Affiliated Hospital of ZhengZhou University from December 2015 to July 2018 were retrospectively studied. The therapeutic effects ( improvement of heartburn and reflux symptoms, 24 h esophageal pH monitoring) and complications were analyzed. Results Anti-reflux mucosectomy was performed successfully in all patients with successful rate of 100％. ESD was performed in 8 cases and EMR in 10 cases. 24 h esophageal pH monitoring results showed that the Demeester score, the time percentage of pH < 4, total reflux events and reflux times of pH < 4 with time longer than 5 minutes after treatment were significantly lower than those before treatment (20. 16±9. 12 VS 74. 16±20. 03, (2. 70±0. 88)％ VS (6. 42±1. 37)％, 43. 78±19. 68 VS 156. 56±41. 22, 2. 89±1. 68 VS 9. 89±2. 95, all P<0. 05) . No bleeding, perforation or infection was observed after the procedure. During a follow-up period of 3-34 months, symptom relief rate was 89％ (16/18). A tightened cardiac was noted in 18 cases and recovery of mucosal damage was found in 16 patients. Conclusion Anti-reflux mucosectomy is safe, effective and easy to operate for gastroesophageal reflux disease.

Effects of timosaponin B-II on differentiation of rat neural stem cells into tyrosine hydroxylase posi-tive neurons in vitro / 中华行为医学与脑科学杂志

Objective To explore the effect of timosaponin B-II ( TB-II) on the differentiation of neural stem cells (NSCs) into tyrosine hydroxylase (TH) positive neurons in neonatal rats. Methods The biological functions of self-proliferation and multi-differentiation of NSCs were identified by primary culture, cell proliferation counting,morphological observation and immunology. NSCs of SD rats were cultured in vitro and treated with different concentrations of TB-II (10 μg/ml,30 μg/ml ,100 μg/ml) for 7 days. Immuno-histochemistry was used to detect the effect of TB-II on the differentiation of NSCs into TH-positive neurons, and Western blot was used to detect the expression of TH protein in neurons. Results ( 1) The cultured cells had the ability to self-proliferation,expressed nestin protein and differentiated into neurons and glial cells. So the cultured cells were conformed to the biological function of neural stem cells. (2)Compared with the control group,the TH positive cell ratio of TB-II 30 μg/ml group and TB-II 100 μg/ml group increased ((10. 03± 1. 36)%),( 20. 01± 3. 37)%),(31. 32± 3. 98)%) ,the difference was significant ( t=6. 15, 16. 54,both P<0. 05). There was no significant difference between TB-II 10 μg/ml group and control group (P>0. 05). (3)Western results showed that the relative expression of TH protein in TB-II 30 g/ml group and TB-II 100 μg/ml group was higher than that in control group,the difference was statistically significant (con-trol group: (1. 02±0. 24),TB-II 30μg/ml group: (3. 64±1. 78),TB-II 100 μg/ml group: (5. 88±2. 34);t=12. 58,9. 15,both P<0. 05). There was no significant difference between TB-II 10 μg/ml group and con-trol group (P>0. 05). Conclusion TB-II can promote the differentiation of NSCs into TH-positive neurons.

Influencing factors of the neurodevelopment of high-risk infants.

BACKGROUND: High-risk infants refer to newborns exposed to high-risk factors in the prenatal, natal or postnatal period. High-risk infants are at high risk of developmental retardation, and early identification of developmental abnormalities plays a vital role in improving high-risk infants' quality of life. AIMS: To describe the neurodevelopment of high-risk infants aged less than 1 year old, and to analyse the incidences and influencing factors of neurodevelopmental abnormalities in order to provide a basis for neurodevelopment monitoring and management of high-risk infants. METHODS: High-risk infants born between January 2016 and December 2016 in the maternity and infant health hospitals of three districts in Shanghai were followed up. The Gesell Developmental Scale was used to assess the neurodevelopmental level at the time of recruitment (0-2 months) and at 9 months. Univariate and multivariate analyses of the influencing factors were conducted. RESULTS: 484 high-risk infants (male 51%, female 49%) with an average gestation age of 36.5±2.2 weeks were recruited. At the time of recruitment, the average age was 2.1 (0.8) months, and the developmental quotient (DQ) scores of full-term high-risk infants in motor (t=3.542, p=0.001), cognitive (t=3.125, p=0.002), language (t=3.189, p=0.002) and social (t=3.316, p=0.001) areas were higher than those of preterm infants. The incidences of developmental abnormalities of full-term high-risk infants in motor (χ2 =9.452, p=0.002), cognitive (χ 2 =6.258, p=0.012), language (χ 2 =12.319, p =0.001) and social (χ 2 =6.811, p=0.009) areas were lower than the preterm infants. At 9 months, there was no difference in the DQ scores and incidences of developmental abnormalities in four areas between full-term and preterm high-risk infants, and the incidence of developmental abnormalities was around 10%. CONCLUSION: The incidence of neurodevelopmental abnormalities in high-risk infants aged less than 1 year old is high. Preterm birth and parental bad habits are significant factors affecting the neurodevelopment. Monitoring and early interventions help to improve high-risk infants' neurodevelopment.

