Molecular dynamics studies of trinucleotide repeat DNA involved in neurodegenerative disorders.

Expansion of trinucleotide repeat DNA of the classes CAG�·CTG, CGG�·CCG and GAA�·TTC are found to be associated with several neurodegenerative disorders. Different mechanisms have been attributed to the expansion of triplets, mainly involving the formation of alternate secondary structures by such repeats. This paper reports the molecular dynamics simulation of triplet repeat DNA sequences to study the basic structural features of DNA that are responsible for the formation of structures such as hairpins and slip-strand DNA leading to expansion. All the triplet repeat sequences studied were found to be more flexible compared to the control sequence unassociated with disease. Moreover, flexibility was found to be in the order CAG�·CTG > CGG�·CCG = GAA�·TTC, the highly flexible CAG�·CTG repeat being the most common cause of neurodegenerative disorders. In another simulation, a single G�·C to T�·A mutation at the 9th position of the CAG�·CTG repeat exhibited a reduction in bending compared to the pure 15-mer CAGâ�¢CTG repeat. EPM1 dodecamer repeat associated with the pathogenesis of progressive myoclonus epilepsy was also simulated and showed flexible nature suggesting a similar expansion mechanism.

Genetic disorders and spermatogenesis.

Male infertility affects one man in twenty and a genetic basis seems likely in at least 30% of those men. Genetic regulation of fertility involves the inter-related processes of testicular development, spermatogenesis (involving germ cell mitosis, meiosis and spermatid maturation), and their endocrine and paracrine regulation. In regard to spermatogenesis, particular attention has been given to the Yq11 region, where some spermatogenesis genes ('azoospermia factors') appear to be located. Several candidate genes have been identified but have not been shown to have a defined or essential role in spermatogenesis. Microdeletions of Yq11 are found in approximately 15% of azoospermic or severely oligospermic men. The complexity of the genetic control of male fertility is demonstrated by the evidence for genes involved in spermatogenesis and sexual differentiation on the X chromosome and autosomes. Better understanding of the genetic regulation of normal spermatogenesis will provide new probes for clinical studies; however, at present the majority of spermatogenic failure remains without an identified genetic linkage. The advent of intracytoplasmic sperm injection permits fertility in many previously sterile men and presents the possibility of their transmission of infertility; appropriate counselling is required.

miR-7 and miR-214 are specifically expressed during neuroblastoma differentiation, cortical development and embryonic stem cells differentiation, and control neurite outgrowth in vitro

The mammalian nervous system exerts essential control on many physiological processes in the organism and is itself controlled extensively by a variety of genetic regulatory mechanisms. microRNA (miR), an abundant class of small non-coding RNA, are emerging as important post-transcriptional regulators of gene expression in the brain. Increasing evidence indicates that miR regulate both the development and function of the nervous system. Moreover, deficiency in miR function has also been implicated in a number of neurological disorders. Expression profile analysis of miR is necessary to understand their complex role in the regulation of gene expression during the development and differentiation of cells. Here we present a comparative study of miR expression profiles in neuroblastoma, in cortical development, and in neuronal differentiation of embryonic stem (ES) cells. By microarray profiling in combination with real time PCR we show that miR-7 and miR-214 are modulated in neuronal differentiation (as compared to miR-1, -16 and -133a), and control neurite outgrowth in vitro. These findings provide an important step toward further elucidation of miR function and miR-related gene regulatory networks in the mammalian central nervous system. (C) 2010 Elsevier Inc. All rights reserved.

A Bayesian analysis of the chromosome architecture of human disorders by integrating reductionist data

In this paper, we present a Bayesian approach to estimate a chromosome and a disorder network from the Online Mendelian Inheritance in Man (OMIM) database. In contrast to other approaches, we obtain statistic rather than deterministic networks enabling a parametric control in the uncertainty of the underlying disorder-disease gene associations contained in the OMIM, on which the networks are based. From a structural investigation of the chromosome network, we identify three chromosome subgroups that reflect architectural differences in chromosome-disorder associations that are predictively exploitable for a functional analysis of diseases.

Real-life Social Attention in Children with Autism Spectrum Disorders

Autism is a neuro-developmental disorder defined by atypical social behaviour, of which atypical social attention behaviours are among the earliest clinical markers (Volkmar et al., 1997). Eye tracking studies using still images and movie clips have provided a method for the precise quantification of atypical social attention in ASD. This is generally characterised by diminished viewing of the most socially pertinent regions (eyes), and increased viewing of less socially informative regions (body, background, objects) (Klin et al., 2002; Riby & Hancock, 2008, 2009). Ecological validity within eye tracking studies has become an increasingly important issue. As of yet, however, little is known about the precise nature of the atypicalities of social attention in ASD in real-life. Objectives: To capture and quantify gaze patterns for children with an ASD within a real life setting, compared to two Typically Developing (TD) comparison groups. Methods: Nine children with an ASD were compared to two age matched TD groups – a verbal (N=9) and a non-verbal (N=9) comparison group. A real-life scenario was created involving an experimenter posing as a magician, and consisted of 3 segments: a conversation segment; a magic trick segment; and a puppet segment. The first segment explored children’s attentional preferences during a real-life conversation; the magic trick segment explored children’s use of the eyes as a communicative cue, and the puppet segment explored attention capture. Finally, part of the puppet section explored children’s use of facial information in response to an unexpected event. Results: The most striking difference between the groups was the diminished viewing of the eyes by the ASD group in comparison to both control groups. This was found particularly during the conversation segment, but also during the magic trick segment, and during the puppet segment. When in conversation, participants with ASD were found to spend a greater proportion time looking off-screen, in comparison to TD participants. There was also a tendency for the ASD group to spend a greater proportion of time looking to the mouth of the experimenter. During the magic trick segment, despite the fact that the eyes were not predictive of a correct location, both TD comparison groups continued to use the eyes as a communicative cue, whereas the ASD group did not. In the puppet segment, all three groups spent a similar amount of time looking between the puppet and regions of the experimenter’s face. However, in response to an unexpected event, the ASD group were significantly slower to fixate back on the experimenter’s face. Conclusions: The results demonstrate the reduced salience of socially pertinent information for children with ASD in real life, and they provide support for the findings from previous eye tracking studies involving scene viewing. However, the results also highlight a pattern looking off-screen for both the TD and ASD groups. This eye movement behaviour is likely to be associated specifically with real-life interaction, as it has functional relevance (Doherty-Sneddon et al., 2002). However, the fact that it is significantly increased in the ASD group has implications for their understanding of real life social interactions.

