The amino acid composition of a protein influences its expression.

The quantity of each protein in a cell only is only partially correlated with its gene transcription rate. Independent influences on protein synthesis levels include mRNA sequence motifs, amino acyl-tRNA synthesis levels, elongation factor action, and protein susceptibility to degradation. Here we report that the amino acid composition of a protein can also influence its expression level in two distinct ways.

Genes associated with amyloid-beta-induced inflammasome-mediated neuronal death identified using functional gene trap mutagenesis approach.

Alzheimer's disease is an irreversible neurodegenerative disease, which accounts for most dementia cases. Neuroinflammation is increasingly recognised for its roles in Alzheimer's disease pathogenesis which, in part, links amyloid-beta to neuronal death. Neuroinflammatory signalling can be exhibited by neurons themselves, potentially leading to widespread neuronal cell death, although neuroinflammation is commonly associated with glial cells.

Genomics of Lithium Action and Response.

(Reprinted with permission from (2017) 14:582-587).

The Role of Neuronal NLRP1 Inflammasome in Alzheimer's Disease: Bringing Neurons into the Neuroinflammation Game.

The innate immune system and inflammatory response in the brain have critical impacts on the pathogenesis of many neurodegenerative diseases including Alzheimer's disease (AD). In the central nervous system (CNS), the innate immune response is primarily mediated by microglia. However, non-glial cells such as neurons could also partake in inflammatory response independently through inflammasome signalling.

PEGylation of polypropylenimine dendrimers: effects on cytotoxicity, DNA condensation, gene delivery and expression in cancer cells.

Diaminobutyric polypropylenimine (DAB) dendrimers have been shown to be highly efficient non-viral gene delivery systems for cancer therapy. However, their cytotoxicity currently limits their applications. To overcome this issue, PEGylation of DAB dendrimer, using various PEG molecular weights and dendrimer generations, has been attempted to decrease the cytotoxicity and enhance the DNA condensation, size and zeta potential, cellular uptake and transfection efficacy of these dendriplexes.

Genomics of Lithium Action and Response.

Lithium is the most successful mood stabilizer treatment for bipolar disorder. However, unlike conventional drugs that are designed to interact with a specific molecular target, the actions of lithium are distributed across many biological processes and pathways. Treatment response is subject to genetic variation between individuals and similar genetic variation may dictate susceptibility to side effects.

Specialized Information Processing Deficits and Distinct Metabolomic Profiles Following TM-Domain Disruption of Nrg1.

Although there is considerable genetic and pathologic evidence for an association between neuregulin 1 (NRG1) dysregulation and schizophrenia, the underlying molecular and cellular mechanisms remain unclear. Mutant mice containing disruption of the transmembrane (TM) domain of the NRG1 gene constitute a heuristic model for dysregulation of NRG1-ErbB4 signaling in schizophrenia. The present study focused on hitherto uncharacterized information processing phenotypes in this mutant line.

Copy Number Variations in DISC1 and DISC1-Interacting Partners in Major Mental Illness.

Robust statistical, genetic and functional evidence supports a role for in the aetiology of major mental illness. Furthermore, many of its protein-binding partners show evidence for involvement in the pathophysiology of a range of neurodevelopmental and psychiatric disorders. Copy number variants (CNVs) are suspected to play an important causal role in these disorders.

The EpiTect Methyl qPCR Assay as novel age estimation method in forensic biology.

Human aging is associated with epigenetic modification of the genome. DNA methylation at cytosines appears currently as the best characterised modification that occurs during the mammalian lifetime. Such methylation changes at regulatory region can provide insights to track contributor age for criminal investigation.

Quantification of global mitochondrial DNA methylation levels and inverse correlation with age at two CpG sites.

Mammalian ageing features biological attrition evident at cellular, genetic and epigenetic levels. Mutation of mitochondrial DNA, and nuclear DNA methylation changes are well established correlates of ageing. The methylation of mitochondrial DNA (mtDNA) is a new and incompletely described phenomenon with unknown biological control and significance.

Enhanced gene expression in the brain following intravenous administration of lactoferrin-bearing polypropylenimine dendriplex.

The possibility of using gene therapy for the treatment of brain diseases such as brain cancer, Alzheimer's and Parkinson's diseases, is currently hampered by the lack of gene delivery systems able to cross the blood-brain barrier and deliver DNA to the brain following intravenous administration. On the basis that lactoferrin can effectively reach the brain by using specific receptors for crossing the blood-brain barrier, we propose to investigate if a lactoferrin-bearing generation 3-diaminobutyric polypropylenimine (DAB) dendrimer would allow the transport of plasmid DNA to the brain after intravenous administration. In this work, we demonstrated that the conjugation of lactoferrin to the dendrimer led to an enhanced DNA uptake by 2.

New data and an old puzzle: the negative association between schizophrenia and rheumatoid arthritis.

Background: A long-standing epidemiological puzzle is the reduced rate of rheumatoid arthritis (RA) in those with schizophrenia (SZ) and vice versa. Traditional epidemiological approaches to determine if this negative association is underpinned by genetic factors would test for reduced rates of one disorder in relatives of the other, but sufficiently powered data sets are difficult to achieve. The genomics era presents an alternative paradigm for investigating the genetic relationship between two uncommon disorders.

Schizophrenia biomarkers: translating the descriptive into the diagnostic.

