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Find video protocols related to scientific articles indexed in Pubmed.
Microbes in Beach Sands: Integrating Environment, Ecology and Public Health.
Rev. Environ. Sci. Biotechnol.
PUBLISHED: 11-11-2014
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Beach sand is a habitat that supports many microbes, including viruses, bacteria, fungi and protozoa (micropsammon). The apparently inhospitable conditions of beach sand environments belie the thriving communities found there. Physical factors, such as water availability and protection from insolation; biological factors, such as competition, predation, and biofilm formation; and nutrient availability all contribute to the characteristics of the micropsammon. Sand microbial communities include autochthonous species/phylotypes indigenous to the environment. Allochthonous microbes, including fecal indicator bacteria (FIB) and waterborne pathogens, are deposited via waves, runoff, air, or animals. The fate of these microbes ranges from death, to transient persistence and/or replication, to establishment of thriving populations (naturalization) and integration in the autochthonous community. Transport of the micropsammon within the habitat occurs both horizontally across the beach, and vertically from the sand surface and ground water table, as well as at various scales including interstitial flow within sand pores, sediment transport for particle-associated microbes, and the large-scale processes of wave action and terrestrial runoff. The concept of beach sand as a microbial habitat and reservoir of FIB and pathogens has begun to influence our thinking about human health effects associated with sand exposure and recreational water use. A variety of pathogens have been reported from beach sands, and recent epidemiology studies have found some evidence of health risks associated with sand exposure. Persistent or replicating populations of FIB and enteric pathogens have consequences for watershed/beach management strategies and regulatory standards for safe beaches. This review summarizes our understanding of the community structure, ecology, fate, transport, and public health implications of microbes in beach sand. It concludes with recommendations for future work in this vastly under-studied area.
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A human vaccine strategy based on chimpanzee adenoviral and MVA vectors that primes, boosts, and sustains functional HCV-specific T cell memory.
Sci Transl Med
PUBLISHED: 11-08-2014
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A protective vaccine against hepatitis C virus (HCV) remains an unmet clinical need. HCV infects millions of people worldwide and is a leading cause of liver cirrhosis and hepatocellular cancer. Animal challenge experiments, immunogenetics studies, and assessment of host immunity during acute infection highlight the critical role that effective T cell immunity plays in viral control. In this first-in-man study, we have induced antiviral immunity with functional characteristics analogous to those associated with viral control in natural infection, and improved upon a vaccine based on adenoviral vectors alone. We assessed a heterologous prime-boost vaccination strategy based on a replicative defective simian adenoviral vector (ChAd3) and modified vaccinia Ankara (MVA) vector encoding the NS3, NS4, NS5A, and NS5B proteins of HCV genotype 1b. Analysis used single-cell mass cytometry and human leukocyte antigen class I peptide tetramer technology in healthy human volunteers. We show that HCV-specific T cells induced by ChAd3 are optimally boosted with MVA, and generate very high levels of both CD8(+) and CD4(+) HCV-specific T cells targeting multiple HCV antigens. Sustained memory and effector T cell populations are generated, and T cell memory evolved over time with improvement of quality (proliferation and polyfunctionality) after heterologous MVA boost. We have developed an HCV vaccine strategy, with durable, broad, sustained, and balanced T cell responses, characteristic of those associated with viral control, paving the way for the first efficacy studies of a prophylactic HCV vaccine.
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Systemic metabolism in frontotemporal dementia.
Neurology
PUBLISHED: 10-10-2014
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To document the metabolic changes in frontotemporal dementia, including serum cholesterol and insulin levels, and compare and contrast these changes to motor neuron disease, where metabolism is proposed to affect disease progression.
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Removal of 8-oxo-GTP by MutT hydrolase is not a major contributor to transcriptional fidelity.
Nucleic Acids Res.
