Protocol for the prediction, interpretation, and mutation evaluation of post-translational modification using MIND-S.

Post-translational modifications (PTMs) serve as key regulatory mechanisms in various cellular processes; altered PTMs can potentially lead to human diseases. We present a protocol for using MIND-S (multi-label interpretable deep-learning approach for PTM prediction-structure version), to study PTMs. This protocol consists of step-by-step guide and includes three key applications of MIND-S: PTM predictions based on protein sequences, important amino acids identification, and elucidation of altered PTM landscape resulting from molecular mutations. For complete details on the use and execution of this protocol, please refer to Yan et al (2023).1.

The structure of schizotypal personality traits: a cross-national study.

BACKGROUND: Schizotypal traits are considered a phenotypic-indicator of schizotypy, a latent personality organization reflecting a putative liability for psychosis. To date, no previous study has examined the comparability of factorial structures across samples originating from different countries and cultures. The main goal was to evaluate the factorial structure and reliability of the Schizotypal Personality Questionnaire (SPQ) scores by amalgamating data from studies conducted in 12 countries and across 21 sites. METHOD: The overall sample consisted of 27 001 participants (37.5% males, n = 4251 drawn from the general population). The mean age was 22.12 years (s.d. = 6.28, range 16-55 years). The SPQ was used. Confirmatory factor analysis (CFA) and Multilevel CFA (ML-CFA) were used to evaluate the factor structure underlying the SPQ scores. RESULTS: At the SPQ item level, the nine factor and second-order factor models showed adequate goodness-of-fit. At the SPQ subscale level, three- and four-factor models displayed better goodness-of-fit indices than other CFA models. ML-CFA showed that the intraclass correlation coefficients values were lower than 0.106. The three-factor model showed adequate goodness of fit indices in multilevel analysis. The ordinal α coefficients were high, ranging from 0.73 to 0.94 across individual samples, and from 0.84 to 0.91 for the combined sample. CONCLUSIONS: The results are consistent with the conceptual notion that schizotypal personality is a multifaceted construct and support the validity and utility of SPQ in cross-cultural research. We discuss theoretical and clinical implications of our results for diagnostic systems, psychosis models and cross-national mental health strategies.

Neural mediator of the schizotypy-antisocial behavior relationship.

Prior studies have established that schizotypal personality traits (schizotypy) were associated with antisocial behavior (crime), but it is unclear what neural factors mediate this relationship. This study assessed the mediating effect that sub-regional prefrontal gray, specifically the orbitofrontal gray matter volume, has on the schizotypy-antisocial behavior relationship. Five prefrontal sub-regional (superior, middle, inferior, orbitofrontal and rectal gyral) gray matter volumes were assessed using structural magnetic resonance imaging in 90 adults from the community, together with schizotypy and antisocial behavior. Among all five prefrontal sub-regions, the orbitofrontal cortex (OFC) was the major region-of-interest in the present study. Mediation analyses showed that orbitofrontal gray fully mediated the association between schizotypy and antisocial behavior. After having controlled the sex, age, socio-economic statuses, whole brain volumes and substance abuse/dependence of test subjects, the orbitofrontal gray still significantly mediated the effect of schizotypy on antisocial behavior by 53.5%. These findings are the first that document a neural mediator of the schizotypy-antisocial behavior relationship. Findings also suggest that functions subserved by the OFC, including impulse control and inhibition, emotion processing and decision-making, may contribute to the above comorbidity.

A longitudinal biosocial study of cortisol and peer influence on the development of adolescent antisocial behavior.

