Particular genomic and virulence traits associated with preterm infant-derived toxigenic Clostridium perfringens strains

Clostridium perfringens is an anaerobic toxin-producing bacterium associated with intestinal diseases, particularly in neonatal humans and animals. Infant gut microbiome studies have recently indicated a link between C. perfringens and the preterm infant disease necrotizing enterocolitis (NEC), with specific NEC cases associated with overabundant C. perfringens termed C. perfringens-associated NEC (CPA-NEC). In the present study, we carried out whole-genome sequencing of 272 C. perfringens isolates from 70 infants across 5 hospitals in the United Kingdom. In this retrospective analysis, we performed in-depth genomic analyses (virulence profiling, strain tracking and plasmid analysis) and experimentally characterized pathogenic traits of 31 strains, including 4 from CPA-NEC patients. We found that the gene encoding toxin perfringolysin O, pfoA, was largely deficient in a human-derived hypovirulent lineage, as well as certain colonization factors, in contrast to typical pfoA-encoding virulent lineages. We determined that infant-associated pfoA+ strains caused significantly more cellular damage than pfoA- strains in vitro, and further confirmed this virulence trait in vivo using an oral-challenge C57BL/6 murine model. These findings suggest both the importance of pfoA+ C. perfringens as a gut pathogen in preterm infants and areas for further investigation, including potential intervention and therapeutic strategies

The Shine-Through Masking Paradigm Is a Potential Endophenotype of Schizophrenia

BACKGROUND: To understand the genetics of schizophrenia, a hunt for so-called intermediate phenotypes or endophenotypes is ongoing. Visual masking has been proposed to be such an endophenotype. However, no systematic study has been conducted yet to prove this claim. Here, we present the first study showing that masking meets the most important criteria for an endophenotype. METHODOLOGY/PRINCIPAL FINDINGS: We tested 62 schizophrenic patients, 39 non-affected first-degree relatives, and 38 healthy controls in the shine-through masking paradigm and, in addition, in the Continuous Performance Test (CPT) and the Wisconsin Card Sorting Test (WCST). Most importantly, masking performance of relatives was significantly in between the one of patients and controls in the shine-through paradigm. Moreover, deficits were stable throughout one year. Using receiver operating characteristics (ROC) methods, we show that the shine-through paradigm distinguishes with high sensitivity and specificity between schizophrenic patients, first-order relatives and healthy controls. CONCLUSIONS/SIGNIFICANCE: The shine-through paradigm is a potential endophenotype

Practice Induces Function-Specific Changes in Brain Activity

Practice can have a profound effect on performance and brain activity, especially if a task can be automated. Tasks that allow for automatization typically involve repeated encoding of information that is paired with a constant response. Much remains unknown about the effects of practice on encoding and response selection in an automated task.To investigate function-specific effects of automatization we employed a variant of a Sternberg task with optimized separation of activity associated with encoding and response selection by means of m-sequences. This optimized randomized event-related design allows for model free measurement of BOLD signals over the course of practice. Brain activity was measured at six consecutive runs of practice and compared to brain activity in a novel task.Prompt reductions were found in the entire cortical network involved in encoding after a single run of practice. Changes in the network associated with response selection were less robust and were present only after the third run of practice.This study shows that automatization causes heterogeneous decreases in brain activity across functional regions that do not strictly track performance improvement. This suggests that cognitive performance is supported by a dynamic allocation of multiple resources in a distributed network. Our findings may bear importance in understanding the role of automatization in complex cognitive performance, as increased encoding efficiency in early stages of practice possibly increases the capacity to otherwise interfering information

DNA origami-based single-molecule forcespectroscopy elucidates RNA Polymerase IIIpre-initiation complex stability

The TATA-binding protein (TBP) and a transcription factor (TF) IIB-like factor are important constituents of all eukaryotic initiation complexes. The reason for the emergence and strict requirement of the additional initiation factor Bdp1 in the RNA polymerase (RNAP) III system, however, remained elusive. A poorly studied aspect in this context is the effect of DNA strain arising from DNA compaction and transcriptional activity on initiation complex formation. We made use of a DNA origami-based force clamp to follow the assembly of human initiation complexes in the RNAP II and RNAP III systems at the single-molecule level under piconewton forces. We demonstrate that TBP-DNA complexes are force-sensitive and TFIIB is sufficient to stabilise TBP on a strained promoter. In contrast, Bdp1 is the pivotal component that ensures stable anchoring of initiation factors, and thus the polymerase itself, in the RNAP III system. Thereby, we offer an explanation for the crucial role of Bdp1 for the high transcriptional output of RNAP III

