Autism Spectrum Disorders: Multiple Routes to, and Multiple Consequences of, Abnormal Synaptic Function and Connectivity

Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders of genetic and environmental etiologies. Some ASD cases are syndromic: associated with clinically defined patterns of somatic abnormalities and a neurobehavioral phenotype (e.g., Fragile X syndrome). Many cases, however, are idiopathic or non-syndromic. Such disorders present themselves during the early postnatal period when language, speech, and personality start to develop. ASDs manifest by deficits in social communication and interaction, restricted and repetitive patterns of behavior across multiple contexts, sensory abnormalities across multiple modalities and comorbidities, such as epilepsy among many others. ASDs are disorders of connectivity, as synaptic dysfunction is common to both syndromic and idiopathic forms. While multiple theories have been proposed, particularly in idiopathic ASDs, none address why certain brain areas (e.g., frontotemporal) appear more vulnerable than others or identify factors that may affect phenotypic specificity. In this hypothesis article, we identify possible routes leading to, and the consequences of, altered connectivity and review the evidence of central and peripheral synaptic dysfunction in ASDs. We postulate that phenotypic specificity could arise from aberrant experience-dependent plasticity mechanisms in frontal brain areas and peripheral sensory networks and propose why the vulnerability of these areas could be part of a model to unify preexisting pathophysiological theories.

Contribution of adipocyte precursors in the phenotypic specificity of intra-articular adipose tissues in knee osteoarthritis patients

Background Intra-articular adipose tissues (IAATs) are involved in osteoarthritis (OA) pathophysiology. We hypothesize that mesenchymal cells residing in IAATs may account for the specific inflammatory and metabolic patterns in OA patients. Methods Adipocyte precursors (preadipocytes and dedifferentiated fat cells (DFATc)) from IAATs (infrapatellar and suprapatellar fat pads) and autologous subcutaneous adipose tissues (SCATs) were isolated from knee OA patients. The ability of these precursors to differentiate into adipocytes was assessed by oil red O staining after 14 days of culture in adipogenic medium. The gene expression of adipocyte-related transcription factors (C/EBP-α and PPAR-γ) and development-related factors (EN1 and SFRP2) were analyzed. The inflammatory pattern was assessed by RT-qPCR and ELISA (interleukin 6 (IL-6), IL-8, Cox2, and prostaglandin E2 (PGE2)) after a 24-h stimulation by IL-1β (1 ng/mL) and by conditioned medium from OA synovium. Results IAAT preadipocytes displayed a significantly higher ability to differentiate into adipocytes and expressed significantly more C/EBP-α mRNA than SCAT preadipocytes. IAAT preadipocytes expressed significantly less EN-1 and SFRP2 mRNA than SCAT preadipocytes. Unstimulated IAAT preadipocytes displayed a less inflammatory pattern (IL-6, IL-8, and Cox2/PGE2) than SCAT preadipocytes. In contrast, the response of IAAT preadipocytes to an inflammatory stimulus (IL-1β and conditioned media of OA synovium) was exacerbated compared to that of SCAT preadipocytes. Similar results were obtained with DFATc. Conclusion IAAT adipocyte precursors from OA patients have a specific phenotype, which may account for the unique phenotype of OA IAATs. The exacerbated response of IAAT preadipocytes to inflammatory stimulation may contribute to OA pathophysiology.

Differential gene retention as an evolutionary mechanism to generate biodiversity and adaptation in yeasts

The evolutionary history of the characters underlying the adaptation of microorganisms to food and biotechnological uses is poorly understood. We undertook comparative genomics to investigate evolutionary relationships of the dairy yeast Geotrichum candidum within Saccharomycotina. Surprisingly, a remarkable proportion of genes showed discordant phylogenies, clustering with the filamentous fungus subphylum (Pezizomycotina), rather than the yeast subphylum (Saccharomycotina), of the Ascomycota. These genes appear not to be the result of Horizontal Gene Transfer (HGT), but to have been specifically retained by G. candidum after the filamentous fungi–yeasts split concomitant with the yeasts’ genome contraction. We refer to these genes as SRAGs (Specifically Retained Ancestral Genes), having been lost by all or nearly all other yeasts and thus contributing to the phenotypic specificity of lineages. SRAG functions include lipases consistent with a role in cheese making and novel endoglucanases associated with degradation of plant material. Similar gene retention was observed in three other distantly related yeasts representative of this ecologically diverse subphylum. The phenomenon thus appears to be widespread in the Saccharomycotina and argues that, alongside neo-functionalization following gene duplication and HGT, specific gene retention must be recognized as an important mechanism for generation of biodiversity and adaptation in yeasts.

Holes and channels between the ventricles revisited

BackgroundAlthough holes, or channels, between the ventricles are the commonest congenital cardiac malformations, there is still no consensus as to how they can best be described and categorised. So as to assess whether it is possible to produce a potentially universally acceptable system, we have analysed the hearts categorised as having ventricular septal defects in a large archive held at Birmingham Children’s Hospital.Materials and methodsWe analysed all the hearts categorised as having isolated ventricular septal defects, or those associated with aortic coarctation or interruption in the setting of concordant ventriculo-arterial connections, in the archive of autopsied hearts held at Birmingham Children’s Hospital, United Kingdom.ResultsWe found 147 hearts within the archive fulfilling our criterions for inclusion. All could be classified within one of three groups depending on their borders as seen from the right ventricle. To provide full description, however, it was also necessary to take account of the way the defects opened to the right ventricle, and the presence or absence of alignment between the septal components.ConclusionsBy combining information on the phenotypic specificity defined on the basis of their borders, the direction of opening into the right ventricle, and the presence or absence of septal malalignment, it proved possible to categorise all hearts examined within the archive of Birmingham Children’s Hospital. Our findings have necessitated creation of new numbers within the European Paediatric Cardiac Code.

Convergent and Divergent Amplification and its Meaning for Social Science

Social science is viewed as requiring a paradigm fundamentally different from that currently in use which reflects essentially the habits of classical physics. Its basic characteristic is the prevalence of minor and major events which amplify sequentially in such a way as to converge toward or diverge from expected outcomes. Other distinguishing characteristics of social science are discussed in the context of amplification and include the historicity of its subject matter, the everpresent tension between stability and change, the frequent primacy of phenotypic specificity over a genotypic generality, the importance of context and meaning in the constitution of data, and the altering effects of theory on reality. Recognition of these characteristics requires a change in the role of the investigator so as to include him more intimately in the research process. It also suggests the usefulness of substitution of an orientative sample for the usual representative sample to take into account the researcher's new role, especially in the context of amplification. The orientative sample permits an accretionary N ≥ 1 initially, as the investigator is sensitized and instructed in the course of his research.

Phenotypic specificity of aneuploid states in Aspergillus nidulans

SUMMARYHyperhaploid and hyperdiploid colonies of Aspergillus nidulans, disomic or trisomic for one or more chromosomes respectively, are abnormal in phenotype and somatically unstable. It has been shown for Glasgow strains that a different specific phenotype arises, depending upon which chromosome is additional (Pollard, Käfer & Johnston, 1968). This report extends this system and shows that irrespective of the residual genetic background of the isolate, the system of phenotypic specificity applies.