Genotype-specific responses in Atlantic salmon (Salmo salar) subject to dietary fish oil replacement by vegetable oil: a liver transcriptomic analysis

<p>Abstract</p> <p>Background</p> <p>Expansion of aquaculture is seriously limited by reductions in fish oil (FO) supply for aquafeeds. Terrestrial alternatives such as vegetable oils (VO) have been investigated and recently a strategy combining genetic selection with changes in diet formulations has been proposed to meet growing demands for aquaculture products. This study investigates the influence of genotype on transcriptomic responses to sustainable feeds in Atlantic salmon.</p> <p>Results</p> <p>A microarray analysis was performed to investigate the liver transcriptome of two family groups selected according to their estimated breeding values (EBVs) for flesh lipid content, 'Lean' or 'Fat', fed diets containing either FO or a VO blend. Diet principally affected metabolism genes, mainly of lipid and carbohydrate, followed by immune response genes. Genotype had a much lower impact on metabolism-related genes and affected mostly signalling pathways. Replacement of dietary FO by VO caused an up-regulation of long-chain polyunsaturated fatty acid biosynthesis, but there was a clear genotype effect as fatty acyl elongase (elovl2) was only up-regulated and desaturases (Δ5 fad and Δ6 fad) showed a higher magnitude of response in Lean fish, which was reflected in liver fatty acid composition. Fatty acid synthase (FAS) was also up-regulated by VO and the effect was independent of genotype. Genetic background of the fish clearly affected regulation of lipid metabolism, as PPARα and PPARβ were down-regulated by the VO diet only in Lean fish, while in Fat salmon SREBP-1 expression was up-regulated by VO. In addition, all three genes had a lower expression in the Lean family group than in the Fat, when fed VO. Differences in muscle adiposity between family groups may have been caused by higher levels of hepatic fatty acid and glycerophospholipid synthesis in the Fat fish, as indicated by the expression of FAS, 1-acyl-sn-glycerol-3-phosphate acyltransferase and lipid phosphate phosphohydrolase 2.</p> <p>Conclusions</p> <p>This study has identified metabolic pathways and key regulators that may respond differently to alternative plant-based feeds depending on genotype. Further studies are required but data suggest that it will be possible to identify families better adapted to alternative diet formulations that might be appropriate for future genetic selection programmes.</p

Auditory Resting-State Network Connectivity in Tinnitus: A Functional MRI Study

The underlying functional neuroanatomy of tinnitus remains poorly understood. Few studies have focused on functional cerebral connectivity changes in tinnitus patients. The aim of this study was to test if functional MRI “resting-state” connectivity patterns in auditory network differ between tinnitus patients and normal controls. Thirteen chronic tinnitus subjects and fifteen age-matched healthy controls were studied on a 3 tesla MRI. Connectivity was investigated using independent component analysis and an automated component selection approach taking into account the spatial and temporal properties of each component. Connectivity in extra-auditory regions such as brainstem, basal ganglia/NAc, cerebellum, parahippocampal, right prefrontal, parietal, and sensorimotor areas was found to be increased in tinnitus subjects. The right primary auditory cortex, left prefrontal, left fusiform gyrus, and bilateral occipital regions showed a decreased connectivity in tinnitus. These results show that there is a modification of cortical and subcortical functional connectivity in tinnitus encompassing attentional, mnemonic, and emotional networks. Our data corroborate the hypothesized implication of non-auditory regions in tinnitus physiopathology and suggest that various regions of the brain seem involved in the persistent awareness of the phenomenon as well as in the development of the associated distress leading to disabling chronic tinnitus

Long-Term Gene Therapy Causes Transgene-Specific Changes in the Morphology of Regenerating Retinal Ganglion Cells

Recombinant adeno-associated viral (rAAV) vectors can be used to introduce neurotrophic genes into injured CNS neurons, promoting survival and axonal regeneration. Gene therapy holds much promise for the treatment of neurotrauma and neurodegenerative diseases; however, neurotrophic factors are known to alter dendritic architecture, and thus we set out to determine whether such transgenes also change the morphology of transduced neurons. We compared changes in dendritic morphology of regenerating adult rat retinal ganglion cells (RGCs) after long-term transduction with rAAV2 encoding: (i) green fluorescent protein (GFP), or (ii) bi-cistronic vectors encoding GFP and ciliary neurotrophic factor (CNTF), brain-derived neurotrophic factor (BDNF) or growth-associated protein-43 (GAP43). To enhance regeneration, rats received an autologous peripheral nerve graft onto the cut optic nerve of each rAAV2 injected eye. After 5–8 months, RGCs with regenerated axons were retrogradely labeled with fluorogold (FG). Live retinal wholemounts were prepared and GFP positive (transduced) or GFP negative (non-transduced) RGCs injected iontophoretically with 2% lucifer yellow. Dendritic morphology was analyzed using Neurolucida software. Significant changes in dendritic architecture were found, in both transduced and non-transduced populations. Multivariate analysis revealed that transgenic BDNF increased dendritic field area whereas GAP43 increased dendritic complexity. CNTF decreased complexity but only in a subset of RGCs. Sholl analysis showed changes in dendritic branching in rAAV2-BDNF-GFP and rAAV2-CNTF-GFP groups and the proportion of FG positive RGCs with aberrant morphology tripled in these groups compared to controls. RGCs in all transgene groups displayed abnormal stratification. Thus in addition to promoting cell survival and axonal regeneration, vector-mediated expression of neurotrophic factors has measurable, gene-specific effects on the morphology of injured adult neurons. Such changes will likely alter the functional properties of neurons and may need to be considered when designing vector-based protocols for the treatment of neurotrauma and neurodegeneration