It is increasingly recognized that in order to understand the complex phenomenon of antisocial behavior, interrelations between biological and social risk factors should be taken into account. In the current study, this biosocial approach was applied to examine the mediating role of deviant peers in longitudinal associations linking the level of hypothalamic-pituitary-adrenal (HPA) axis activity to aggression and rule-breaking. Participants were 425 boys and girls from the general population, who were assessed yearly at ages 15, 16, and 17. As a measure of HPA axis activity, cortisol was assessed at awakening, 30, and 60 min later (the cortisol awakening response, CAR). Participants, as well as their best friend, reported on their own aggressive and rule-breaking behavior, thereby allowing to assess bidirectional influences within friendships. Aggression was only predicted by a decreased cortisol level at awakening, and not by aggressive behavior of their friend. Decreased levels of cortisol at awakening predicted adolescents' rule-breaking, which subsequently predicted increased rule-breaking of their best friend. The latter was only found for adolescents who changed friends, as compared to adolescents with the same friend in every year. Gender differences were not found. These findings suggest that interrelations between biological and social risk factors are different for the development of aggression versus rule-breaking. Furthermore, decreased levels of HPA axis activity may represent a susceptibility to selecting deviant peers.

Sex differences in orbitofrontal gray as a partial explanation for sex differences in antisocial personality.

Attention is increasingly being given to understanding sex difference in psychopathology to better understand the etiology of disorders. This study tests the hypothesis that sex differences in ventral and middle frontal gray volume contribute to sex differences in antisocial personality disorder (APD) and crime. Participants were recruited from temporary employment agencies, consisting of normal controls, substance/alcohol-dependent controls, axis I/II psychiatric controls and individuals with APD. An independent sample of female volunteers was also recruited. Magnetic resonance imaging volumes of superior frontal, middle frontal, inferior frontal, orbital frontal and rectal gyral frontal gray matter, and dimensional scores of APD and criminal behavior were assessed. APD males when compared with male controls showed an 8.7% reduction in orbitofrontal gray volume, a 17.3% reduction in middle frontal gray and a 16.1% reduction in right rectal gray. Reduced middle and orbitofrontal volumes were significantly associated with increased APD symptoms and criminal offending in both males and females. Males as a whole had reduced orbitofrontal and middle frontal gray volume when compared with females, and controlling for these brain differences reduced the gender difference in the antisocial personality/behavior by 77.3%. Findings were not a function of psychiatric comorbidity, psychosocial risk factors, head injury or trauma exposure. Findings implicate structural differences in the ventral and middle frontal gray as both a risk factor for APD and as a partial explanation for sex differences in APD.

Psychopathic personality in children: genetic and environmental contributions.

BACKGROUND: The current study investigates whether the underlying factor structure of psychopathic personality traits found in adults is similar to that in children and what the extent of the genetic and environmental influences are on these psychopathic traits. METHOD: Psychopathic personality traits were assessed in a community sample of 1219 twins and triplets (age 9-10 years) through caregiver reports of each child's behavior using the Child Psychopathy Scale (CPS). RESULTS: Confirmatory factor analyses revealed an optimal two-factor solution (callous/disinhibited and manipulative/deceitful) to the CPS subscales. Bivariate genetic modeling of the two computed factor scores revealed significant genetic as well as unique environmental influences on psychopathic personality traits in both boys and girls, with heritability estimates of 0.64 and 0.46, respectively, in boys and 0.49 and 0.58, respectively, in girls. No shared environmental influences on psychopathic personality traits were found. CONCLUSIONS: The relationship between the two factors was mediated by both genetic and unique environmental factors common to both traits.

Early maternal and paternal bonding, childhood physical abuse and adult psychopathic personality.

BACKGROUND: A significant gap in the literature on risk factors for psychopathy is the relative lack of research on parental bonding.MethodThis study examines the cross-sectional relationship between maternal and paternal bonding, childhood physical abuse and psychopathic personality at age 28 years in a community sample of 333 males and females. It also assesses prospectively whether children separated from their parents in the first 3 years of life are more likely to have a psychopathic-like personality 25 years later. RESULTS: Hierarchical regression analyses indicated that: (1) poor parental bonding (lack of maternal care and low paternal overprotection) and childhood physical abuse were both associated with a psychopathic personality; (2) parental bonding was significantly associated with psychopathic personality after taking into account sex, social adversity, ethnicity and abuse; (3) those separated from parents in the first 3 years of life were particularly characterized by low parental bonding and a psychopathic personality in adulthood; and (4) the deviant behavior factor of psychopathy was more related to lack of maternal care whereas the emotional detachment factor was related to both lack of maternal care and paternal overprotection. CONCLUSIONS: Findings draw attention to the importance of different components of early bonding in relation to adult psychopathy, and may have potential implications for early intervention and prevention of psychopathy.