PUBLISHED: 10-07-2014
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Living in an oxygen-rich environment is dangerous for a cell. Reactive oxygen species can damage DNA, RNA, protein and lipids. The MutT protein in Escherichia coli removes 8-oxo-deoxyguanosine triphosphate (8-oxo-dGTP) and 8-oxo-guanosine triphosphate (8-oxo-GTP) from the nucleotide pools precluding incorporation into DNA and RNA. While 8-oxo-dGTP incorporation into DNA is mutagenic, it is not clear if 8-oxo-GTP incorporation into RNA can have phenotypic consequences for the cell. We use a bistable epigenetic switch sensitive to transcription errors in the Escherichia coli lacI transcript to monitor transient RNA errors. We do not observe any increase in epigenetic switching in mutT cells. We revisit the original observation of partial phenotypic suppression of a lacZamber allele in a mutT background that was attributed to RNA errors. We find that Lac(+) revertants can completely account for the increase in ?-galactosidase levels in mutT lacZamber cultures, without invoking participation of transient transcription errors. Moreover, we observe a fluctuation type of distribution of ?-galactosidase appearance in a growing culture, consistent with Lac(+) DNA revertant events. We conclude that the absence of MutT produces a DNA mutator but does not equally create an RNA mutator.
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High-resolution MRI assessment of dactylitis in psoriatic arthritis shows flexor tendon pulley and sheath-related enthesitis.
Ann. Rheum. Dis.
PUBLISHED: 09-28-2014
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Dactylitis is a hallmark of psoriatic arthritis (PsA) where flexor tenosynovitis is common. This study explored the microanatomical basis of dactylitis using high-resolution MRI (hrMRI) to visualise the small entheses around the digits.
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Long-term functional results and isokinetic strength evaluation after arthroscopic tenotomy of the long head of biceps tendon.
Int J Shoulder Surg
PUBLISHED: 09-27-2014
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The objective of this study is to evaluate the biomechanical function of the upper arm after arthroscopic long head of biceps (LHB) tenotomy at long-term follow-up.
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Biomarkers in dementia: clinical utility and new directions.
J. Neurol. Neurosurg. Psychiatr.
PUBLISHED: 09-26-2014
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Imaging, cerebrospinal fluid (CSF) and blood-based biomarkers have the potential to improve the accuracy by which specific causes of dementia can be diagnosed in vivo, provide insights into the underlying pathophysiology, and may be used as inclusion criteria and outcome measures for clinical trials. While a number of imaging and CSF biomarkers are currently used for each of these purposes, this is an evolving field, with numerous potential biomarkers in varying stages of research and development. We review the currently available biomarkers for the three most common forms of neurodegenerative dementia, and give an overview of research techniques that may in due course make their way into the clinic.
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Distribution of pathology in frontal variant Alzheimer's disease.
J. Alzheimers Dis.
PUBLISHED: 09-04-2014
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Atypical presentations of Alzheimer's disease (AD) have been described, including a "frontal" variant (fvAD), which presents with personality change and executive dysfunction similar to that seen in behavioral variant frontotemporal dementia (bvFTD). This clinical variation is thought to reflect the regional distribution of pathology, although few reports include autopsy confirmation. We compared three clinicopathological groups matched for age at diagnosis and disease duration; those with possible bvFTD who at autopsy had only AD (fvAD), those with typical AD clinically and pathologically, and those with typical clinical bvFTD confirmed pathologically. The density of neurons and AD-type pathology was quantified in the frontal association, occipital association, and entorhinal cortices and hippocampal CA1 regions. Immunohistochemistry for phosphorylated tau and amyloid-? deposition was used to detect neurofibrillary tangles and plaques. Of the six core clinical features of the International Consensus Criteria, disinhibition, stereotyped behaviors, and executive dysfunction were most common, occurring in five of the six fvAD patients. Other features were rare. While there was no significant difference in neuron density between groups for any of the four regions, when the ratio of frontal:occipital pathology was examined, neuronal density in fvAD was significantly less than AD but similar to bvFTD. The frontal:occipital ratio of AD-type pathology was also greater in fvAD than AD. The findings of this study suggest a frontal variant of AD exists with features that mimic bvFTD and that this reflects a differential distribution of neurodegeneration with more marked pathology in the frontal cortex compared with the occipital cortex.