Mapping genetic variations to three- dimensional protein structures to enhance variant interpretation: a proposed framework

The translation of personal genomics to precision medicine depends on the accurate interpretation of the multitude of genetic variants observed for each individual. However, even when genetic variants are predicted to modify a protein, their functional implications may be unclear. Many diseases are caused by genetic variants affecting important protein features, such as enzyme active sites or interaction interfaces. The scientific community has catalogued millions of genetic variants in genomic databases and thousands of protein structures in the Protein Data Bank. Mapping mutations onto three-dimensional (3D) structures enables atomic-level analyses of protein positions that may be important for the stability or formation of interactions; these may explain the effect of mutations and in some cases even open a path for targeted drug development. To accelerate progress in the integration of these data types, we held a two-day Gene Variation to 3D (GVto3D) workshop to report on the latest advances and to discuss unmet needs. The overarching goal of the workshop was to address the question: what can be done together as a community to advance the integration of genetic variants and 3D protein structures that could not be done by a single investigator or laboratory? Here we describe the workshop outcomes, review the state of the field, and propose the development of a framework with which to promote progress in this arena. The framework will include a set of standard formats, common ontologies, a common application programming interface to enable interoperation of the resources, and a Tool Registry to make it easy to find and apply the tools to specific analysis problems. Interoperability will enable integration of diverse data sources and tools and collaborative development of variant effect prediction methods

Hawking Radiation from Higher-Dimensional Black Holes

We review the quantum field theory description of Hawking radiation from evaporating black holes and summarize what is known about Hawking radiation from black holes in more than four space-time dimensions. In the context of the Large Extra Dimensions scenario, we present the theoretical formalism for all types of emitted fields and a selection of results on the radiation spectra. A detailed analysis of the Hawking fluxes in this case is essential for modelling the evaporation of higher-dimensional black holes at the LHC, whose creation is predicted by low-energy models of quantum gravity. We discuss the status of the quest for black-hole solutions in the context of the Randall-Sundrum brane-world model and, in the absence of an exact metric, we review what is known about Hawking radiation from such black holes

Exploring the definition of «acute» neck pain: a prospective cohort observational study comparing the outcomes of chiropractic patients with 0-2 weeks, 2-4 weeks and 4-12 weeks of symptoms

Abstract Background Neck pain is a common complaint in chiropractic patients. Amongst other baseline variables, numerous studies identify duration of symptoms as a strong predictor of outcome in neck pain patients. The usual time frame used for ‘acute’ onset of pain is between 0 and 4 weeks. However, the appropriateness of this time frame has been challenged for chiropractic low back pain patients. Therefore, the purpose of this study was to compare outcomes in neck pain patients with 0–2 vs 2–4 and 4–12 weeks of symptoms undergoing chiropractic treatment. Methods This is a prospective cohort observational study with 1 year follow-up including 495 patients whose data was collected between October 2009 and March 2015. Patients were divided into high-acute (0–2 weeks), mid-acute (2–4 weeks) and subacute (4–12 weeks) corresponding to duration of their symptoms at initial treatment. Patients completed the numerical pain rating scale (NRS) and Bournemouth questionnaire for neck pain (BQN) at baseline. At follow-up time points of 1 week, 1 month, 3 months, 6 months and 1 year the NRS and BQN were completed along with the Patient Global Impression of Change (PGIC) scale. The PGIC responses were dichotomized into ‘improved’ and ‘not improved’ patients and compared between the 3 subgroups. The Chi-square test was used to compare improved patients between the 3 subgroups and the unpaired Student’s t-test was used for the NRS and BQN change scores. Results The proportion of patients ‘improved’ was only significantly higher for patients with symptoms of 0–2 weeks compared to 2–4 weeks at the 1 week outcome time point (p = 0.015). The NRS changes scores were significantly greater for patients with 2–4 weeks of symptoms compared to 4–12 weeks of symptoms only at 1 week (p = 0.035). Conclusions The time period of 0–4 weeks of symptoms as the definition of “acute” neck pain should be maintained. Independent of the exact duration of symptoms, medium-term and long-term outcome is favourable for acute as well as subacute neck pain patients. Trial registration Not applicable for prospective cohort studies. Ethics approval prior to study EK 19/2009