State-related alterations of gene expression in bipolar disorder : a systematic review

Objective:  Alterations in gene expression in bipolar disorder have been found in numerous studies. It is unclear whether such alterations are related to specific mood states. As a biphasic disorder, mood state-related alterations in gene expression have the potential to point to markers of disease activity, and trait-related alterations might indicate vulnerability pathways. This review therefore evaluated the evidence for whether gene expression in bipolar disorder is state or trait related.

Methods:  A systematic review, using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guideline for reporting systematic reviews, based on comprehensive database searches for studies on gene expression in patients with bipolar disorder in specific mood states, was conducted. We searched Medline, Embase, PsycINFO, and The Cochrane Library, supplemented by manually searching reference lists from retrieved publications.

Results:  A total of 17 studies were included, comprising 565 patients and 418 control individuals. Six studies evaluated intraindividual alterations in gene expression across mood states. Two of five studies found evidence of intraindividual alterations in gene expression between a depressed state and a euthymic state. No studies evaluated intraindividual differences in gene expression between a manic state and a euthymic state, while only one case study evaluated differences between a manic state and a depressed state, finding altered expression in seven genes. No study investigated intraindividual variations in gene expression between a euthymic state and multiple states of various polarities (depressive, manic, hypomanic). Intraindividual alterations in expression of the same genes were not investigated across studies. Only one gene (the brain-derived neurotrophic factor gene; BDNF) was investigated across multiple studies, showing no alteration between bipolar disorder patients and control individuals.

Conclusions:  There is evidence of some genes exhibiting state-related alterations in expression in bipolar disorder; however, this finding is limited by the lack of replication across studies. Further prospective studies are warranted, measuring gene expression in various affective phases, allowing for assessment of intraindividual differences.

Alterations

Alterations
A project conceived by Paul Carter, Professor of Design / Urbanism, Architecture & Design, that explores the theme of 'Alterations' in clothes, identities and spaces. The project is inspired by Dandenong's rapidly mutating public and commercial spaces and the multicultural communities that animate them. The project features a multi-monitor video work Loops, textile-based installation, documentary photography, and poster manifestos. Artists featured include Dirk de Bruyn, Ed Carter, Paul Carter and Soo Yeun You.

Alterations in Notch signalling in skeletal muscles from mdx and dko dystrophic mice and patients with Duchenne muscular dystrophy.

New Findings What is the central question of this study? The Notch signalling pathway plays an important role in muscle regeneration, and activation of the pathway has been shown to enhance muscle regeneration in aged mice. It is unknown whether Notch activation will have a similarly beneficial effect on muscle regeneration in the context of Duchenne muscular dystrophy (DMD). What is the main finding and its importance? Although expression of Notch signalling components is altered in both mouse models of DMD and in human DMD patients, activation of the Notch signalling pathway does not confer any functional benefit on muscles from dystrophic mice, suggesting that other signalling pathways may be more fruitful targets for manipulation in treating DMD. Abstract In Duchenne muscular dystrophy (DMD), muscle damage and impaired regeneration lead to progressive muscle wasting, weakness and premature death. The Notch signalling pathway represents a central regulator of gene expression and is critical for cellular proliferation, differentiation and apoptotic signalling during all stages of embryonic muscle development. Notch activation improves muscle regeneration in aged mice, but its potential to restore regeneration and function in muscular dystrophy is unknown. We performed a comprehensive examination of several genes involved in Notch signalling in muscles from dystrophin-deficient mdx and dko (utrophin- and dystrophin-null) mice and DMD patients. A reduction of Notch1 and Hes1 mRNA in tibialis anterior muscles of dko mice and quadriceps muscles of DMD patients and a reduction of Hes1 mRNA in the diaphragm of the mdx mice were observed, with other targets being inconsistent across species. Activation and inhibition of Notch signalling, followed by measures of muscle regeneration and function, were performed in the mouse models of DMD. Notch activation had no effect on functional regeneration in C57BL/10, mdx or dko mice. Notch inhibition significantly depressed the frequency-force relationship in regenerating muscles of C57BL/10 and mdx mice after injury, indicating reduced force at each stimulation frequency, but enhanced the frequency-force relationship in muscles from dko mice. We conclude that while Notch inhibition produces slight functional defects in dystrophic muscle, Notch activation does not significantly improve muscle regeneration in murine models of muscular dystrophy. Furthermore, the inconsistent expression of Notch targets between murine models and DMD patients suggests caution when making interspecies comparisons.

