One-year follow-up of the effectiveness and mediators of cognitive behavioural therapy among adults with attention-deficit/hyperactivity disorder: secondary outcomes of a randomised controlled trial.

BACKGROUND: The long-term effectiveness of cognitive behavioural therapy (CBT) in medicated attention-deficit/hyperactivity disorder (ADHD) adults with residual symptoms needs to be verified across multiple dimensions, especially with respect to maladaptive cognitions and psychological quality of life (QoL). An exploration of the mechanisms underlying the additive benefits of CBT on QoL in clinical samples may be helpful for a better understanding of the CBT conceptual model and how CBT works in medicated ADHD. METHODS: We conducted a secondary analysis of a randomised controlled trial including 98 medicated ADHD adults with residual symptoms who were randomly allocated to the CBT combined with medication (CBT + M) group or the medication (M)-only group. Outcomes included ADHD-core symptoms (ADHD Rating Scale), depression symptoms (Self-rating Depression Scale), maladaptive cognitions (Automatic Thoughts Questionnaire and Dysfunctional Attitude Scale), and psychological QoL (World Health Organization Quality of Life-Brief Version-psychological domain). Mixed linear models (MLMs) were used to analyse the long-term effectiveness at one-year follow-up, and structural equation modeling (SEM) was performed to explore the potential mechanisms of CBT on psychological QoL. RESULTS: ADHD patients in the CBT + M group outperformed the M-only group in reduction of ADHD core symptoms (d = 0.491), depression symptoms (d = 0.570), a trend of reduction of maladaptive cognitions (d = 0.387 and 0.395, respectively), and improvement of psychological QoL (d = - 0.433). The changes in above dimensions correlated with each other (r = 0.201 ~ 0.636). The influence of CBT on QoL was mediated through the following four pathways: 1) changes in ADHD core symptoms; 2) changes in depressive symptoms; 3) changes in depressive symptoms and then maladaptive cognitions; and 4) changes firstly in depressive symptoms, maladaptive cognitions, and then ADHD core symptoms. CONCLUSIONS: The long-term effectiveness of CBT in medicated ADHD adults with residual symptoms was further confirmed. The CBT conceptual model was verified in clinical samples, which would be helpful for a deeper understanding of how CBT works for a better psychological QoL outcome. TRIAL REGISTRATION: ChiCTR1900021705 (2019-03-05).

Efficacy of cognitive behavioural therapy in medicated adults with attention-deficit/hyperactivity disorder in multiple dimensions: a randomised controlled trial.

The study aimed to evaluate the efficacy of group cognitive behavioural therapy (CBT) in medicated adults with attention-deficit/hyperactivity disorder (ADHD) with a multidimensional evaluation and follow-up to week 36. Ninety-eight adult ADHD were randomly allocated to the CBT combined with medication (CBT + M) group or the medication (M) only group. The primary endpoint was the ADHD-Rating Scale (ADHD-RS). Secondary endpoints included emotional symptoms, self-esteem, automatic thoughts, quality of life (QoL), and executive function (EF). The outcome measures were obtained at baseline (T1), after the 12-week CBT treatment (T2), and at two follow-up time points (week 24, T3, and week 36, T4). Compared to the M-only group, the patients in the CBT + M group showed an overall significantly greater reduction from baseline in ADHD core symptoms (ADHD-RS total score at T3, and inattention subscale at T2 and T3), depression and anxiety symptoms (T2-T4), state anxiety (T2 and T3) and trait anxiety (T2), automatic thoughts questionnaire at T3, and QoL (physical domain, psychological domain, and social domain, most significant at T3 and weakened at T4). These findings further confirmed the efficacy of CBT on multiple dimensions and verified improvements in automatic thinking in adult ADHD. The superiority of the combination treatment mainly manifested in reduced inattention, emotional symptoms, and maladaptive thoughts and improved QoL. Trial registration number ChiCTR1900021705 (March-05-2019).

Interactions between MAOA and SYP polymorphisms were associated with symptoms of attention-deficit/hyperactivity disorder in Chinese Han subjects.