While schizophrenia and mental health are qualitatively distinct at the level of clinical presentation, the specific molecular signatures that underlie, or associate with, illness are not. Biomarker identification in schizophrenia is intended to offer a number of important benefits to patient well-being including prediction of future illness, diagnostic clarity and a level of disease description that would guide treatment choice. However, the choice of sample and form of analysis used to produce useful biomarkers is still uncertain.

A genome wide survey supports the involvement of large copy number variants in schizophrenia with and without intellectual disability.

Background: Copy number variants (CNVs) have been shown to play a role in schizophrenia and intellectual disability.

Methods: We compared the CNV burden in 66 patients with intellectual disability and no symptoms of psychosis (ID-only) with the burden in 64 patients with intellectual disability and schizophrenia (ID + SCZ). Samples were genotyped on three plates by the Broad Institute using the Affymetrix 6.

A gene trap mutagenesis screen for genes underlying cellular response to the mood stabilizer lithium.

Identifying the biological pathways mediating the action of a therapeutic compound may help the development of more specific treatments while also increasing our understanding of the underlying disease pathology. Salts of the metal lithium are commonly used as a front-line mood stabilizing treatment for bipolar disorder. Lithium's action has been variously linked to inositol phosphate metabolism and the WNT/Glycogen Synthase Kinase 3β (GSK3β)/β-Catenin signalling cascade, but, to date, little is known about which of these provides the principal therapeutic benefit for patients and, more specifically, which constituent genes, through presumed sequence variation, determine differences in patient response to treatment.

Rare copy number variants in neuropsychiatric disorders: Specific phenotype or not?

From a number of genome-wide association studies it was shown that de novo and/or rare copy number variants (CNVs) are found at an increased frequency in neuropsychiatric diseases. In this study we examined the prevalence of CNVs in six genomic regions (1q21.1, 2p16.

GRIK4/KA1 protein expression in human brain and correlation with bipolar disorder risk variant status.

The kainate class of ionotropic glutamate receptors is involved in the regulation of neuronal transmission and synaptic plasticity. Previously we reported that a deletion variant within the gene GRIK4, which encodes the KA1 kainate receptor subunit, was associated with a reduced risk of bipolar disorder and increased GRIK4 mRNA abundance. Using a high resolution immunohistochemistry technique, we characterized KA1 protein localization in human brain and performed a genotype-protein expression correlation study.

A novel balanced chromosomal translocation found in subjects with schizophrenia and schizotypal personality disorder: altered l-serine level associated with disruption of PSAT1 gene expression.

l-Serine is required for the synthesis of glycine and d-serine, both of which are NMDA receptor co-agonists. Although roles for d-serine and glycine have been suggested in schizophrenia, little is known about the role of the l-serine synthesizing cascade in schizophrenia or related psychiatric conditions. Here we report a patient with schizophrenia carrying a balanced chromosomal translocation with the breakpoints localized to 3q13.

A cytogenetic abnormality and rare coding variants identify ABCA13 as a candidate gene in schizophrenia, bipolar disorder, and depression.

Schizophrenia and bipolar disorder are leading causes of morbidity across all populations, with heritability estimates of approximately 80% indicating a substantial genetic component. Population genetics and genome-wide association studies suggest an overlap of genetic risk factors between these illnesses but it is unclear how this genetic component is divided between common gene polymorphisms, rare genomic copy number variants, and rare gene sequence mutations. We report evidence that the lipid transporter gene ABCA13 is a susceptibility factor for both schizophrenia and bipolar disorder.

Disrupted-in-Schizophrenia-1.

Chromosomal abnormalities can be powerful tools to identify genes that influence disease risk. The study of a chromosome translocation that segregated with severe psychiatric illness in a large family led directly to the discovery of a gene disrupted by a chromosomal breakpoint. Disrupted-in-Schizophrenia-1 (DISC1) is now an important candidate risk gene for schizophrenia and affective disorders.

Homozygosity mapping in a family presenting with schizophrenia, epilepsy and hearing impairment.

Homozygosity mapping within consanguineous families is a powerful method of localising genes for autosomal recessive disease. We investigated a family from Punjab, Pakistan, a region where consanguineous marriages are frequent. The parents have no detectable clinical disorders.

The PDE4B gene confers sex-specific protection against schizophrenia.

Background: Phosphodiesterase 4B (PDE4B) is a candidate gene for schizophrenia and affective disorders through its disruption by a chromosomal translocation in an individual with schizophrenia, its inhibition by the antidepressant rolipram, and its physical interaction with another key candidate, Disrupted in Schizophrenia (DISC1).

Objective: To determine the contribution made by PDE4B to the population risk of schizophrenia and bipolar disorder by carrying out a case-control association study.

Methods: Twenty-six tagging single nucleotide polymorphisms were selected across the PDE4B gene and genotyped in DNA samples from 386 schizophrenia cases, 368 bipolar disorder cases and 455 controls.

The NPAS3 gene--emerging evidence for a role in psychiatric illness.

NPAS3 is a member of the basic helix-loop-helix PAS domain class of transcription factors expressed in the brain. Evidence from a human chromosomal rearrangement and a mouse knock-out strain suggest that it may play a part in the aetiology of psychiatric illness. In this review, we describe evolutionary constraints on the NPAS3 gene, relevant functional studies from a related gene and the behavioural and hippocampal neurogenesis deficit observed in the mutant mouse.