Integrated intracellular organization and its variations in human iPS cells.

Understanding how a subset of expressed genes dictates cellular phenotype is a considerable challenge owing to the large numbers of molecules involved, their combinatorics and the plethora of cellular behaviours that they determine1,2. Here we reduced this complexity by focusing on cellular organization-a key readout and driver of cell behaviour3,4-at the level of major cellular structures that represent distinct organelles and functional machines, and generated the WTC-11 hiPSC Single-Cell Image Dataset v1, which contains more than 200,000 live cells in 3D, spanning 25 key cellular structures. The scale and quality of this dataset permitted the creation of a generalizable analysis framework to convert raw image data of cells and their structures into dimensionally reduced, quantitative measurements that can be interpreted by humans, and to facilitate data exploration. This framework embraces the vast cell-to-cell variability that is observed within a normal population, facilitates the integration of cell-by-cell structural data and allows quantitative analyses of distinct, separable aspects of organization within and across different cell populations. We found that the integrated intracellular organization of interphase cells was robust to the wide range of variation in cell shape in the population; that the average locations of some structures became polarized in cells at the edges of colonies while maintaining the 'wiring' of their interactions with other structures; and that, by contrast, changes in the location of structures during early mitotic reorganization were accompanied by changes in their wiring.

Tri6 is a global transcription regulator in the phytopathogen Fusarium graminearum.

In F. graminearum, the transcriptional regulator Tri6 is encoded within the trichothecene gene cluster and regulates genes involved in the biosynthesis of the secondary metabolite deoxynivalenol (DON). The Tri6 protein with its Cys2His2 zinc-finger may also conform to the class of global transcription regulators. This class of global transcriptional regulators mediate various environmental cues and generally responds to the demands of cellular metabolism. To address this issue directly, we sought to find gene targets of Tri6 in F. graminearum grown in optimal nutrient conditions. Chromatin immunoprecipitation followed by Illumina sequencing (ChIP-Seq) revealed that in addition to identifying six genes within the trichothecene gene cluster, Tri1, Tri3, Tri6, Tri7, Tri12 and Tri14, the ChIP-Seq also identified 192 additional targets potentially regulated by Tri6. Functional classification revealed that, among the annotated genes, ∼40% are associated with cellular metabolism and transport and the rest of the target genes fall into the category of signal transduction and gene expression regulation. ChIP-Seq data also revealed Tri6 has the highest affinity toward its own promoter, suggesting that this gene could be subject to self-regulation. Electro mobility shift assays (EMSA) performed on the promoter of Tri6 with purified Tri6 protein identified a minimum binding motif of GTGA repeats as a consensus sequence. Finally, expression profiling of F. graminearum grown under nitrogen-limiting conditions revealed that 49 out of 198 target genes are differentially regulated by Tri6. The identification of potential new targets together with deciphering novel binding sites for Tri6, casts new light into the role of this transcriptional regulator in the overall growth and development of F. graminearum.

An herbal nasal drop enhanced frontal and anterior cingulate cortex activity.

The present study examined the neuro-electrophysiological activity of the brain associated with the application of a herbal remedy developed by a Shaolin monk based upon the Chan healing principle of clearing the orifices (i.e., the nasal cavities). A repeated-measures design was used. Fourteen normal adults were administered herbal remedy and saline solution intranasally on separate sessions. Two intervals of eyes-closed resting EEG data were obtained individually before and after each administration. Results showed that only the herbal remedy but not the saline solution induced elevation in cordance, an index correlated with cerebral perfusion, in the anterior brain region. In addition, the activity of the anterior cingulate cortex (ACC), as examined by the LORETA analysis, was also increased after the application of the herbal remedy but not saline solution. The present study provided some preliminary evidence suggesting that the herbal nasal drop enhanced the activity of the frontal lobe and ACC. Implications for the potential clinical application of the herbal remedy to treat patients with frontal lobe disorders were discussed.

Dejian mind-body intervention improves the cognitive functions of a child with autism.