Partial divergence of cytokine mRNA expression in bronchial tissues compared to bronchoalveolar lavage cells in horses with recurrent airway obstruction.

The aim of this study was to investigate mRNA levels of cytokines in bronchial epithelium in horses with recurrent airway obstruction (RAO) during acute crisis and remission. Additionally, cytokine mRNA levels in endobronchial biopsies and bronchoalveolar lavage (BAL) cells were compared. Seven RAO horses were examined while in respiratory crisis following provocation and again while in remission after 2 months on pasture, during which time six healthy horses on pasture were also examined. Quantitative real-time PCR (RT-PCR) was used to assess mRNA expression for cytokines IL-5, IL-6, IL-8, IL-10, IL-17 and transforming growth factor beta1 (TGF-beta1) in endobronchial biopsies and bronchoalveolar lavage. Expression of IL-8 mRNA was significantly upregulated during crisis in both endobronchial biopsies and BAL cells (p=0.036), while there was a similar trend for upregulation of IL-10 mRNA only in BAL cells that approached significance (p=0.059). Moreover, during crisis the expression of IL-8 mRNA in BAL cells was positively correlated to relative IL-6 mRNA expression (r(s)=0.971, p=0.001) and bronchial epithelial expression of IL-10 and TGF-beta1 mRNA were positively correlated (r(s)=0.943, p=0.005). In comparing the relationship of mRNA expression in BAL to biopsy in individual RAO horses, there was a positive correlation with IL-6 to IL-8 mRNA expression in BAL during respiratory crisis (r(s)=0.971, p=0.001) that also correlated positively with IL-8 expression in biopsies on pasture (r(s)=0.986, p<0.0001 for both). Regarding RAO horses at pasture versus controls neither the cytokine mRNA levels in endobronchial biopsy nor in BAL cells differed significantly. These results further support previous findings that IL-8 mRNA in both BAL cells and bronchial epithelium is upregulated in RAO horses during crisis. However, apart from IL-8, it appears that expression of other cytokines, including IL-5, IL-6, IL-10, IL-17 and TGF-beta1 in bronchial epithelium does not necessarily mirror cytokine expression in BAL cells in individual horses with RAO. Accordingly, examination of markers of inflammation in endobronchial tissue provides complementary but not necessarily identical information to that obtained in BAL cells. Given the potential for repeated sampling over time bronchial biopsy can serve as an invaluable additional tool for investigation of time-dependent changes in inflammatory process in this animal model of asthma.

Clinical alterations and mRNA levels of IL-4 and IL-5 in bronchoalveolar cells of horses with transient pulmonary eosinophilia.

The aim of this study was to assess clinical signs and altered pulmonary cell expression of cytokines related to eosinophil kinetics in horses with pulmonary eosinophilia. Pulmonary eosinophilia was detected by bronchoalveolar lavage (BAL) in a group of standardbreds in training. Horses had detailed clinical examination, bronchoscopy, endobronchial biopsy and BAL on three occasions at approximately 6 month intervals. During the second sampling period BAL eosinophils were significantly elevated (p>0.010), with five horses having from 5% to 37% eosinophils in BAL. Neither detailed clinical examination parameters nor gene expression of IL-4 and IL-5 mRNA (real-time-PCR) were associated with BAL eosinophilia. Pulmonary eosinophilia abated without treatment apart from deworming. It appears that pronounced lung eosinophilia in horses can be transient, abate without specific treatment, and in this instance, lack correlation to upregulation of expression of either IL-4 or IL-5.

Diastolic dysfunction and abnormality of the Na+/Ca2+ exchanger in single uremic cardiac myocytes.

