Compound heterozygous inheritance of two novel COQ2 variants results in familial coenzyme Q deficiency.

BACKGROUND: Primary coenzyme Q10 deficiency is a rare disease that results in diverse and variable clinical manifestations. Nephropathy, myopathy and neurologic involvement are commonly associated, however retinopathy has also been observed with certain pathogenic variants of genes in the coenzyme Q biosynthesis pathway. In this report, we describe a novel presentation of the disease that includes nephropathy and retinopathy without neurological involvement, and which is the result of a compound heterozygous state arising from the inheritance of two recessive potentially pathogenic variants, previously not described. MATERIALS AND METHODS: Retrospective report, with complete ophthalmic examination, multimodal imaging, electroretinography, and whole exome sequencing performed on a family with three affected siblings. RESULTS: We show that affected individuals in the described family inherited two heterozygous variants of the COQ2 gene, resulting in a frameshift variant in one allele, and a predicted deleterious missense variant in the second allele (c.288dupC,p.(Ala97Argfs*56) and c.376C > G,p.(Arg126Gly) respectively). Electroretinography results were consistent with rod-cone dystrophy in the affected individuals. All affected individuals in the family exhibited the characteristic retinopathy as well as end-stage nephropathy, without evidence of any neurological involvement. CONCLUSIONS: We identified two novel compound heterozygous variants of the COQ2 gene that result in primary coenzyme Q deficiency. Targeted sequencing of coenzyme Q biosynthetic pathway genes may be useful in diagnosing oculorenal clinical presentations syndromes not explained by more well known syndromes (e.g., Senior-Loken and Bardet-Biedl syndromes).

SCAPER-associated nonsyndromic autosomal recessive retinitis pigmentosa.

Mutations in the gene SCAPER (S-phase CyclinA Associated Protein residing in the Endoplasmic Reticulum) have recently been identified as causing syndromic autosomal recessive retinitis pigmentosa with the extraocular manifestations of intellectual disability and attention-deficit/hyperactivity disorder. We present the case of an 11-year-old boy that presented to our clinic with the complaint of decreased night vision. Clinical presentation, family history, and diagnostic imaging were congruent with the diagnosis of autosomal recessive retinitis pigmentosa. Genetic testing of the patient and both parents via whole-exome sequencing revealed the homozygous mutation c.2023-2A>G in SCAPER. Unique to our patient's presentation is the absence of intellectual disability and attention-deficit/hyperactivity disorder, suggesting that SCAPER-associated retinitis pigmentosa can also present without systemic manifestations.

The validity of open-source data when assessing jail suicides.

BACKGROUND: The Bureau of Justice Statistics' Deaths in Custody Reporting Program is the primary source for jail suicide research, though the data is restricted from general dissemination. This study is the first to examine whether jail suicide data obtained from publicly available sources can help inform our understanding of this serious public health problem. METHODS: Of the 304 suicides that were reported through the DCRP in 2009, roughly 56 percent (N = 170) of those suicides were identified through the open-source search protocol. Each of the sources was assessed based on how much information was collected on the incident and the types of variables available. A descriptive analysis was then conducted on the variables that were present in both data sources. The four variables present in each data source were: (1) demographic characteristics of the victim, (2) the location of occurrence within the facility, (3) the location of occurrence by state, and (4) the size of the facility. RESULTS: Findings demonstrate that the prevalence and correlates of jail suicides are extremely similar in both open-source and official data. However, for almost every variable measured, open-source data captured as much information as official data did, if not more. Further, variables not found in official data were identified in the open-source database, thus allowing researchers to have a more nuanced understanding of the situational characteristics of the event. CONCLUSIONS: This research provides support for the argument in favor of including open-source data in jail suicide research as it illustrates how open-source data can be used to provide additional information not originally found in official data. In sum, this research is vital in terms of possible suicide prevention, which may be directly linked to being able to manipulate environmental factors.

Isolation of Aggressive Behavior Mutants in Drosophila Using a Screen for Wing Damage.

Aggression is a complex social behavior that is widespread in nature. To date, only a limited number of genes that affect aggression have been identified, in large part because the complexity of the phenotype makes screening difficult and time-consuming regardless of the species that is studied. We discovered that aggressive group-housed Drosophila melanogaster males inflict damage on each other's wings, and show that wing damage negatively affects their ability to fly and mate. Using this wing-damage phenotype, we screened males from ∼1400 chemically mutagenized strains and found ∼40 mutant strains with substantial wing damage. Five of these mutants also had increased aggressive behavior. To identify the causal mutation in one of our top aggressive strains, we used whole-genome sequencing and genomic duplication rescue strategies. We identified a novel mutation in the voltage-gated potassium channel Shaker (Sh) and show that a nearby previously identified Sh mutation also results in increased aggression. This simple screen can be used to dissect the molecular mechanisms underlying aggression.

Children's Brain Responses to Optic Flow Vary by Pattern Type and Motion Speed.

Structured patterns of global visual motion called optic flow provide crucial information about an observer's speed and direction of self-motion and about the geometry of the environment. Brain and behavioral responses to optic flow undergo considerable postnatal maturation, but relatively little brain imaging evidence describes the time course of development in motion processing systems in early to middle childhood, a time when psychophysical data suggest that there are changes in sensitivity. To fill this gap, electroencephalographic (EEG) responses were recorded in 4- to 8-year-old children who viewed three time-varying optic flow patterns (translation, rotation, and radial expansion/contraction) at three different speeds (2, 4, and 8 deg/s). Modulations of global motion coherence evoked coherent EEG responses at the first harmonic that differed by flow pattern and responses at the third harmonic and dot update rate that varied by speed. Pattern-related responses clustered over right lateral channels while speed-related responses clustered over midline channels. Both children and adults show widespread responses to modulations of motion coherence at the second harmonic that are not selective for pattern or speed. The results suggest that the developing brain segregates the processing of optic flow pattern from speed and that an adult-like pattern of neural responses to optic flow has begun to emerge by early to middle childhood.