As candidate genes of attention--deficit/hyperactivity disorder (ADHD), monoamine oxidase A (MAOA), and synaptophysin (SYP) are both on the X chromosome, and have been suggested to be associated with the predominantly inattentive subtype (ADHD-I). The present study is to investigate the potential gene-gene interaction (G × G) between rs5905859 of MAOA and rs5906754 of SYP for ADHD in Chinese Han subjects. For family-based association study, 177 female trios were included. For case-control study, 1,462 probands and 807 normal controls were recruited. The ADHD Rating Scale-IV (ADHD-RS-IV) was used to evaluate ADHD symptoms. Pedigree-based generalized multifactor dimensionality reduction (PGMDR) for female ADHD trios indicated significant gene interaction effect of rs5905859 and rs5906754. Generalized multifactor dimensionality reduction (GMDR) indicated potential gene-gene interplay on ADHD RS-IV scores in female ADHD-I. No associations were observed in male subjects in case-control analysis. In conclusion, our findings suggested that the interaction of MAOA and SYP may be involved in the genetic mechanism of ADHD-I subtype and predict ADHD symptoms.

BAIAP2 exhibits association to childhood ADHD especially predominantly inattentive subtype in Chinese Han subjects.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a common chronic neurodevelopmental disorder with a high heritability. Much evidence of hemisphere asymmetry has been found for ADHD probands from behavioral level, electrophysiological level and brain morphology. One previous research has reported possible association between BAIAP2, which is asymmetrically expressed in the two cerebral hemispheres, with ADHD in European population. The present study aimed to investigate the association between BAIAP2 and ADHD in Chinese Han subjects. METHODS: A total of 1,397 ADHD trios comprised of one ADHD proband and their parents were included for family-based association tests. Independent 569 ADHD cases and 957 normal controls were included for case-control studies. Diagnosis was performed according to the DSM-IV criteria. Nine single nucleotide polymorphisms (SNPs) of BAIAP2 were chosen and performed genotyping for both family-based and case-control association studies. RESULTS: Transmission disequilibrium tests (TDTs) for family-based association studies showed significant association between the CA haplotype comprised by rs3934492 and rs9901648 with predominantly inattentive type (ADHD-I). For case-control study, chi-square tests provided evidence for the contribution of SNP rs4969239, rs3934492 and rs4969385 to ADHD and its two clinical subtypes, ADHD-I and ADHD-C. However, only the associations for ADHD and ADHD-I retained significant after corrections for multiplicity or logistic regression analyses adjusting the potential confounding effect of gender and age. CONCLUSIONS: These above results indicated the possible involvement of BAIAP2 in the etiology of ADHD, especially ADHD-I.

Bidirectional associations between maladaptive cognitions and emotional symptoms, and their mediating role on the quality of life in adults with ADHD: a mediation model.

Background/objectives: Adults with attention-deficit/hyperactivity disorder (ADHD) have more maladaptive cognitions, emotional problems and a poorer quality of life (QoL). A verification of the psychological model in clinical samples is needed for a better understanding of the mechanisms of ADHD diagnosis on QoL via maladaptive cognitions, emotional symptoms, and their interactions. Methods: 299 ADHD participants and 122 healthy controls were recruited. ADHD core symptoms, maladaptive cognitions, emotional symptoms and psychological QoL were rated. Pearson's correlation and structural equation modeling were analyzed to explore the relationship and influence of ADHD diagnosis on QoL. Results: More maladaptive cognitions, emotional symptoms, and poorer QoL were found in the ADHD group, and the dysfunctional attitudes were on par between ADHD with or without medication (p = 0.368). Moderate to strong correlations were found between emotional symptoms, maladaptive cognitions and QoL, and ADHD core symptoms presented correlations among the above scores (r = 0.157 ~ 0.416, p < 0.01) in ADHD participants. The influence of ADHD diagnosis on QoL was mediated through maladaptive cognitions, emotional symptoms, and their bidirectional interactions (p < 0.05), especially those with stable medication. Conclusion: Our study is the first to verify the psychological model in adults with ADHD in China. The findings determined the direct influence of ADHD diagnosis on QoL and the indirect influence through maladaptive cognitions, emotional symptoms, and their interactions, emphasizing the importance of interventions for emotional symptoms and maladaptive cognitions for ADHD patients both with or without medication for a better QoL outcome.