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Multiscale digital Arabidopsis predicts individual organ and whole-organism growth.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 09-02-2014
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Understanding how dynamic molecular networks affect whole-organism physiology, analogous to mapping genotype to phenotype, remains a key challenge in biology. Quantitative models that represent processes at multiple scales and link understanding from several research domains can help to tackle this problem. Such integrated models are more common in crop science and ecophysiology than in the research communities that elucidate molecular networks. Several laboratories have modeled particular aspects of growth in Arabidopsis thaliana, but it was unclear whether these existing models could productively be combined. We test this approach by constructing a multiscale model of Arabidopsis rosette growth. Four existing models were integrated with minimal parameter modification (leaf water content and one flowering parameter used measured data). The resulting framework model links genetic regulation and biochemical dynamics to events at the organ and whole-plant levels, helping to understand the combined effects of endogenous and environmental regulators on Arabidopsis growth. The framework model was validated and tested with metabolic, physiological, and biomass data from two laboratories, for five photoperiods, three accessions, and a transgenic line, highlighting the plasticity of plant growth strategies. The model was extended to include stochastic development. Model simulations gave insight into the developmental control of leaf production and provided a quantitative explanation for the pleiotropic developmental phenotype caused by overexpression of miR156, which was an open question. Modular, multiscale models, assembling knowledge from systems biology to ecophysiology, will help to understand and to engineer plant behavior from the genome to the field.
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Systems-based analyses of brain regions functionally impacted in Parkinson's disease reveals underlying causal mechanisms.
PLoS ONE
PUBLISHED: 08-29-2014
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Detailed analysis of disease-affected tissue provides insight into molecular mechanisms contributing to pathogenesis. Substantia nigra, striatum, and cortex are functionally connected with increasing degrees of alpha-synuclein pathology in Parkinson's disease. We undertook functional and causal pathway analysis of gene expression and proteomic alterations in these three regions, and the data revealed pathways that correlated with disease progression. In addition, microarray and RNAseq experiments revealed previously unidentified causal changes related to oligodendrocyte function and synaptic vesicle release, and these and other changes were reflected across all brain regions. Importantly, subsets of these changes were replicated in Parkinson's disease blood; suggesting peripheral tissue may provide important avenues for understanding and measuring disease status and progression. Proteomic assessment revealed alterations in mitochondria and vesicular transport proteins that preceded gene expression changes indicating defects in translation and/or protein turnover. Our combined approach of proteomics, RNAseq and microarray analyses provides a comprehensive view of the molecular changes that accompany functional loss and alpha-synuclein pathology in Parkinson's disease, and may be instrumental to understand, diagnose and follow Parkinson's disease progression.
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Heritability in frontotemporal dementia: more missing pieces?
J. Neurol.
PUBLISHED: 08-26-2014
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Frontotemporal dementia (FTD) is reportedly highly heritable, even though a recognized genetic cause is often absent. To explain this contradiction, we explored the "strength" of family history in FTD, Alzheimer's disease (AD), and controls. Clinical syndromes associated with heritability of FTD and AD were also examined. FTD and AD patients were recruited from an FTD-specific research clinic, and patients were further sub-classified into FTD or AD phenotypes. The strength of family history was graded using the Goldman score (GS), and GS of 1-3 was regarded as a "strong" family history. A subset of FTD patients underwent screening for the main genetic causes of FTD. In total, 307 participants were included (122 FTD, 98 AD, and 87 controls). Although reported positive family history did not differ between groups, a strong family history was more common in FTD (FTD 17.2 %, AD 5.1 %, controls 2.3 %, P < 0.001). The bvFTD and FTD-ALS groups drove heritability, but 12.2 % of atypical AD patients also had a strong family history. A pathogenic mutation was identified in 16 FTD patients (10 C9ORF72 repeat expansion, 5 GRN, 1 MAPT), but more than half of FTD patients with a strong family history had no mutation detected. FTD is a highly heritable disease, even more than AD, and patients with bvFTD and FTD-ALS drive this heritability. Atypical AD also appears to be more heritable than typical AD. These results suggest that further genetic influences await discovery in FTD.
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Visual hallucinations in Parkinson's disease: Theoretical models.