Long-term efficacy of peroral endoscopic circular myotomy and full-thickness myotomy on treatment of achalasia of cardia / 中华消化内镜杂志

Objective To compare the long-term efficacy and complications of peroral endoscopic circular myotomy and full-thickness myotomy for patients with achalasia of cardia. Methods A retrospective analysis was performed on the data of 53 patients with achalasia of cardia, who underwent peroral endoscopic myotomy in the First Affiliated Hospital of Zhengzhou University from June 2012 to December 2014 and were followed-up regularly.Twenty-one patients underwent circular myotomy, and the other 32 patients underwent full-thickness myotomy. The postoperative long-term efficacy and gastroesophageal reflux complications of the two groups were compared. Results The effective rate of the circular myotomy group and the full-thickness myotomy group was 90. 5%( 19/21) and 100. 0%( 32/32), respectively ( P＝ 0. 152). There were no significant differences between the two groups on postoperative Eckardt scores, lower esophageal sphincter pressure and 4 s integrated relaxation pressure ( P ＞ 0. 05 ). The incidence of clinically relevant gastroesophageal reflux of full-thickness myotomy group was higher than that of circular myotomy group (40. 6% VS 14. 3%, χ2＝4. 174, P＝0. 041). Conclusion The long-term efficacy of circular myotomy is similar to that of full-thickness myotomy, but the incidence of clinically relevant gastroesophageal reflux is higher in full-thickness myotomy.

[Exploring the clinical characters of Shugan Jieyu capsule through text mining].

The study was main to explore the clinical characters of Shugan Jieyu capsule through text mining. The data sets of Shugan Jieyu capsule were downloaded from CMCC database by the method of literature retrieved from May 2009 to Jan 2016. Rules of Chinese medical patterns, diseases, symptoms and combination treatment were mined out by data slicing algorithm, and they were demonstrated in frequency tables and two dimension based network. Then totally 190 literature were recruited. The outcomess suggested that SC was most frequently correlated with liver Qi stagnation. Primary depression, depression due to brain disease, concomitant depression followed by physical diseases, concomitant depression followed by schizophrenia and functional dyspepsia were main diseases treated by Shugan Jieyu capsule. Symptoms like low mood, psychic anxiety, somatic anxiety and dysfunction of automatic nerve were mainy relieved bv Shugan Jieyu capsule.For combination treatment. Shugan Jieyu capsule was most commonly used with paroxetine, sertraline and fluoxetine. The research suggested that syndrome types and mining results of Shugan Jieyu capsule were almost the same as its instructions. Syndrome of malnutrition of heart spirit was the potential Chinese medical pattern of Shugan Jieyu capsule. Primary comorbid anxiety and depression, concomitant comorbid anxiety and depression followed by physical diseases, and postpartum depression were potential diseases treated by Shugan Jieyu capsule.For combination treatment, Shugan Jieyu capsule was most commonly used with paroxetine, sertraline and fluoxetine.

Benchmark integral neutron experiments for Fe, Be and C with DT neutron by liquid scintillation detector.

The measurements of iron, beryllium and carbon sphere neutron leakage spectra using BC501A detector by DT neutron source are presented. The experiments were carried out in Institute of Nuclear Physics and Chemistry (INPC), China. Neutron leakage spectra in a wide energy range at angles of 0° and 30° from the direction of incident deuteron beam were obtained. The results show the leakage neutron flux decreases notably with the spherical shell increasing when neutron energy >10MeV. When neutron energy <6MeV the leakage neutron distribution tends to lower energy side with the shell increase. The total uncertainty evaluation of the neutron spectra is also provided: in the high-energy parts the uncertainty is about 5-7%, while in the low-energy parts the uncertainty is about 7-9%. In order to compare the experiment results a Monte-carlo calculation was made using the MCNP5 Code with the ENDF/B-VII.1 nuclear data files.

TSC1 R509X Mutation in a Chinese Family with Tuberous Sclerosis Complex.

Tuberous sclerosis complex is a rare autosomal dominant disorder caused by mutations in either of TSC1 and TSC2 genes. Tuberous sclerosis complex presents diverse clinical characteristics, and either of TSC1 and TSC2 genes shows a wide range of mutations in their coding regions. However, the correlation between genotype and phenotype is yet unknown. We describe the clinical characteristics of a Chinese family with TSC1 gene mutation and present a literature review of Chinese patients with tuberous sclerosis complex gene mutation reported since 2004. This is the first report of TSC1 R509X mutation in a Chinese family, which might deepen our insight into the clinical and molecular pathogenesis of tuberous sclerosis complex.