Fatty acid-specific alterations in leptin, PPARα, and CPT-1 gene expression in the rainbow trout

It is known that fatty acids (FA) regulate lipid metabolism by modulating the expression of numerous genes. In order to gain a better understanding of the effect of individual FA on lipid metabolism related genes in rainbow trout (Oncorhynchus mykiss), an in vitro time-course study was implemented where twelve individual FA (butyric 4:0; caprylic 8:0; palmitic (PAM) 16:0; stearic (STA) 18:0; palmitoleic16:1n-7; oleic 18:1n-9; 11-cis-eicosenoic 20:1n-9; linoleic (LNA) 18:2n-6; α-linolenic (ALA) 18:3n-3; eicosapentenoic (EPA) 20:5n-3; docosahexaenoic (DHA) 22:6n-3; arachidonic (ARA) 20:4n-6) were incubated in rainbow trout liver slices. The effect of FA administration over time was evaluated on the expression of leptin, PPARα and CPT-1 (lipid oxidative related genes). Leptin mRNA expression was down regulated by saturated fatty acids (SFA) and LNA, and was up regulated by monounsaturated fatty acids (MUFA) and long chain PUFA, whilst STA and ALA had no effect. PPARα and CPT-1mRNA expression were up regulated by SFA, MUFA, ALA, ARA and DHA; and down regulated by LNA and EPA. These results suggest that there are individual and specific FA induced modifications of leptin, PPARα and CPT-1 gene expression in rainbow trout, and it is envisaged that such results may provide highly valuable information for future practical applications in fish nutrition.

Age-related proteostasis and metabolic alterations in Caspase-2-deficient mice.

Ageing is a complex biological process for which underlying biochemical changes are still largely unknown. We performed comparative profiling of the cellular proteome and metabolome to understand the molecular basis of ageing in Caspase-2-deficient (Casp2(-/-)) mice that are a model of premature ageing in the absence of overt disease. Age-related changes were determined in the liver and serum of young (6-9 week) and aged (18-24 month) wild-type and Casp2(-/-) mice. We identified perturbed metabolic pathways, decreased levels of ribosomal and respiratory complex proteins and altered mitochondrial function that contribute to premature ageing in the Casp2(-/-) mice. We show that the metabolic profile changes in the young Casp2(-/-) mice resemble those found in aged wild-type mice. Intriguingly, aged Casp2(-/-) mice were found to have reduced blood glucose and improved glucose tolerance. These results demonstrate an important role for caspase-2 in regulating proteome and metabolome remodelling during ageing.

New insights into the thermal behaviour of organic ionic plastic crystals: magnetic resonance imaging of polycrystalline morphology alterations induced by solid-solid phase transitions

Organic ionic plastic crystals (OIPCs) show strong potential as solid-state electrolytes for lithium battery applications, demonstrating promising electrochemical performance and eliminating the need for a volatile and flammable liquid electrolyte. The ionic conductivity (σ) in these systems has recently been shown to depend strongly on polycrystalline morphology, which is largely determined by the sample's thermal history. [K. Romanenko et al., J. Am. Chem. Soc., 2014, 136, 15638]. Tailoring this morphology could lead to conductivities sufficiently high for battery applications, so a more complete understanding of how phenomena such as solid-solid phase transitions can affect the sample morphology is of significant interest. Anisotropic relaxation of nuclear spin magnetisation provides a new MRI based approach for studies of polycrystalline materials at both a macroscopic and molecular level. In this contribution, morphology alterations induced by solid-solid phase transitions in triisobutyl(methyl)phosphonium bis(fluorosulfonyl)imide (P1444FSI) and diethyl(methyl)(isobutyl)phosphonium hexafluorophosphate (P1224PF6) are examined using magnetic resonance imaging (MRI), alongside nuclear magnetic resonance (NMR) spectroscopy, diffusion measurements and conductivity data. These observations are linked to molecular dynamics and structural behaviour crucial for the conductive properties of OIPCs. A distinct correlation is established between the conductivity at a given temperature, σ(T), and the intensity of the narrow NMR signal that is attributed to a mobile fraction, fm(T), of ions in the OIPC. To explain these findings we propose an analogy with the well-studied relationship between permeability (k) and void fraction (θ) in porous media, with k(θ) commonly quantified by a power-law dependence that can also be employed to describe σ(fm).