There has been increasing empirical evidence for the enhancing effects of Dejian Mind-Body Intervention (DMBI), a traditional Chinese Shaolin healing approach, on human frontal brain activity/functions, including patients with autism who are well documented to have frontal lobe problems. This study aims to compare the effects of DMBI with a conventional behavioural/cognitive intervention (CI) on enhancing the executive functions and memory of a nine-year-old boy with low-functioning autism (KY) and to explore possible underlying neural mechanism using EEG theta cordance. At post-one-month DMBI, KY's inhibitory control, cognitive flexibility, and memory functioning have significantly improved from "severely-to-moderately impaired" to "within-normal" range. This improvement was not observed from previous 12-month CI. Furthermore, KY showed increased cordance gradually extending from the anterior to the posterior brain region, suggesting possible neural mechanism underlying his cognitive improvement. These findings have implicated potential applicability of DMBI as a rehabilitation program for patients with severe frontal lobe and/or memory disorders.

Seven-star needle stimulation improves language and social interaction of children with autistic spectrum disorders.

This is a randomized controlled trial that aimed to evaluate the effect of the Seven-star Needle Stimulation treatment on children with Autistic Spectrum Disorders (ASD). Thirty-two children with ASD were assigned randomly into the treatment and control groups. Children in the treatment group underwent 30 sessions of stimulation over 6 weeks, while children in the control group were on a waiting list and did not receive treatment during this period of time. Intervention consisted of a treatment regime comprising of 30 sessions of Seven-star Needle Stimulation, delivered over 6 weeks. Each session lasted 5 to 10 min, children in the treatment group were stimulated at the front and back sides of their body and the head by using Seven-star Needles. The change in the children's behavior was evaluated using parents' report and neurophysiological changes were measured by quantitative EEG (qEEG). Results showed that the treatment group demonstrated significant improvement in language and social interaction, but not in stereotyped behavior or motor function, compared to the control group. qEEG spectral amplitudes in the treatment, but not in the control group, were also reduced significantly. The results suggested that Seven-star Needle Stimulation might be an effective intervention to improve language and social functioning of children with ASD.

Functional implications of neuropsychological normality and symptom remission in older outpatients diagnosed with schizophrenia: A cross-sectional study.

Cognitive impairments in schizophrenia are well documented and correlated with functional disability. Although some patients demonstrate normal neuropsychological (NP) functioning, little is known about their functional disability. We examined the cross-sectional functional implications of NP normality and symptomatic remission in older outpatients diagnosed with schizophrenia or schizoaffective disorder, who were administered a NP battery and performance-based measures of functional and social competence, with their real-world functioning rated by case managers. NP status was classified by the General Deficit Score (GDS) and remission status was based on the Positive and Negative Syndrome Scale (PANSS), yielding four subsamples of patients: NP normal-remitted (n = 21), NP normal-symptomatic (n = 22), NP impaired-remitted (n = 90), and NP impaired-symptomatic (n = 97). NP normal patients demonstrated better functional and social competence and better ratings of real world functioning, after controlling for premorbid abilities. However, compared to normative date, NP normal patients manifested disability in several real-world domains, including residential status. These results suggest that NP status is a better predictor of functional outcome then symptom status or the interaction of the two factors. The disability seen in NP normal cases indicates that factors other than cognitive impairments may determine aspects of everyday outcomes in schizophrenia.

Neuropsychological functioning and social anhedonia: results from a community high-risk study.

Social anhedonia has shown promise as a vulnerability marker for schizophrenia-spectrum pathology. Validity data have come, in part, from findings indicating that cognitive deficits occurring in schizophrenia are also evident in individuals with elevated levels of social anhedonia. However, prior research on this topic has been limited because it has been based almost exclusively on the study of selective samples of college students. The present article reports baseline findings of neuropsychological functioning in social anhedonics and controls from a representative community sample. Data on a wide array of neuropsychological abilities from 18-19 year-old participants with (n = 85) vs. without (n = 87) elevated levels of social anhedonia were analyzed. We hypothesized that, compared to controls, social anhedonics would show impairments in memory and sustained attention. Additionally, we sought to determine if more severe cognitive impairment in anhedonics was associated with greater schizophrenia-spectrum pathology and poorer overall functioning. Compared to controls, socially anhedonic participants performed more poorly on two visual-spatial memory tasks and a test of visual-spatial construction. The groups did not statistically differ on any of the other neuropsychological measures including general cognitive ability and sustained attention. Group differences were not the result of depression, bipolar or substance abuse disorders. Neuropsychological functioning showed little relationship to current clinical symptoms and functioning. Longitudinal assessment of these participants as they move through the risk period should provide important insights into the neuropsychological correlates of the schizophrenia prodrome.