The sympathetic release test: a test used to assess thermoregulation and autonomic control of blood flow

When a subject is heated, the stimulation of temperature-sensitive nerve endings in the skin, and the raising of the central body temperature, results in the reflex release of sympathetic vasoconstrictor tone in the skin of the extremities, causing a measurable temperature increase at the site of release. In the sympathetic release test, the subject is gently heated by placing the feet and calves in a commercially available foot warming pouch or immersing the feet and calves in warm water and wrapping the subject in blankets. Skin blood flow is estimated from measurements of skin temperature in the fingers. Normally skin temperature of the fingers is 65-75 degrees F in cool conditions (environmental temperature: 59-68 degrees F) and rises to 85-95 degrees F during body heating. Deviations in this pattern may mean that there is abnormal sympathetic vasoconstrictor control of skin blood flow. Abnormal skin blood flow can substantially impair an individual's ability to thermoregulate and has important clinical implications. During whole body heating, the skin temperature from three different skin sites is monitored and oral temperature is monitored as an index of core temperature. Students determine the fingertip temperature at which the reflex release of sympathetic activity occurs and its maximal attainment, which reflects the vasodilating capacity of this cutaneous vascular bed. Students should interpret typical sample data for certain clinical conditions (Raynaud's disease, peripheral vascular disease, and postsympathectomy) and explain why there may be altered skin blood flow in these disorders.

Clinical features of psychotic disorders and polymorphisms in HT2A, DRD2, DRD4, SLC6A3 (DAT1), and BDNF:a family based association study

Schizophrenia is clinically heterogeneous and multidimensional, but it is not known whether this is due to etiological heterogeneity. Previous studies have not consistently reported association between any specific polymorphisms and clinical features of schizophrenia, and have primarily used case-control designs. We tested for the presence of association between clinical features and polymorphisms in the genes for the serotonin 2A receptor (HT2A), dopamine receptor types 2 and 4, dopamine transporter (SLC6A3), and brain-derived neurotrophic factor (BDNF). Two hundred seventy pedigrees were ascertained on the basis of having two or more members with schizophrenia or poor outcome schizoaffective disorder. Diagnoses were made using a structured interview based on the SCID. All patients were rated on the major symptoms of schizophrenia scale (MSSS), integrating clinical and course features throughout the course of illness. Factor analysis revealed positive, negative, and affective symptom factors. The program QTDT was used to implement a family-based test of association for quantitative traits, controlling for age and sex. We found suggestive evidence of association between the His452Tyr polymorphism in HT2A and affective symptoms (P = 0.02), the 172-bp allele of BDNF and negative symptoms (P = 0.04), and the 480-bp allele in SLC6A3 (= DAT1) and negative symptoms (P = 0.04). As total of 19 alleles were tested, we cannot rule out false positives. However, given prior evidence of involvement of the proteins encoded by these genes in psychopathology, our results suggest that more attention should be focused on the impact of these alleles on clinical features of schizophrenia.

Postural Control Deficits in Autism Spectrum Disorder: The Role of Sensory Integration

We investigated the nature of sensory integration deficits in postural control of young adults with ASD. Postural control was assessed in a fixed environment, and in three environments in which sensory information about body sway from visual, proprioceptive or both channels was inaccurate. Furthermore, two levels of inaccurate information were used within each channel (gain 1 and 1.6). ASD participants showed greater postural sway when information from proprioceptive and both channels were inaccurate. In addition, control participants' ellipse area at gain 1.6 was identical to ASD participants' at gain 1, reflecting hyper-reactivity in ASD. Our results provide evidence for hyper-reactivity in posture-related sensory information, which reflects a general, rather than channel-specific sensory integration impairment in ASD.

LNK mutations and myeloproliferative disorders

The lymphocyte adaptor protein (LNK) is one of a family of adaptor proteins involved cell signalling and control of B cell populations. It has a critical role in regulation of signalling in hematopoiesis. Lnk negatively regulates cytokine initiated cell signalling and it functions as a negative regulator of the mutant protein in myeloproliferative neoplasms JAK2V617F. A number of mutations in LNK have been described in a variety of myeloproliferative neoplasms some of which have been demonstrated to cause increased cellular proliferation. The majority of mutations occur in exon 2. In a small number of cases idiopathic erythrocytosis with subnormal erythropoietin levels LNK mutations have been found which may account for the clinical phenotype. Thus investigation for LNK mutations should be considered in the investigation of idiopathic erythrocytosis and perhaps other myeloproliferative neoplasms.