Cardiovascular alterations and management

This chapter reviews the support of cardiovascular function in the face of
many compromises to the system. It focuses on two of the most prevalent and fatal diseases affecting the heart: coronary heart disease and heart failure. These diseases are also a common comorbidity in elderly patients admitted to critical care units. The first section on coronary heart disease reviews the pathophysiological concepts of myocardial ischaemia and associated complications, with detailed consideration of the clinical implications, assessment and associated management. Heart failure is discussed in terms of the body’s compensatory mechanisms and the clinical sequelae and associated clinical features of heart failure. Nursing and medical management is outlined including the management of acute exacerbations of heart failure. Finally, other cardiovascular disorders commonly managed in critical care units are reviewed, ranging from other forms of heart failure to hypertensive emergencies and aortic aneurysms. The case study presented at the end of the chapter highlights the key aspects of the management of coronary heart disease and heart failure in patients admitted to critical care units.

Alterations in microRNAs miR-21 and let-7a correlate with aberrant STAT3 signaling and downstream effects during cervical carcinogenesis

BACKGROUND: Present study provides clinical evidence of existence of a functional loop involving miR-21 and let-7a as potential regulators of aberrant STAT3 signaling recently reported by our group in an experimental setup (Shishodia et al. BMC Cancer 2014, 14:996). The study is now extended to a set of cervical tissues that represent natural history of human papillomavirus (HPV)-induced tumorigenic transformation. MATERIALS AND METHODS: Cervical tissues from histopathologically-confirmed pre-cancer (23) and cancer lesions (56) along with the normal control tissues (23) were examined for their HPV infection status, expression level of miR-21 & let-7a and STAT3 & pSTAT3 (Y705) by PCR-based genotyping, quantitative real-time PCR and immunoblotting. RESULTS: Analysis of cancer tissues revealed an elevated miR-21 and reduced let-7a expression that correspond to the level of STAT3 signaling. While miR-21 showed direct association, let-7a expression was inversely related to STAT3 expression and its activation. In contrast, a similar reciprocal expression kinetics was absent in LSIL and HSIL tissues which overexpressed let-7a. miR-21 was found differentially overexpressed in HPV16-positive lesions with a higher oncoprotein E6 level. Overexpression of miR-21 was accompanied by elevated level of other STAT3-regulated gene products MMP-2 and MMP-9. Enhanced miR-21 was found associated with decreased level of STAT3 negative regulator PTEN and negative regulator of MMPs, TIMP-3. CONCLUSION: Overall, our study suggests that the microRNAs, miR-21 and let-7a function as clinically relevant integral components of STAT3 signaling and are responsible for maintaining activated state of STAT3 in HPV-infected cells during cervical carcinogenesis.

Nucleus accumbens deep-brain stimulation efficacy in ACTH-pretreated rats: alterations in mitochondrial function relate to antidepressant-like effects

Mitochondrial dysfunction has a critical role in the pathophysiology of mood disorders and treatment response. To investigate this, we established an animal model exhibiting a state of antidepressant treatment resistance in male Wistar rats using 21 days of adrenocorticotropic hormone (ACTH) administration (100 μg per day). First, the effect of ACTH treatment on the efficacy of imipramine (10 mg kg(-1)) was investigated alongside its effect on the prefrontal cortex (PFC) mitochondrial function. Second, we examined the mood-regulatory actions of chronic (7 day) high-frequency nucleus accumbens (NAc) deep-brain stimulation (DBS; 130 Hz, 100 μA, 90 μS) and concomitant PFC mitochondrial function. Antidepressant-like responses were assessed in the open field test (OFT) and forced swim test (FST) for both conditions. ACTH pretreatment prevented imipramine-mediated improvement in mobility during the FST (P<0.05). NAc DBS effectively improved FST mobility in ACTH-treated animals (P<0.05). No improvement in mobility was observed for sham control animals (P>0.05). Analyses of PFC mitochondrial function revealed that ACTH-treated animals had decreased capacity for adenosine triphosphate production compared with controls. In contrast, ACTH animals following NAc DBS demonstrated greater mitochondrial function relative to controls. Interestingly, a proportion (30%) of the ACTH-treated animals exhibited heightened locomotor activity in the OFT and exaggerated escape behaviors during the FST, together with general hyperactivity in their home-cage settings. More importantly, the induction of this mania-like phenotype was accompanied by overcompensative increased mitochondrial respiration. Manifestation of a DBS-induced mania-like phenotype in imipramine-resistant animals highlights the potential use of this model in elucidating mechanisms of mood dysregulation.