Multifunctional Probes with High Utilization Rates: Self-Assembled Merocyanine Nanoparticles in Water as Acid-Base Indicators and Mitochondrion-Targeting Chemotherapeutic Agents.

Multifunctional probes with high utilization rates have great value in practical applications in various fields such as cancer diagnosis and therapy. Here we have synthesized two organic molecules based on merocyanine. They can self-assemble in water to form ∼1.5 nm nanoparticles. Both of them have good application potential in fluorescent anticounterfeit printing ink and pH detection. More importantly, they have excellent mitochondrial targeting ability, intracellular red light and near-infrared dual-channel imaging ability, strong antiphotobleaching ability, and in vivo and in vitro near-infrared imaging capabilities, showing superior chemotherapy capabilities and biocompatibility in the 4T1 tumor-bearing mouse model.

Trait value and phenotypic integration contribute to the response of exotic Rhus typhina to heterogeneous nitrogen deposition: A comparison with native Rhus chinensis.

The temporal heterogeneity of nitrogen availability in soils is increasing due to agricultural deposition. We here compared the effects of gradually increasing nitrogen deposition rate and its increasing temporal heterogeneity patterns on the functional traits of seedlings of exotic species Rhus typhina and the native species Rhus chinensis. Nitrogen deposition rates of 0, 8, 20 g N m-2 year-1 and constant, single-peak, and double-peak nitrogen were added to simulate deposition rate and temporal heterogeneity. After 60 days of treatment, R. typhina seedlings had several advantageous growth trait values, such as higher total biomass production, but lower phenotypic plasticity than R. chinensis seedlings. R. typhina seedlings also had higher phenotypic integration, measured as the correlation among functional traits. The increased nitrogen deposition rate affected several traits of the two species differently. Thus, while R. chinensis seedlings allocated more biomass to leaves and less to roots with increasing N deposition, R. typhina seedlings had stable biomass allocation among all N treatments. Chlorophyll content, leaf phosphorus concentration, and water use efficiency increased, but the maximum net photosynthetic rate decreased, with N availability in R. chinensis, but not in R. typhina. Temporal heterogeneity had no significant effect on the total biomass of R. typhina and R. chinensis seedlings. Overall, the performance of R. typhina is better than that of R. chinensis seedlings under different nitrogen deposition treatments, which is due to the significantly advantageous trait values and greater phenotypic integration of R. typhina seedlings, whereas R. chinensis seedlings have higher phenotypic plasticity.

Association analyses of MAOA in Chinese Han subjects with attention-deficit/hyperactivity disorder: family-based association test, case-control study, and quantitative traits of impulsivity.

Monoamine oxidase A (MAOA) plays a critical role in the metabolism of monoamine neurotransmitters including serotonin (5-HT), norepinephrine (NE), and dopamine (DA). Genetic studies have found an association between MAOA and attention-deficit/hyperactivity disorder (ADHD), especially impulsivity. However, there has been inconsistency among studies which may be due to the complexity and heterogeneity of ADHD, including its sexual dimorphism and the presence of several subtypes. We conducted transmission disequilibrium tests (TDTs) in 1,253 trios and found no association between five single nucleotide polymorphisms (SNPs) of MAOA with ADHD in general or in the predominantly inattentive (ADHD-I) or combined types (ADHD-C), but with the predominantly hyperactive/impulsivity type (ADHD-HI). The association with MAOA was restricted to males, especially males with ADHD-HI. Logistic regression analyses of data from 1,824 cases and 957 controls did not indicate any association. We used analysis of covariance to analyze the association between MAOA genotype with the "inhibit" factor of the Behavior Rating Inventory of Executive Function (BRIEF) in 640 probands and performance on the Stroop test in 810 probands. Probands homozygous for risk alleles found in the TDT test had higher "inhibit" scores on the BRIEF scale which represents more severe impulsivity; this results also was restricted to males. No association was found with Stroop test performance. In conclusion, our results provide some evidence that MAOA may be associated with the ADHD-HI subtype and support the association between MAOA and impulsivity, which may be a potential endophenotype of ADHD. However, the results were strongly influenced by gender.

Dopamine ß-hydroxylase gene associates with stroop color-word task performance in Han Chinese children with attention deficit/hyperactivity disorder.