Differentiating autistic children with quantitative encephalography: a 3-month longitudinal study.

The present study used a single-channel quantitative electroencephalographic (EEG) assessment to differentiate autistic children from normal control subjects. One hundred five normal and 17 autistic children participated in the study. In addition to amplitude measures of the frequency bands of delta, theta, alpha, sensorimotor rhythm, and beta and the theta to beta ratio, intra- (6 minutes) and intersessional (3 months) consistencies were also examined. The results indicated that autistic children showed significantly higher quantitative EEG amplitudes in many of the frequency bands than normal children; furthermore, their quantitative EEG activities were found to be relatively unstable within a 6-minute session compared with normal children. Discriminant function analyses revealed that absolute sensorimotor rhythm and beta amplitudes were the best predictors that correctly differentiated autistic children from normal children in the present sample, with a high accuracy rate of 95.2%. In addition, quantitative EEG measurements of normal and autistic children were found to be generally consistent across the 3-month period.

Vocational functioning in schizotypal and paranoid personality disorders.

Impaired vocational functioning is a hallmark of schizophrenia, but limited research has evaluated the relationships between work and schizophrenia-spectrum personality disorders, including schizotypal (SPD) and paranoid personality disorder (PPD). This study compared employment history and job characteristics of 174 individuals drawn from the community or clinic, based on four personality disorder groups: SPD Only, PPD Only, SPD+PPD, and No SPD or PPD. Symptoms and cognitive functioning were also assessed. Both PPD and/or SPD were associated with lower rates of current employment, and a history of having worked at less cognitively complex jobs than people without these disorders. Participants with PPD were less likely to have a history of competitive work for one year, whereas those with SPD tended to have worked at jobs involving lower levels of social contact, compared with those without these disorders. When the effects of symptoms and cognitive functioning were statistically controlled, PPD remained a significant predictor of work history, and SPD remained a significant predictor of social contact on the job. The findings suggest that impaired vocational functioning is an important characteristic of SPD and PPD.

Social anhedonia and schizotypy in a community sample: the Maryland longitudinal study of schizotypy.

Social anhedonia has been employed in psychometric high-risk studies to identify putative schizotypes. To date, this research has focused almost exclusively on college samples. The current study sought to examine the validity of social anhedonia as an indicator of risk for schizophrenia-spectrum disorders within a community sample. Furthermore, we evaluated the role of other individual difference variables in accounting for variable clinical severity within the social anhedonia group including trait affectivity, social support, and family environment. Following the mailed questionnaire screening of 2434 eighteen-year olds, laboratory assessments were conducted with individuals identified as being high in social anhedonia (n=86) and a comparison sample (n=89). Compared with the control group, individuals in the social anhedonia group were found to have higher rates of mood disorders, elevated schizophrenia-spectrum personality disorder characteristics, greater negative symptom characteristics, and lower global functioning. Individuals within the social anhedonia group also reported greater trait negative affectivity, lower positive affectivity, less social support, and more family conflict. Low social support and problematic family environment were found to be related to elevations in spectrum personality disorder characteristics and poorer functioning within the social anhedonia group. These cross-sectional findings from a community sample provide further support for social anhedonia as a possible indicator of schizotypy.

Is social anhedonia related to emotional responsivity and expressivity? A laboratory study in women.