Individual differences in first- and second-order temporal judgment

The ability of subjects to identify and reproduce brief temporal intervals is influenced by many factors whether they be stimulus-based, task-based or subject-based. The current study examines the role individual differences play in subsecond and suprasecond timing judgments, using the schizoptypy personality scale as a test- case approach for quantifying a broad range of individual differences. In two experiments, 129 (Experiment 1) and 141 (Experiment 2) subjects completed the O-LIFE personality questionnaire prior to performing a modified temporal-bisect ion task. In the bisection task, subjects responded to two identical instantiations of a luminance grating presented in a 4deg window, 4deg above fixation for 1.5 s Experiment 1) or 3 s (Experiment 2). Subjects initiated presentation with a button- press, and released the button when they considered the stimulus to be half-way through (750/1500 ms). Subjects were then asked to indicate their ‘most accurate estimate’ of the two intervals. In this way we measure both performance on the task (a first-order measure) and the subjects’ knowledge of their performance (a second-order measure). In Experiment 1 the effect of grating-drift and feedback on performance was also examined. Experiment 2 focused on the static/no-feedback condition. For the group data, Experiment 1 showed a significant effect of presentation order in the baseline condition (no feedback), which disappeared when feedback was provided. Moving the stimulus had no effect on perceived duration. Experiment 2 showed no effect of stimulus presentation order. This elimination of the subsecond order-effect was at the expense of accuracy, as the mid-point of the suprasecond interval was generally underestimated. Response precision increased as a proportion of total duration, reducing the variance below that predicted by Weber’s law. This result is consistent with a breakdown of the scalar properties of time perception in the early suprasecond range. All subjects showed good insight into their own performance, though that insight did not necessarily correlate with the veridical bisection point. In terms of personality, we found evidence of significant differences in performance along the Unusual Experiences subscale, of most theoretical interest here, in the subsecond condition only. There was also significant correlation with Impulsive Nonconformity and Cognitive Disorganisation in the sub- and suprasecond conditions, respectively. Overall, these data support a partial dissocation of timing mechanisms at very short and slightly longer intervals. Further, these results suggest that perception is not the only critical mitigator of confidence in temporal experience, since individuals can effectively compensate for differences in perception at the level of metacognition in early suprasecond time. Though there are individual differences in performance, these are perhaps less than expected from previous reports and indicate an effective timing mechanism dealing with brief durations independent of the influence of significant personality trait differences

Reappraisal of the interplay between psychosis and depression symptoms in the pathogenesis of psychotic syndromes: results from a twenty-year prospective community study

The interplay of psychotic and affective symptoms is a crucial challenge in understanding the pathogenesis of psychosis. In this study, we analyzed the interplay between two subclinical psychosis symptoms dimensions, and one depression symptoms dimension, using longitudinal data from Zurich. The Zurich study started in 1979 with a representative sample of 591 participants who were aged 20/21. Follow-up interviews were conducted at age 23, 28, 30, 35, and 41. The psychiatric symptoms were assessed with a semi-structured interview and the SCL 90-R. In this study, we analyzed three SCL-90-R subscales: the depression symptoms dimension and two distinct symptoms dimensions of subclinical psychosis, one representing a schizophrenia nuclear symptom dimension, the other representing a schizotypal symptoms dimension. Modeling was done with hybrid latent growth models, thereby including simultaneous and cross-lagged effects. The interplay between the two subclinical psychosis symptoms dimensions and the depression symptoms dimension includes several intertwined pathways. The schizotypal symptoms dimension has strong direct effects on the schizophrenia nuclear symptoms dimension, but also on the depression symptoms dimension. The latter has for its part an effect on the schizophrenia nuclear symptoms dimension. The main driving force within the dynamic interplay between depression and psychosis symptoms is a schizotypal symptoms dimension, which represents social and interpersonal deficiencies, ideas of reference, suspiciousness, paranoid ideation, and odd behavior. It does not only directly influence subclinical nuclear schizophrenia symptoms but also the symptoms of depression