The cognitive deficits observed in attention deficit/hyperactivity disorder (ADHD) are candidate endophenotypes for genetic association studies. Dopamine ß-hydroxylase (DßH) converts dopamine to norepinephrine, and its activity is under strong genetic control. Prior studies suggest association between ADHD and DBH gene. The present study examined associations between a putative functional single nucleotide polymorphism (SNP) at DBH with performance on the Stroop task in patients with ADHD and in healthy control subjects. A total of 812 Han Chinese youths with DSM-IV ADHD and 233 unaffected controls were included in the study. Comprehensive phenotype data were collected, including performance on a series of Stroop interference tests examining inhibition of response to interfering stimuli. DBH SNP -1021C/T was genotyped using the 5'-exonuclease (TaqMan®) method. Compared to unaffected controls, children with ADHD performed significantly worse in all categories of the Stroop test. In ADHD cases, DBH genotype at -1021C/T significantly associates with reaction times of incongruent color word parts but not the interference times, with TT genotype performing significantly better in both reaction time and interference time than other two genotype groups. DBH genotype did not associate with cognitive performance in unaffected controls or in the combined group. DBH genotype at -1021C/T associates with differences in performance on the Stroop task in children with ADHD.

Relationship Between Childhood Left-Behind Experience and Quality of Life Among Chinese University Freshmen: Place of Origin Matters.

Background: Childhood left-behind experience (LBE) has a long-term detrimental effect on the mental health of Chinese University students, but it remains unclear whether childhood LBE negatively impacts the quality of life (QOL) of University students and whether the LBE-QOL association differs between students of rural origin and students of urban origin. This study examined the LBE-QOL relationship and the interactive effect between LBE and place of origin on QOL among Chinese University freshmen. Methods: By using a two-stage random cluster sampling approach, a total of 5,033 freshmen were recruited from two comprehensive universities. The students completed an online, self-administered questionnaire that included sociodemographic variables, a 2-week physical morbidity assessment, and assessments of depressive symptoms, academic stress, and QOL. The Chinese six-item QOL scale was used to assess QOL. Multiple linear regression was used to test the independent LBE-QOL association and the interaction between LBE and place of origin. Results: Students with childhood LBE had significantly lower QOL scores than those without LBE (60.1 ± 13.1 vs. 64.3 ± 11.7, p < 0.001). After adjusting for the potential confounding effects of other sociodemographic variables, 2-week physical morbidity, depressive symptoms, and academic stress, childhood LBE was significantly associated with a lower QOL score (ß: -3.022, p < 0.001) and the LBE-place of origin interaction was still significantly associated with the QOL score (ß: -2.413, p < 0.001). Overall, compared to non-LBE, LBE was associated with a QOL score decrease of 5.93 among freshmen of urban origin and of 3.01 among freshmen of rural origin. Conclusion: In Chinese University freshmen, childhood LBE is independently associated with poor QOL, and the LBE-QOL association is greater among freshmen from urban backgrounds than among freshmen from rural backgrounds.

Enzymatic acylation of rutin with benzoic acid ester and lipophilic, antiradical, and antiproliferative properties of the acylated derivatives.

Rutin (3',4',5,7-tetrahydroxy-flavone-3-rutinoside) was enzymatically acylated with benzoic acid and its esters (methyl benzoate and vinyl benzoate) using Thermomyces lanuginosus lipase (Lipozyme TLIM). The acylation reaction was optimized by varying the reaction medium, reaction temperature, acyl donor, substrate molar ratio, and reaction time. The highest conversion yield (76%) was obtained in tert-amyl alcohol (60 °C, 72 hr) using vinyl benzoate (molar ratio of 1:10) as acyl donor. The acylation occurred at the 2'''-OH and 4'''-OH of the rhamnose unit and the 2''-OH position of the glucose moieties. Three novel rutin acylated derivatives (compounds 1-3) were purified and characterized by HR-MS and 1D and 2D NMR spectroscopy. We found that acylation significantly improved lipophilicity, capacity to inhibit lipid peroxidation, anticancer capacity and substantially maintained the antioxidant activity of rutin. This research provides important insights in the acylation of flavonoids with different glycosyl moieties. PRACTICAL APPLICATION: In this study, three novel rutin derivatives were successfully synthesized and the highest conversion yield (76%) was obtained by reacting the rutin and vinyl benzoate at molar ratio of 1:10 in tert-amyl alcohol for 72 hr at 60 °C. Introducing a benzoic acid substituent into rutin molecule significantly improved their lipophilicity and inhibition of lipid peroxidation in lipophilic system. Furthermore, this study demonstrated that acylation significantly improved anticancer capacity and substantially maintained the antioxidant activity.