Social anhedonia is an important feature of schizophrenia and it is a promising indicator of schizotypy. Although social anhedonia is defined as an affective construct (less pleasure derived from social encounters), little is known about the emotional responsivity and expressivity of individuals with high levels of social anhedonia. After screening a large sample of female undergraduate students (N = 1 085), a cohort of psychometrically identified individuals with high levels of social anhedonia (n = 34) and normally hedonic controls (n = 45) participated in laboratory assessments involving trait affectivity, self-reported dispositional emotional expressiveness, and the expression and experience of emotion in response to neutral, non-affiliative (i.e., comedy) and affiliative film clips. Results revealed that individuals with high levels of social anhedonia are characterized by lower positive affect, both as a trait and in response to emotionally evocative stimuli, and are less facially expressive, both by their own self-report and in response to film clips. Attenuated positive affect was observed across film stimuli, indicating a general reduction in affective response rather than a specific decrease in responsivity for affiliative stimuli. Future work should continue to investigate whether there is a unique role for social stimuli in the emotional lives of individuals with high levels of social anhedonia or whether these individuals tend to experience anhedonia more broadly regardless of social context.

Executive function deficits and neural discordance in children with Autism Spectrum Disorders.

OBJECTIVE: This study examined neurophysiologic activities, executive dysfunctions, and their association in children with Autism Spectrum Disorders (ASD). METHODS: Thirty-eight normal and 16 children with ASD participated with parental consent. Executive functions were measured using neuropsychological tests and parent ratings, and neurophysiologic activities were measured using EEG to yield cordance values, an indirect measure of brain perfusion. RESULTS: Children with ASD made significantly more intrusion errors and False Alarms on the Hong Kong List Learning Test (HKLLT) and Object Recognition Test (OR) than normal children, but were comparable to normal children on the Rey-Osterrieth Complex Figure Test and Continuous Performance Test. They also showed significantly poorer executive functions in everyday activities as shown on the Behavior Rating Inventory of Executive Function (BRIEF), and had lower frontal perfusion patterns than normal children as shown in the neurophysiologic cordance measures. Frontal cordance values were found to be significantly associated with executive dysfunctions in HKLLT Delayed Intrusions, OR False Alarms and BRIEF. CONCLUSIONS: Children with ASD were impaired in everyday executive functioning and response inhibition. The cordance value, which has been shown to correlate with brain perfusion in a number of studies, was significantly correlated with executive dysfunctions. SIGNIFICANCE: Exploration of this measure as an index for response to intervention is warranted.

A psychometric study of the Test of Everyday Attention for Children in the Chinese setting.

OBJECTIVE: To explore the psychometric properties of the Test of Everyday Attention for Children (TEA-Ch) in the context of a Chinese setting. METHODS: Confirmatory factor analysis was conducted to examine the construct validity of the Chinese version of the TEA-Ch among a group of 232 children without attention deficit hyperactivity disorder (ADHD). Test-retest reliability was tested on a random sub-sample of 20 children at a 4-week interval. Clinical discrimination was also examined by comparing children with and without ADHD (22 in each group) on the performances of the TEA-Ch. RESULTS: The current Chinese sample demonstrated a three-factor solution for attentional performance among children without ADHD, namely selective attention, executive control/switch, and sustained attention (chi(2)(24)=34.56; RMSEA=.044; p=.075). Moreover, the whole test demonstrated acceptable test-retest reliability at a 4-week interval among a small sub-sample. Children with ADHD performed significantly more poorly than healthy controls in most of the subtests of the TEA-Ch. CONCLUSIONS: The results of the present study demonstrate that the test items remain useful in China, a culture very different from that in which the test originated. Finally, the TEA-Ch also presents several advantages when compared to other conventional objective measures of attention.

Measuring vocabulary by free expression and recognition tasks: Implications for assessing children, adolescents, and young adults.

Vocabulary tests are commonly used for assessing verbal ability. Most vocabulary tests employ the free expressive format that taps both verbal knowledge and expressive ability. The recognition format, which requires less expressive ability, has been suggested to be more sensitive in assessing the fund of verbal knowledge. We assessed vocabulary performance of 285 normal individuals (aged 6 to 23 years) using both free expressive and recognition tasks. Results showed that participants aged 6 to 15 performed significantly better on the recognition than on the free expressive task. While the recognition task significantly correlated with the Test of Nonverbal Intelligence-Third Edition (TONI-III) IQ for individuals aged 9 and above, the free expressive task correlated with TONI-III IQ only for young adults. Shortened 18-item versions yielded high reliability and correlation with the full version and reliable association with TONI-III IQ. These results highlight the utility of recognition tasks in measuring the fund of knowledge and suggest the possibility of developing shorter vocabulary tests for more cost-effective assessment.

