A cooperative interaction between LPHN3 and 11q doubles the risk for ADHD

In previous studies of a genetic isolate, we identified significant linkage of attention deficit hyperactivity disorder (ADHD) to 4q, 5q, 8q, 11q and 17p. The existence of unique large size families linked to multiple regions, and the fact that these families came from an isolated population, we hypothesized that two-locus interaction contributions to ADHD were plausible. Several analytical models converged to show significant interaction between 4q and 11q (P<1 × 10−8) and 11q and 17p (P<1 × 10−6). As we have identified that common variants of the LPHN3 gene were responsible for the 4q linkage signal, we focused on 4q–11q interaction to determine that single-nucleotide polymorphisms (SNPs) harbored in the LPHN3 gene interact with SNPs spanning the 11q region that contains DRD2 and NCAM1 genes, to double the risk of developing ADHD. This interaction not only explains genetic effects much better than taking each of these loci effects by separated but also differences in brain metabolism as depicted by proton magnetic resonance spectroscopy data and pharmacogenetic response to stimulant medication. These findings not only add information about how high order genetic interactions might be implicated in conferring susceptibility to develop ADHD but also show that future studies of the effects of genetic interactions on ADHD clinical information will help to shape predictive models of individual outcome

A common genetic network underlies substance use disorders and disruptive or externalizing disorders

Here we summarize evidence obtained by our group during the last two decades, and contrasted it with a review of related data from the available literature to show that behavioral syndromes involving attention deficit/hyperactivity disorder (ADHD), externalizing disorders, and substance-use disorder (SUD) share similar signs and symptoms (i.e., have a biological basis as common syndromes), physiopathological and psychopathological mechanisms, and genetic factors. Furthermore, we will show that the same genetic variants harbored in different genes are associated with different syndromes and that non-linear interactions between genetic variants (epistasis) best explain phenotype severity, long-term outcome, and response to treatment. These data have been depicted in our studies by extended pedigrees, where ADHD, externalizing symptoms, and SUD segregate and co-segregate. Finally, we applied here a new formal network analysis using the set of significantly replicated genes that have been shown to be either associated and/or linked to ADHD, disruptive behaviors, and SUD in order to detect significantly enriched gene categories for protein and genetic interactions, pathways, co-expression, co-localization, and protein domain similarity. We found that networks related to pathways involved in axon guidance, regulation of synaptic transmission, and regulation of transmission of nerve impulse are overrepresented. In summary, we provide compiled evidence of complex networks of genotypes underlying a wide phenotype that involves SUD and externalizing disorders

Defining Natural History: Assessment of the Ability of College Students to Aid in Characterizing Clinical Progression of Niemann-Pick Disease, Type C

Niemann-Pick Disease, type C (NPC) is a fatal, neurodegenerative, lysosomal storage disorder. It is a rare disease with broad phenotypic spectrum and variable age of onset. These issues make it difficult to develop a universally accepted clinical outcome measure to assess urgently needed therapies. To this end, clinical investigators have defined emerging, disease severity scales. The average time from initial symptom to diagnosis is approximately 4 years. Further, some patients may not travel to specialized clinical centers even after diagnosis. We were therefore interested in investigating whether appropriately trained, community-based assessment of patient records could assist in defining disease progression using clinical severity scores. In this study we evolved a secure, step wise process to show that pre-existing medical records may be correctly assessed by non-clinical practitioners trained to quantify disease progression. Sixty-four undergraduate students at the University of Notre Dame were expertly trained in clinical disease assessment and recognition of major and minor symptoms of NPC. Seven clinical records, randomly selected from a total of thirty seven used to establish a leading clinical severity scale, were correctly assessed to show expected characteristics of linear disease progression. Student assessment of two new records donated by NPC families to our study also revealed linear progression of disease, but both showed accelerated disease progression, relative to the current severity scale, especially at the later stages. Together, these data suggest that college students may be trained in assessment of patient records, and thus provide insight into the natural history of a disease

CpG-creating mutations are costly in many human viruses.

Mutations can occur throughout the virus genome and may be beneficial, neutral or deleterious. We are interested in mutations that yield a C next to a G, producing CpG sites. CpG sites are rare in eukaryotic and viral genomes. For the eukaryotes, it is thought that CpG sites are rare because they are prone to mutation when methylated. In viruses, we know less about why CpG sites are rare. A previous study in HIV suggested that CpG-creating transition mutations are more costly than similar non-CpG-creating mutations. To determine if this is the case in other viruses, we analyzed the allele frequencies of CpG-creating and non-CpG-creating mutations across various strains, subtypes, and genes of viruses using existing data obtained from Genbank, HIV Databases, and Virus Pathogen Resource. Our results suggest that CpG sites are indeed costly for most viruses. By understanding the cost of CpG sites, we can obtain further insights into the evolution and adaptation of viruses

Regeneration of the axotomised sciatic nerve in dogs using the tubulisation technique with chitosan bioma terial preloaded with progesterone [Regeneración del nervio ciático axotomizado del perro mediante la técnica de tubulización con el biomaterial quitosana precargado con progesterona]