Mov. Disord.
PUBLISHED: 08-22-2014
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One of the most challenging tasks in neuroscience is to be able to meaningfully connect information across the different levels of investigation, from molecular or structural biology to the resulting behavior and cognition. Visual hallucinations are a frequent occurrence in Parkinson's disease and significantly contribute to the burden of the disease. Because of the widespread pathological processes implicated in visual hallucinations in Parkinson's disease, a final common mechanism that explains their manifestation will require an integrative approach, in which consideration is taken across all complementary levels of analysis. This review considers the leading hypothetical frameworks for visual hallucinations in Parkinson's disease, summarizing the key aspects of each in an attempt to highlight the aspects of the condition that such a unifying hypothesis must explain. These competing hypotheses include implications of dream imagery intrusion, deficits in reality monitoring, and impairments in visual perception and attention. © 2014 International Parkinson and Movement Disorder Society.
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Cerebellar integrity in the amyotrophic lateral sclerosis-frontotemporal dementia continuum.
PLoS ONE
PUBLISHED: 08-21-2014
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Amyotrophic lateral sclerosis (ALS) and behavioural variant frontotemporal dementia (bvFTD) are multisystem neurodegenerative disorders that manifest overlapping cognitive, neuropsychiatric and motor features. The cerebellum has long been known to be crucial for intact motor function although emerging evidence over the past decade has attributed cognitive and neuropsychiatric processes to this structure. The current study set out i) to establish the integrity of cerebellar subregions in the amyotrophic lateral sclerosis-behavioural variant frontotemporal dementia spectrum (ALS-bvFTD) and ii) determine whether specific cerebellar atrophy regions are associated with cognitive, neuropsychiatric and motor symptoms in the patients. Seventy-eight patients diagnosed with ALS, ALS-bvFTD, behavioural variant frontotemporal dementia (bvFTD), most without C9ORF72 gene abnormalities, and healthy controls were investigated. Participants underwent cognitive, neuropsychiatric and functional evaluation as well as structural imaging using voxel-based morphometry (VBM) to examine the grey matter subregions of the cerebellar lobules, vermis and crus. VBM analyses revealed: i) significant grey matter atrophy in the cerebellum across the whole ALS-bvFTD continuum; ii) atrophy predominantly of the superior cerebellum and crus in bvFTD patients, atrophy of the inferior cerebellum and vermis in ALS patients, while ALS-bvFTD patients had both patterns of atrophy. Post-hoc covariance analyses revealed that cognitive and neuropsychiatric symptoms were particularly associated with atrophy of the crus and superior lobule, while motor symptoms were more associated with atrophy of the inferior lobules. Taken together, these findings indicate an important role of the cerebellum in the ALS-bvFTD disease spectrum, with all three clinical phenotypes demonstrating specific patterns of subregional atrophy that associated with different symptomology.
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A murine macrofilaricide pre-clinical screening model for onchocerciasis and lymphatic filariasis.