Of Fighting Flies, Mice, and Men: Are Some of the Molecular and Neuronal Mechanisms of Aggression Universal in the Animal Kingdom?

Aggressive behavior is widespread in the animal kingdom, but the degree of molecular conservation between distantly related species is still unclear. Recent reports suggest that at least some of the molecular mechanisms underlying this complex behavior in flies show remarkable similarities with such mechanisms in mice and even humans. Surprisingly, some aspects of neuronal control of aggression also show remarkable similarity between these distantly related species. We will review these recent findings, address the evolutionary implications, and discuss the potential impact for our understanding of human diseases characterized by excessive aggression.

Cortical responses to optic flow and motion contrast across patterns and speeds.

Motion provides animals with fast and robust cues for navigation and object detection. In the first case, stereotyped patterns of optic flow inform a moving observer about the direction and speed of its own movement. In the case of object detection, regional differences in motion allow for the segmentation of figures from their background, even in the absence of color or shading cues. Previous research has investigated human electrophysiological responses to global motion across speeds, but only focused upon one type of optic flow pattern. Here, we compared steady-state visual evoked potential (SSVEP) responses across patterns and speeds, both for optic flow and for motion-defined figure patterns, to assess the extent to which the processes are pattern-general or pattern-specific. For optic flow, pattern and speed effects on response amplitudes varied substantially across channels, suggesting pattern-specific processing at slow speeds and pattern-general activity at fast speeds. Responses for coherence- and direction-defined figures were comparatively more uniform, with similar response profiles and spatial distributions. Self- and object-motion patterns activate some of the same circuits, but these data suggest differential sensitivity: not only across the two classes of motion, but also across the patterns within each class, and across speeds. Thus, the results demonstrate that cortical processing of global motion is complex and activates a distributed network.

Tailless and Atrophin control Drosophila aggression by regulating neuropeptide signalling in the pars intercerebralis.

Aggressive behaviour is widespread throughout the animal kingdom. However, its mechanisms are poorly understood, and the degree of molecular conservation between distantly related species is unknown. Here we show that knockdown of tailless (tll) increases aggression in Drosophila, similar to the effect of its mouse orthologue Nr2e1. Tll localizes to the adult pars intercerebralis (PI), which shows similarity to the mammalian hypothalamus. Knockdown of tll in the PI is sufficient to increase aggression and is rescued by co-expressing human NR2E1. Knockdown of Atrophin, a Tll co-repressor, also increases aggression, and both proteins physically interact in the PI. tll knockdown-induced aggression is fully suppressed by blocking neuropeptide processing or release from the PI. In addition, genetically activating PI neurons increases aggression, mimicking the aggression-inducing effect of hypothalamic stimulation. Together, our results suggest that a transcriptional control module regulates neuropeptide signalling from the neurosecretory cells of the brain to control aggressive behaviour.

Investigation of the effect of probiotic exposure on filaggrin expression in an experimental model of canine atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) results from complex interactions between an impaired skin barrier and immunological stimulation. Filaggrin is a key protein for the skin barrier, and its expression is decreased in subsets of atopic dogs and can be modified by inflammation; thus, immunomodulatory approaches may alter its expression. Probiotics have been explored for the prevention and treatment of allergies, owing to their immunomodulatory properties; however, it is currently unknown whether they can modulate filaggrin expression. OBJECTIVE: The purpose of this study was to evaluate whether probiotics can modulate filaggrin expression in an experimental model of canine AD. ANIMALS AND METHODS: Eighteen atopic (11 probiotic exposed and seven control) and five normal beagles were challenged for three consecutive days with Dermatophagoides farinae. Skin biopsies were taken before (day 0), at the peak (day 3) and after the end of the allergen challenge (day 10). Immunohistochemistry for filaggrin was done using a polyclonal antibody specific for canine filaggrin, and staining was scored both subjectively (for intensity, granularity and continuity) and objectively, by tracing the stratum granulosum and calculating the percentage of filaggrin per unit traced area. RESULTS: Analysis of variance of the percentage of filaggrin in the stratum granulosum showed a significant effect of group (P = 0.0414, AD < normal), time (P = 0.0066, days 3 and 10 > day 0) and marginal group × time interaction (P = 0.0606). Within the atopic group, exposure to probiotics did not change filaggrin expression. No significant differences were found in the subjective scores among groups. CONCLUSIONS AND CLINICAL IMPORTANCE: It is concluded that probiotic exposure early in life does not alter filaggrin expression in this AD model.

Motor contagion in young children: Exploring social influences on perception-action coupling.

Human development occurs in a social environment in which learning is tightly coupled to the behavior of other supportive humans. One aspect of this coupling may occur through motor contagion, in which observing the actions of other people is associated with the activation of related motor representations. In order to explore the overlap between action observation and action execution in early childhood, a novel task was developed in which 4-year-old children were instructed to move a stylus on a graphics tablet in the presence of a background video which showed a model moving her arm in a direction that was either congruent or incongruent with the instructed axis of the child's stylus movements. The presence of incongruent background movements was associated with a significant interference effect on children's stylus movements. This interference effect was stronger when the background movements were performed by a same-age peer rather than by an adult. It is suggested that early childhood is a particularly interesting age period to study motor contagion, since the transition from infancy to childhood involves concurrent changes in cognitive control and in the ability to flexibly decouple perception and action. The examination of motor contagion provides an important consideration of social influences on cognitive control in early childhood--influences that have been somewhat neglected in the developmental literature on the related construct of executive functioning.