Cortical Morphometric Abnormality and Its Association with Working Memory in Children with Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in children and adolescents. The present study investigated the cortical morphology features and their relationship with working memory (WM). METHODS: In the present study, a total of 36 medication naïve children with ADHD (aged from 8 to 15 years) and 36 age- and gendermatched healthy control (HC) children were included. The digit span test was used to evaluate WM. The magnetic resonance imaging (MRI) was used to examine the characteristics of cortical morphology. Firstly, we compared the cortical morphology features between two groups to identify the potential structural alterations of cortical volume, surface, thickness, and curvature in children with ADHD. Then, the correlation between the brain structural abnormalities and WM was further explored in children with ADHD. RESULTS: Compared with the HC children, the children with ADHD showed reduced cortical volumes in the left lateral superior temporal gyrus (STG) (p=6.67×10-6) and left anterior cingulate cortex (ACC) (p=3.88×10-4). In addition, the cortical volume of left lateral STG was positively correlated with WM (r=0.36, p=0.029). CONCLUSION: Though preliminary, these findings suggest that the reduced cortical volumes of left lateral STG may contribute to the pathogenesis of ADHD and correlate with WM in children with ADHD.

Enzymatic acylation of lutein with a series of saturated fatty acid vinyl esters and the thermal stability and anti-lipid oxidation properties of the acylated derivatives.

Lutein was enzymatically acylated with saturated fatty acid vinyl esters of different lengths of carbon chain (C6 -C14 ) under the action of Candida antarctica lipase B (Novozyme 435). The acylation reaction was optimized by considering substrate molar ratio, reaction solvent, type of enzyme, and reaction time. The highest yield (88%) was obtained using the Novozyme 435 to catalyze the acylation reaction of lutein and vinyl decanoate (lutein/vinyl decanoate molar ratio of 1/10) for 16 h in methyl tert-butyl ether. Ten lutein esters were synthesized, isolated, and purified, which were characterized by Fourier-transform infrared spectroscopy, high-resolution mass spectrometry, and nuclear magnetic resonance spectroscopy. We found that the acylation of lutein improved its antioxidant capacity in lipid system and thermal stability. Our study extended the potential application of lutein in lipophilic food, cosmetic, and pharmaceutical industries. Practical Application: Enzyme acylation of lutein improved its antioxidant capacity in lipid system and thermal stability, extended its potential application in food, cosmetic, and pharmaceutical industries. In addition, our study also provided a new perspective and cognition for the further development and utilization of lutein.

A potential association of RNF219-AS1 with ADHD: Evidence from categorical analysis of clinical phenotypes and from quantitative exploration of executive function and white matter microstructure endophenotypes.

AIMS: Attention-deficit/hyperactivity disorder (ADHD) is a neuropsychiatric disorder of substantial heritability, yet emerging evidence suggests that key risk variants might reside in the noncoding regions of the genome. Our study explored the association of lncRNAs (long noncoding RNAs) with ADHD as represented at three different phenotypic levels guided by the Research Domain Criteria (RDoC) framework: (i) ADHD caseness and symptom dimension, (ii) executive functions as functional endophenotype, and (iii) potential genetic influence on white matter architecture as brain structural endophenotype. METHODS: Genotype data of 107 tag single nucleotide polymorphisms (SNP) from 10 candidate lncRNAs were analyzed in 1040 children with ADHD and 630 controls of Chinese Han descent. Executive functions including inhibition and set-shifting were assessed by STROOP and trail making tests, respectively. Imaging genetic analyses were performed in a subgroup of 33 children with ADHD and 55 controls using fractional anisotropy (FA). RESULTS: One SNP rs3908461 polymorphism in RNF219-AS1 was found to be significantly associated with ADHD caseness: with C-allele detected as the risk genotype in the allelic model (P = 8.607E-05) and dominant genotypic model (P = 9.628E-05). Nominal genotypic effects on inhibition (p = 0.020) and set-shifting (p = 0.046) were detected. While no direct effect on ADHD core symptoms was detected, mediation analysis suggested that SNP rs3908461 potentially exerted an indirect effect through inhibition function [B = 0.21 (SE = 0.12), 95% CI = 0.02-0.49]. Imaging genetic analyses detected significant associations between rs3908461 genotypes and FA values in corpus callosum, left superior longitudinal fasciculus, left posterior limb of internal capsule, left posterior thalamic radiate (include optic radiation), and the left anterior corona radiate (P FWE corrected  < 0.05). CONCLUSION: Our present study examined the potential roles of lncRNA in genetic etiological of ADHD and provided preliminary evidence in support of the potential RNF219-AS1 involvement in the pathophysiology of ADHD in line with the RDoC framework.