Parasit Vectors
PUBLISHED: 08-19-2014
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BackgroundNew drugs effective against adult filariae (macrofilaricides) would accelerate the elimination of lymphatic filariasis and onchocerciasis. Anti-Onchocerca drug development is hampered by the lack of a facile model. We postulated that SCID mice could be developed as a fmacrofilaricide screening model.MethodsThe filaricides: albendazole (ABZ), diethylcarbamazine (DEC), flubendazole (FBZ), ivermectin (IVM) and the anti-Wolbachia macrofilaricide, minocycline (MIN) were tested in Brugia malayi (Bm)-parasitized BALB/c SCID mice vs vehicle control (VC). Responses were compared to BALB/c wild type (WT). Onchocerca ochengi male worms or onchocercomata were surgically implanted into BALB/c SCID, CB.17 SCID, BALB/c WT mice or Meriones gerbils. Survival was evaluated at 7¿15 days. BALB/c SCID were tested to evaluate the responsiveness of pre-clinical macrofilaricides FBZ and rifapentine (RIFAP) against male Onchocerca. ResultsWT and SCID responded with >95% efficacy following ABZ or DEC treatments against Bm larvae (P < 0.0001). IVM was partially filaricidal against Bm larvae in WT and SCID (WT; 39.8%, P = 0.0356 and SCID; 56.7%, P = 0.026). SCID responded similarly to WT following IVM treatment of microfilaraemias (WT; 79%, P = 0.0194. SCID; 76%, P = 0.0473). FBZ induced a total macrofilaricidal response against adult Bm in WT and SCID (WT; P = 0.0067, SCID; P = 0.0071). MIN induced a >90% reduction in Bm Wolbachia burdens (P < 0.0001) and a blockade of microfilarial release (P = 0.0215) in SCID. Male Onchocerca survival was significantly higher in SCID vs WT mice, but not gerbils, after +15 days (60% vs 22% vs 39% P = 0.0475). Onchocercoma implants had engrafted into host tissues, with evidence of neovascularisation, after +7 days and yielded viable macro/microfilariae ex vivo. FBZ induced a macrofilaricidal effect in Onchocerca male implanted SCID at +5 weeks (FBZ; 1.67% vs VC; 43.81%, P = 0.0089). Wolbachia loads within male Onchocerca were reduced by 99% in implanted SCID receiving RIFAP for +2 weeks.ConclusionsWe have developed a `pan-filarial¿ small animal research model that is sufficiently robust, with adequate capacity and throughput, to screen existing and future pre-clinical candidate macrofilaricides. Pilot data suggests a murine onchocercoma xenograft model is achievable.
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ABCA5 Regulates Amyloid-? Peptide Production and is Associated with Alzheimer's Disease Neuropathology.
J. Alzheimers Dis.
PUBLISHED: 08-13-2014
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Brain cholesterol homeostasis is regulated by a group of proteins called ATP-binding cassette subfamily A (ABCA) transporters. Certain ABCA transporters regulate amyloid-? protein precursor (A?PP) processing to generate amyloid-? peptides (A?) and are associated with an increased risk for late-onset Alzheimer's disease (AD). ABCA5 is a little-known member of the ABCA subfamily with no known function. In this study we undertook a comprehensive analysis of ABCA5 expression in the human and mouse brains. We explored the potential role of ABCA5 in A?PP processing associated with AD pathology. ABCA5 was differentially expressed in multiple regions of both human and mouse brains. It was strongly expressed in neurons with only weak expression in microglia, astrocytes, and oligodendrocytes. ABCA5 was able to stimulate cholesterol efflux in neurons. ABCA5 expression was specifically elevated in the hippocampus of AD brains. Using two in vitro cell systems we demonstrated that ABCA5 reduces A? production, both A?40 and A?42, without altering A?PP mRNA and protein levels, indicating that the decrease in the A? levels was due to changes in A?PP processing and not A?PP expression. This report represents the first extensive expression and functional study of ABCA5 in the human brain and our data suggest a plausible function of ABCA5 in the brain as a cholesterol transporter associated with A? generation, information that may offer a potential new target for controlling A? levels in the brain.
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Altered lipid levels provide evidence for myelin dysfunction in multiple system atrophy.
Acta Neuropathol Commun
PUBLISHED: 08-05-2014
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Multiple system atrophy (MSA) is a rapidly-progressive neurodegenerative disease characterized by parkinsonism, cerebellar ataxia and autonomic failure. A pathological hallmark of MSA is the presence of ¿-synuclein deposits in oligodendrocytes, the myelin-producing support cells of the brain. Brain pathology and in vitro studies indicate that myelin instability may be an early event in the pathogenesis of MSA. Lipid is a major constituent (78% w/w) of myelin and has been implicated in myelin dysfunction in MSA. However, changes, if any, in lipid level/distribution in MSA brain are unknown. Here, we undertook a comprehensive analysis of MSA myelin. We quantitatively measured three groups of lipids, sphingomyelin, sulfatide and galactosylceramide, which are all important in myelin integrity and function, in affected (under the motor cortex) and unaffected (under the visual cortex) white matter regions. For all three groups of lipids, most of the species were severely decreased (40¿69%) in affected but not unaffected MSA white matter. An analysis of the distribution of lipid species showed no significant shift in fatty acid chain length/content with MSA. The decrease in lipid levels was concomitant with increased ¿-synuclein expression. These data indicate that the absolute levels, and not distribution, of myelin lipids are altered in MSA, and provide evidence for myelin lipid dysfunction in MSA pathology. We propose that dysregulation of myelin lipids in the course of MSA pathogenesis may trigger myelin instability.