Predicting schizophrenia patients' real-world behavior with specific neuropsychological and functional capacity measures.

BACKGROUND: Significant neuropsychological (NP) and functional deficits are found in most schizophrenia patients. Previous studies have left questions as to whether global NP impairment or discrete domains affect functional outcomes, and none have addressed distinctions within and between ability and performance domains. This study examined the different predictive relationships between NP domains, functional competence, social competence, symptoms, and real-world behavior in domains of work skills, interpersonal relationships, and community activities. METHODS: Two hundred twenty-two schizophrenic outpatients were tested with an NP battery and performance-based measures of functional and social competence and rated for positive, negative, and depressive symptoms. Case managers generated ratings of three functional disability domains. RESULTS: Four cognitive factors were derived from factor analysis. Path analyses revealed both direct and mediated effects of NP on real-world outcomes. All NP domains predicted functional competence, but only processing speed and attention/working memory predicted social competence. Both competence measures mediated the effects of NP on community activities and work skills, but only social competence predicted interpersonal behaviors. The attention/working memory domain was directly related to work skills, executive functions had a direct effect on interpersonal behaviors, and processing speed had direct effects on all three real-world behaviors. Symptoms were directly related to outcomes, with fewer relationships with competence. CONCLUSIONS: Differential predictors of functional competence and performance were found from discrete NP domains. Separating competence and performance provides a more precise perspective on correlates of disability. Changes in specific NP or functional skills might improve specific outcomes, rather than promoting global functional improvement.

Catechol-O-methyltransferase Val158Met genotype in healthy and personality disorder individuals: Preliminary results from an examination of cognitive tests hypothetically differentially sensitive to dopamine functions.

A functional polymorphism of the gene coding for Catechol-O-methyltrasferase (COMT), an enzyme responsible for the degradation of the catecholamine dopamine (DA), epinephrine, and norepinephrine, is associated with cognitive deficits. However, previous studies have not examined the effects of COMT on context processing, as measured by the AX-CPT, a task hypothesized to be maximally relevant to DA function. 32 individuals who were either healthy, with schizotypal personality disorder, or non-cluster A, personality disorder (OPD) were genotyped at the COMT Val158Met locus. Met/Met (n = 6), Val/Met (n = 10), Val/Val (n = 16) individuals were administered a neuropsychological battery, including the AX-CPT and the N-back working memory test. For the AX-CPT, Met/Met demonstrated more AY errors (reflecting good maintenance of context) than the other genotypes, who showed equivalent error rates. Val/Val demonstrated disproportionately greater deterioration with increased task difficulty from 0-back to 1-back working memory demands as compared to Met/Met, while Val/Met did not differ from either genotypes. No differences were found on processing speed or verbal working memory. Both context processing and working memory appear related to COMT genotype and the AX-CPT and N-back may be most sensitive to the effects of COMT variation.

Differentiating Autistic Children With Quantitative Encephalography: A 3-Month Longitudinal Study.

The present study used a single-channel quantitative electroencephalographic (EEG) assessment to differentiate autistic children from normal control subjects. One hundred five normal and 17 autistic children participated in the study. In addition to amplitude measures of the frequency bands of delta, theta, alpha, sensorimotor rhythm, and beta and the theta to beta ratio, intra- (6 minutes) and intersessional (3 months) consistencies were also examined. The results indicated that autistic children showed significantly higher quantitative EEG amplitudes in many of the frequency bands than normal children; furthermore, their quantitative EEG activities were found to be relatively unstable within a 6-minute session compared with normal children. Discriminant function analyses revealed that absolute sensorimotor rhythm and beta amplitudes were the best predictors that correctly differentiated autistic children from normal children in the present sample, with a high accuracy rate of 95.2%. In addition, quantitative EEG measurements of normal and autistic children were found to be generally consistent across the 3-month period. (J Child Neurol 2006;21:391-399; DOI 10.2310/7010.2006.00094).