Changes of Hypocretin (Orexin) System in Schizophrenia: From Plasma to Brain.

Hypocretin (also called orexin) regulates various functions, such as sleep-wake rhythms, attention, cognition, and energy balance, which show significant changes in schizophrenia (SCZ). We aimed to identify alterations in the hypocretin system in SCZ patients. We measured plasma hypocretin-1 levels in SCZ patients and healthy controls and found significantly decreased plasma hypocretin-1 levels in SCZ patients, which was mainly due to a significant decrease in female SCZ patients compared with female controls. In addition, we measured postmortem hypothalamic hypocretin-1-immunoreactivity (ir), ventricular cerebrospinal fluid (CSF) hypocretin-1 levels, and hypocretin receptor (Hcrt-R) mRNA expression in the superior frontal gyrus (SFG) in SCZ patients and controls We observed a significant decrease in the amount of hypothalamic hypocretin-1 ir in SCZ patients, which was due to decreased amounts in female but not male patients. Moreover, Hcrt-R2 mRNA in the SFG was decreased in female SCZ patients compared with female controls, while male SCZ patients showed a trend of increased Hcrt-R1 mRNA and Hcrt-R2 mRNA expression compared with male controls. We conclude that central hypocretin neurotransmission is decreased in SCZ patients, especially female patients, and this is reflected in the plasma.

Adult ADHD, executive function, depressive/anxiety symptoms, and quality of life: A serial two-mediator model.

BACKGROUND: Adult attention-deficit/hyperactivity disorder (ADHD) is associated with impaired executive function (EF), depressive/anxiety symptoms, and poor quality of life (QoL). In this study, we aimed to investigate correlations among these variables and to build a simple or serial mediation model for exploring the mechanisms between adult ADHD and QoL. METHODS: This was a cross-sectional study. The sample included 223 participants with ADHD and 54 healthy volunteers. Participants were required to complete the following scales: ADHD Rating Scale (ADHD-RS), Brief Version of the World Health Organization Quality of Life Scale (WHOQOL-BREF), Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A), Self-rating Depression Scale (SDS) and Self-rating Anxiety Scale (SAS). Correlations among EF, depressive/anxiety symptoms and QoL were analyzed using Pearson correlation. The simple and serial mediation models were analyzed using PROCESS (version 3.3). RESULTS: The correlations between EF and QoL, depressive/anxiety symptoms and QoL, and depressive/anxiety symptoms and EF were statistically significant. In ADHD adults with comorbidities, the correlation coefficients were between -0.19 and -0.47, -0.20 and -0.62, 0.28 and 0.50, respectively. In simple mediation models, EF and depressive/anxiety symptoms were significant mediators respectively between ADHD and QoL, respectively. In a serial two-mediator model, ADHD could affect QoL indirectly via EF and then via depressive/anxiety symptoms significantly. LIMITATIONS: The average age was young, the degree of education was high, and only self-reported scales were relied on. CONCLUSIONS: There is a mutual effect between EF and emotional symptoms. This was the first study to build a serial two-mediator model between ADHD and QoL, suggesting the importance of EF and depressive/anxiety symptoms.

Mutant Allele Frequency-Based Intra-Tumoral Genetic Heterogeneity Related to the Tumor Shrinkage Mode After Neoadjuvant Chemotherapy in Breast Cancer Patients.