Cardiovascular disease is the most common cause of death in patients with end-stage renal disease, possibly due to a specific "uremic cardiomyopathy". This study investigated the function of the Na(+)/Ca(2+) exchanger in single cardiac myocytes from a model of early renal impairment. Mild uremia was induced by partial (5/6) nephrectomy in male Wistar rats. After 4 weeks, ventricular myocytes were isolated, loaded with the fluorescent Ca(2+) indicator indo-1, and contractile function and calcium transients recorded following electrical pacing at 0.2 Hz. Relaxation from rapid cooling contractures (RCCs) was also studied. Cells from uremic animals (U) were hypertrophied compared with controls (C), with a significant increase in width (14%; P<0.02) and cross-sectional area (13%; P<0.03). There was a significant increase in diastolic intracellular Ca(2+) ratio in the uremic cells (C, 0.33+/-0.00 vs U, 0.37+/-0.02; P<0.02), although the amount of calcium released per twitch was similar. Uremic cells were slower to relax following RCCs, however when Na(+)/Ca(2+) exchange was inhibited using a Na(+)-free/Ca(2+)-free solution, this difference was abolished. Under these conditions, there was little difference in the relaxation rate of control cells, indicating that the Na(+)/Ca(2+) exchanger plays only a minor role in relaxation in normal rat myocytes. However in uremia, the data indicate that the Na(+)/Ca(2+) exchanger actively interfered with relaxation, possibly by working in reverse rather than forward mode. These results indicate that myocyte relaxation and Ca(2+) handling are abnormal in early uremia and may provide further evidence for the existence of a specific "uremic cardiomyopathy".

Temporal lobe deficits in murderers: EEG findings undetected by PET.

This study evaluates electroencephalography (EEG) and positron emission tomography (PET) in the same subjects. Fourteen murderers were assessed by using both PET (while they were performing the continuous performance task) and EEG during a resting state. EEG revealed significant increases in slow-wave activity in the temporal, but not frontal, lobe in murderers, in contrast to prior PET findings that showed reduced prefrontal, but not temporal, glucose metabolism. Results suggest that resting EEG shows empirical utility distinct from PET activation findings.

Solution structure of the lipoyl domain of the chimeric dihydrolipoyl dehydrogenase P64K from Neisseria meningitidis.

The antigenic P64K protein from the pathogenic bacterium Neisseria meningitidis is found in the outer membrane of the cell, and consists of two parts: an 81-residue N-terminal region and a 482-residue C-terminal region. The amino-acid sequence of the N-terminal region is homologous with the lipoyl domains of the dihydrolipoyl acyltransferase (E2) components, and that of the C-terminal region with the dihydrolipoyl dehydrogenase (E3) components, of 2-oxo acid dehydrogenase multienzyme complexes. The two parts are separated by a long linker region, similar to the linker regions in the E2 chains of 2-oxo acid dehydrogenase complexes, and it is likely this region is conformationally flexible. A subgene encoding the P64K lipoyl domain was created and over-expressed in Escherichia coli. The product was capable of post-translational modification by the lipoate protein ligase but not aberrant modification by the biotin protein ligase of E. coli. The solution structure of the apo-domain was determined by means of heteronuclear NMR spectroscopy and found to be a flattened beta barrel composed of two four-stranded antiparallel beta sheets. The lysine residue that becomes lipoylated is in an exposed beta turn that, from a [1H]-15N heteronuclear Overhauser effect experiment, appears to enjoy substantial local motion. This structure of a lipoyl domain derived from a dihydrolipoyl dehydrogenase resembles that of lipoyl domains normally found as part of the dihydrolipoyl acyltransferase component of 2-oxo acid dehydrogenase complexes and will assist in furthering the understanding of its function in a multienzyme complex and in the membrane-bound P64K protein itself.

Autonomic stress reactivity and executive functions in successful and unsuccessful criminal psychopaths from the community.