Introduction. Injuries to peripheral nerves can have different causes and may lead to disorders affecting mobility, sensitivity and loss of motor function as they progress. Weiss, in 1944, introduced tubulisation to promote the regeneration of a sectioned nerve. In this study the biomaterial Chitosan was used to induce and stimulate the regeneration of the sciatic nerve in dogs. At the same time, we took advantage of the characteristics offered by Chitosan to include the neurosteroid progesterone in its matrix, as a promoter of axonal growth. Aims. The aim of our study was to determine the degree of regeneration of the sciatic nerve in dogs when axotomised-tubulised with a Chitosan prosthesis steeped in the neurosteroid progesterone. Materials and methods. Young adult female dogs were used to evaluate the regeneration of the sciatic nerve induced at a standard of 15 mm; regeneration was determined by means of an axonal growth chamber. Nerve growth was studied through histological analysis and by electron microscope. Results. The statistical analysis showed that there were no significant differences in the number of myelinated fibres between the experimental groups. The electron microscope images of the transmission in the regenerated nerves in the groups that were tubulised with Chitosan, with and without neurosteroid preloading, revealed an advanced regenerative process. This was evidenced by the fact that collagen fibres, elastin, Schwann cells and both myelinated and non-myelinated fibres were observed in all cases. Conclusions. The regeneration of axotomised, tubulised nerves was achieved regardless of the treatment that was applied. The distal nerve segment that was analysed revealed a similar structure to that of a normal nerve

Regeneration of the axotomised sciatic nerve in dogs using the tubulisation technique with chitosan bioma terial preloaded with progesterone [Regeneraci�n del nervio ci�tico axotomizado del perro mediante la t�cnica de tubulizaci�n con el biomaterial quitosana precargado con progesterona]

Introduction. Injuries to peripheral nerves can have different causes and may lead to disorders affecting mobility, sensitivity and loss of motor function as they progress. Weiss, in 1944, introduced tubulisation to promote the regeneration of a sectioned nerve. In this study the biomaterial Chitosan was used to induce and stimulate the regeneration of the sciatic nerve in dogs. At the same time, we took advantage of the characteristics offered by Chitosan to include the neurosteroid progesterone in its matrix, as a promoter of axonal growth. Aims. The aim of our study was to determine the degree of regeneration of the sciatic nerve in dogs when axotomised-tubulised with a Chitosan prosthesis steeped in the neurosteroid progesterone. Materials and methods. Young adult female dogs were used to evaluate the regeneration of the sciatic nerve induced at a standard of 15 mm; regeneration was determined by means of an axonal growth chamber. Nerve growth was studied through histological analysis and by electron microscope. Results. The statistical analysis showed that there were no significant differences in the number of myelinated fibres between the experimental groups. The electron microscope images of the transmission in the regenerated nerves in the groups that were tubulised with Chitosan, with and without neurosteroid preloading, revealed an advanced regenerative process. This was evidenced by the fact that collagen fibres, elastin, Schwann cells and both myelinated and non-myelinated fibres were observed in all cases. Conclusions. The regeneration of axotomised, tubulised nerves was achieved regardless of the treatment that was applied. The distal nerve segment that was analysed revealed a similar structure to that of a normal nerve

Pathogenicity of Isolates of Serratia Marcescens towards Larvae of the Scarab Phyllophaga Blanchardi (Coleoptera)

Serratia marcescens is a Gram negative bacterium (Enterobacteriaceae) often associated with infection of insects. In order to find pathogenic bacteria with the potential to control scarab larvae, several bacterial strains were isolated from the hemocoel of diseased Phyllophaga spp (Coleoptera:Scarabaeidae) larvae collected from cornfields in Mexico. Five isolates were identified as Serratia marcescens by 16S rRNA gene sequencing and biochemical tests. Oral and injection bioassays using healthy Phyllophaga blanchardi larvae fed with the S. marcescens isolates showed different degrees of antifeeding effect and mortality. No insecticidal activity was observed for Spodoptera frugiperda larvae (Lepidoptera: Noctuidae) by oral inoculation. S. marcescens (Sm81) cell-free culture supernatant caused significant antifeeding effect and mortality to P. blanchardi larvae by oral bioassay and also mortality by injection bioassay. Heat treated culture broths lost the ability to cause disease symptoms, suggesting the involvement of proteins in the toxic activity. A protein of 50.2 kDa was purified from the cell-free broth and showed insecticidal activity by injection bioassay towards P. blanchardi. Analysis of the insecticidal protein by tandem- mass spectrometry (LC-MS/MS) showed similarity to a Serralysin-like protein from S. marcescens spp. This insecticidal protein could have applications in agricultural biotechnology

[Regeneration of the axotomised sciatic nerve in dogs using the tubulisation technique with Chitosan biomaterial preloaded with progesterone]

INTRODUCTION: Injuries to peripheral nerves can have different causes and may lead to disorders affecting mobility, sensitivity and loss of motor function as they progress. Weiss, in 1944, introduced tubulisation to promote the regeneration of a sectioned nerve. In this study the biomaterial Chitosan was used to induce and stimulate the regeneration of the sciatic nerve in dogs. At the same time, we took advantage of the characteristics offered by Chitosan to include the neurosteroid progesterone in its matrix, as a promoter of axonal growth. AIMS. The aim of our study was to determine the degree of regeneration of the sciatic nerve in dogs when axotomised tubulised with a Chitosan prosthesis steeped in the neurosteroid progesterone. MATERIALS AND METHODS: Young adult female dogs were used to evaluate the regeneration of the sciatic nerve induced at a standard of 15 mm; regeneration was determined by means of an axonal growth chamber. Nerve growth was studied through histological analysis and by electron microscope. RESULTS: The statistical analysis showed that there were no significant differences in the number of myelinated fibres between the experimental groups. The electron microscope images of the transmission in the regenerated nerves in the groups that were tubulised with Chitosan, with and without neurosteroid preloading, revealed an advanced regenerative process. This was evidenced by the fact that collagen fibres, elastin, Schwann cells and both myelinated and non myelinated fibres were observed in all cases. CONCLUSIONS: The regeneration of axotomised, tubulised nerves was achieved regardless of the treatment that was applied. The distal nerve segment that was analysed revealed a similar structure to that of a normal nerve