The shrinkage mode of tumor extent after neoadjuvant chemotherapy (NAC) is an important index to evaluate the odds of breast-conserving surgery. However, there is no sufficient measurement to predict the shrinkage mode after NAC. In this study, we analyzed 24 patients' formalin-fixed, paraffin-embedded samples before and after treatment and analyzed 456 cancer-related genes panel by using target next-generation sequencing. Meanwhile, the pathological shrinkage mode was reconstructed in three dimensions after surgery, and the genetic heterogeneity level was estimated by mutant-allele tumor heterogeneity (MATH). We measured the genetic intra-tumor heterogeneity and explored its correlation with the shrinkage mode after NAC. A total of 17 matched pair samples of primary tumor tissue and residual tumor tissue were successfully accessed. It was found that the most common mutated genes were TP53 and PIK3CA in both samples before and after NAC, and no recurrent mutations were significantly associated with the shrinkage mode. Besides, the MATH value of formalin-fixed, paraffin-embedded samples before and after NAC was analyzed by the area under the curve of the receiver operating characteristic, and it is feasible to classify patients into concentric shrinkage mode and non-concentric shrinkage mode in NAC based on the MATH threshold of 58. Our findings indicate that the MATH value was associated with the shrinkage mode of breast cancer in a non-linear model. Patients with the MATH value below the threshold of 58 before and after NAC displayed a concentric shrinkage mode. The area under the curve was 0.89, with a sensitivity of 0.69 and specificity of 1. Our study might provide a promising application of intra-tumor heterogeneity that is measured by MATH to make a choice of surgery.

Discovery of new genetic loci for male sexual orientation in Han population.

Epidemiological studies have demonstrated that the genetic factors partly influence the development of same-sex sexual behavior, but most genetic studies have focused on people of primarily European ancestry, potentially missing important biological insights. Here, we performed a two-stage genome-wide association study (GWAS) with a total sample of 1478 homosexual males and 3313 heterosexual males in Han Chinese populations and identified two genetic loci (rs17320865, Xq27.3, FMR1NB, Pmeta = 8.36 × 10-8, OR = 1.29; rs7259428, 19q12, ZNF536, Pmeta = 7.58 × 10-8, OR = 0.75) showing consistent association with male sexual orientation. A fixed-effect meta-analysis including individuals of Han Chinese (n = 4791) and European ancestries (n = 408,995) revealed 3 genome-wide significant loci of same-sex sexual behavior (rs9677294, 2p22.1, SLC8A1, Pmeta = 1.95 × 10-8; rs2414487, 15q21.3, LOC145783, Pmeta = 4.53 × 10-9; rs2106525, 7q31.1, MDFIC, Pmeta = 6.24 × 10-9). These findings may provide new insights into the genetic basis of male sexual orientation from a wider population scope. Furthermore, we defined the average ZNF536-immunoreactivity (ZNF536-ir) concentration in the suprachiasmatic nucleus (SCN) as lower in homosexual individuals than in heterosexual individuals (0.011 ± 0.001 vs 0.021 ± 0.004, P = 0.013) in a postmortem study. In addition, compared with heterosexuals, the percentage of ZNF536 stained area in the SCN was also smaller in the homosexuals (0.075 ± 0.040 vs 0.137 ± 0.103, P = 0.043). More homosexual preference was observed in FMR1NB-knockout mice and we also found significant differences in the expression of serotonin, dopamine, and inflammation pathways that were reported to be related to sexual orientation when comparing CRISPR-mediated FMR1NB knockout mice to matched wild-type target C57 male mice.

[Mechanisms of the mechanically activated ion channel Piezo1 protein in mediating osteogenic differentiation of periodontal ligament stem cells via the Notch signaling pathway].