A significant gap in the psychopathy literature is the lack of studies comparing "successful," nonconvicted psychopaths with "unsuccessful," convicted psychopaths. This study tested the hypothesis that successful psychopaths show increased autonomic stress reactivity and better neuropsychological function compared with unsuccessful psychopaths. A total of 26 controls, 16 unsuccessful psychopaths, and 13 successful psychopaths were assessed on psychophysiological measures recorded during an emotional manipulation, the Wisconsin Card Sorting Test (WCST), Wechsler Memory Scale--Revised subtests, and childhood stressors. Compared with controls, unsuccessful psychopaths showed reduced cardiovascular stress reactivity. In contrast, successful psychopaths showed heightened reactivity, better WCST performance, and more parental absence than unsuccessful psychopaths and controls. The implications of these findings and the generalizability of existing psychopathy research are discussed.

Early educational and health enrichment at age 3-5 years is associated with increased autonomic and central nervous system arousal and orienting at age 11 years: evidence from the Mauritius Child Health Project.

Little is known about the effects of environmental enrichment on psychophysiological measures of arousal and orienting in humans. This study tests the hypothesis that early educational and health enrichment is associated with long-term increases in psychophysiological orienting and arousal. One hundred children were experimentally assigned to a two-year enriched nursery school intervention at ages 3-5 years and matched at age 3 years on psychophysiological measures, gender, and ethnicity to 100 comparisons who received the normal educational experience. Children were retested 6-8 years later at age 11 years on skin conductance (SC) and electroencephalogram (EEG) measures of arousal and attention during pre- and postexperimental rest periods and during the continuous performance task. Nursery enrichment was associated with increased SC amplitudes, faster SC rise times, faster SC recovery times, and less slow-wave EEG during both rest and CPT conditions. This is believed to be the first study to show that early environmental enrichment is associated with long-term increases in psychophysiological orienting and arousal in humans. Results draw attention to the important influence of the early environment in shaping later psychophysiological functioning.

Increased height and bulk in antisocial personality disorder and its subtypes.

Research suggests that those with antisocial tendencies are larger than controls, but studies have not assessed this association in antisocial personality disorder (APD) or its hypothesized sub-types (i.e. adolescence-limited, late-onset). Height, weight, body mass index, bulk, and psychosocial adversity were assessed in 44 controls, nine adolescent-limited antisocials, 21 APDs, and 13 late-onset antisocials from the community. Adult antisocial individuals, regardless of age of onset, were significantly taller and had greater body bulk than controls. Although groups tended to differ on weight, they did not differ on body mass index. In addition, APDs and adolescent-limited individuals reported greater psychosocial adversity than the other groups. Adversity did not account for height or bulk differences. Results suggest prior findings on height and bulk may apply to APD and support differentiating adolescent-limited and life-course persistent subgroups.

Invariance of the MAST across religious groups.

OBJECTIVE: The Michigan Alcoholism Screening Test (MAST), a commonly used instrument of alcohol-related problems, was examined to determine whether it assessed the same constructs in individuals from religions with different proscriptions regarding the use of alcohol. METHOD: The MAST was completed by participants in the longitudinal Joint Child Health Project when they were approximately 23 years old. Subjects of this study (N= 747; 505 men) were 465 Hindus, 223 Catholics and 59 Muslims who reported drinking alcohol. Measurement invariance, the determination that the same constructs are being measured across groups, was tested by comparing factor invariance using multigroup structural equation modeling. RESULTS: The Hindu and Catholic groups had similar factor structures to those found in previous Australian, Canadian and U.S. samples. Metric invariance was obtained for the Hindu and Catholic groups, but not for the Muslim group. CONCLUSIONS: These findings suggest the measurement of MAST factors is invariant across a fairly broad segment of the population in which the MAST might be used. However, the lack of invariance in this sample of Muslims suggests that the MAST is not an appropriate instrument to use among all groups of drinkers. These findings highlight the importance of testing for invariance when using psychological measures to compare heterogeneous samples.

Elevated levels of cognitive-perceptual deficits in individuals with a family history of schizophrenia spectrum disorders.

This study finds that the relatives of schizophrenics have elevated scores on the cognitive-perceptual factor of the schizotypal personality questionnaire (SPQ), particularly for the 'unusual perceptual experiences' and 'ideas of reference' subscales. These results support recent findings by Kremen et al. (1998) and suggest that previous failures to demonstrate elevated scores on 'positive' symptoms of schizotypy may be a function of instrumentation.