OBJECTIVE: To explore the mechanism of Piezo1 protein in mediating the osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs) via the Notch signaling pathway. METHODS: In this study, young permanent teeth extracted from impacted teeth of 8-14-year-old children from January 1, 2016 to January 1, 2018 in the Department of Orthodontic, Beijing Children's Hospital were selected as cell sources. hPDLSCs were extracted by enzymatic digestion. Immunohistochemical staining was used to detect the expression of keratin and vimentin, and flow cytometry was used to identify the markers (CD146 and STRO-1) of hPDLSCs. The construction and screening of Piezo1 siRNA gene interference vector and Piezo1 gene overexpression plasmid were completed. Flexcell 4000T mechanical distraction stress instrument was used to construct hPDLSC cell model in vitro. According to the preliminary results, the experiment was divided into five groups: siRNA interference group, overexpression group, blank control group, stretch stress group, and negative control group. Real time quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression of Piezo1, Notch1, alkaline phosphatase (ALP), Runt-related transcription factor 2 (Runx2), osteocalcin (OCN), and bone sialoprotein (BSP). Western blot was used to detect the expression of ALP and Runx2. Fluo-3 AM probe was used to detect intracellular calcium content. RESULTS: Vimentin staining of hPDLSCs was positive, and keratin staining was negative. Flow cytometry was used to detect the expression of STRO-1 and CD146, markers of hPDLSC. Empty viral vectors, siRNA-Piezo1 interference sequence, and Piezo1 overexpression vector sequence could be transfected into hPDLSC by lentivirus, and the transfection efficiency was high (approximately 90%). The reverse transcription-polymerase chain reaction (RT-PCR) results showed that there were significant differences in Piezo1 gene levels among the siRNA interference group, overexpression group, blank control group, stretch stress group, and negative control group (F=9.573, P<0.05). The level of Piezo1 in the overexpression group was significantly higher than that in the siRNA interference group (q=3.893, P<0.05). The level of Piezo1 in the stretch stress group was significantly higher than that in the blank control group (q=2.006, P<0.05). The expression of Notch1 and osteogenic genes ALP, Runx2, OCN, and BSP had the same trend. Western blot results showed that there were significant differences in the expression of ALP in the siRNA interference group, overexpression group, blank control group, stretch stress group, and negative control group (F=11.207, P<0.001). The expression level of ALP in the overexpression group was significantly higher than that in the siRNA interference group (q=2.991, P<0.05). The expression of ALP in the stretch stress group was significantly higher than that in the blank control group (q=3.007, P<0.05). The expression of Runx2 protein showed the same trend. The intracellular calcium fluorescence intensity of the overexpression group was significantly higher than that of the siRNA interference group, and the intracellular calcium fluorescence intensity of the stretch stress group was significantly higher than that of the siRNA interference group. CONCLUSIONS: Mechanical stretch stress can promote the expression of Piezo1 protein. Ca2+ is the second messenger, activates the Notch1 signaling pathway and the expression of ALP, Runx2, OCN, and BSP; and promotes the osteogenic differentiation of hPDLSC. The siRNA-Piezo1 interfering plasmid can block this process. On the contrary, the overexpression plasmid of Piezo1 can promote the osteogenic differentiation of PDLSCs.

Cognitive behavioural therapy in groups for medicated adults with attention deficit hyperactivity disorder: protocol for a randomised controlled trial.

INTRODUCTION: Cognitive behavioural therapy (CBT) is an evidence-based treatment for adults with attention deficit hyperactivity disorder (ADHD). However, it is still inconsistent whether a combination of CBT would have additive effects in medicated ADHD in adulthood. And if CBT would have additional effects, what kind and which dimension would CBT play a part? This study estimates the efficacy of CBT in stable medicated adult ADHD, using long-term outcomes and multidimensional evaluations. METHODS AND ANALYSIS: It is a two-armed, randomised controlled trial on the superiority of the efficacy of 12 weeks of CBT on medicated adult ADHD. We compare the short-term and long-term outcomes between CBT combined with medication (CBT+M) group and the medication-only (M) group, including ADHD core symptoms, emotional symptoms, executive function, self-esteem, life quality and brain function using functional near-infrared spectroscopy data. Participants are outpatients of the Peking University Sixth Hospital and those recruited online, diagnosed as adult ADHD and with stable medication treatment. We estimate ADHD core symptoms and combined symptoms at baseline (T1) and week 12 (T2), week 24 (T3), week 36 (T4) and week 48 (T5). ETHICS AND DISSEMINATION: This trial has been approved by the Ethics and Clinical Research Committees of Peking University Sixth Hospital and will be performed under the Declaration of Helsinki with the Medical Research Involving Human Subjects Act (WMO). The results will be disseminated in a peer-reviewed journal and a conference presentation. TRIAL REGISTRATION NUMBER: ChiCTR (ChiCTR1900021705).