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Transcriptome analysis of grey and white matter cortical tissue in multiple system atrophy.
Neurogenetics
PUBLISHED: 07-24-2014
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Multiple system atrophy (MSA) is a distinct member of a group of neurodegenerative diseases known as ?-synucleinopathies, which are characterized by the presence of aggregated ?-synuclein in the brain. MSA is unique in that the principal site for ?-synuclein deposition is in the oligodendrocytes rather than neurons. The cause of MSA is unknown, and the pathogenesis of MSA is still largely speculative. Brain transcriptome perturbations during the onset and progression of MSA are mostly unknown. Using RNA sequencing, we performed a comparative transcriptome profiling analysis of the grey matter (GM) and white matter (WM) of the frontal cortex of MSA and control brains. The transcriptome sequencing revealed increased expression of the alpha and beta haemoglobin genes in MSA WM, decreased expression of the transthyretin (TTR) gene in MSA GM and numerous region-specific long intervening non-coding RNAs (lincRNAs). In contrast, we observed only moderate changes in the expression patterns of the ?-synuclein (SNCA) gene, which confirmed previous observations by other research groups. Our study suggests that at the transcriptional level, MSA pathology may be related to increased iron levels in WM and perturbations of the non-coding fraction of the transcriptome.
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Longitudinal white matter changes in frontotemporal dementia subtypes.
Hum Brain Mapp
PUBLISHED: 07-23-2014
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Frontotemporal dementia is a degenerative brain condition characterized by focal atrophy affecting the frontal and temporal lobes predominantly. Changes in white matter with disease progression and their relationship to grey matter atrophy remain unknown in FTD. This study aimed to establish longitudinal white matter changes and compare these changes to regional grey matter atrophy in the main FTD subtypes. Diffusion and T?-weighted images were collected from behavioral-variant FTD (bvFTD: 12), progressive non-fluent aphasia (PNFA: 10), semantic dementia (SD: 11), and 15 controls at baseline and 12 months apart. Changes in white matter integrity were established by fractional anisotropy, mean, axial and radial diffusivity measurements using tract-based spatial statistics. Patterns of cortical grey matter atrophy were measured using voxel-based morphometry. At baseline, bvFTD showed severe cross-sectional changes in orbitofrontal and anterior temporal tracts, which progressed to involve posterior temporal and occipital white matter over the 12-month. In PNFA, cross-sectional changes occurred bilaterally in frontotemporal white matter (left > right), with longitudinal changes more prominent on the right. Initial white matter changes in SD were circumscribed to the left temporal lobe, with longitudinal changes extending to bilateral frontotemporal tracts. In contrast, progression of grey matter change over time was less pronounced in all FTD subtypes. Mean diffusivity was most sensitive in detecting baseline changes while fractional anisotropy and radial diffusivity revealed greatest changes over time, possibly reflecting different underlying pathological processes with disease progression. Our results indicate that investigations of white matter changes reveal important differences across FTD syndromes with disease progression.
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?-Synucleinopathy phenotypes.
Parkinsonism Relat. Disord.
PUBLISHED: 07-12-2014
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?-Synucleinopathies are neurodegenerative diseases characterised by the abnormal accumulation of ?-synuclein aggregates in neurons, nerve fibres or glial cells. While small amounts of these ?-synuclein pathologies can occur in some neurologically normal individuals who do not have associated neurodegeneration, the absence of neurodegeneration in such individuals precludes them from having a degenerative ?-synucleinopathy, and it has yet to be established whether such individuals have a form of preclinical disease. There are three main types of ?-synucleinopathy, Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), with other rare disorders also having ?-synuclein pathologies, such as various neuroaxonal dystrophies. Multiple clinical phenotypes exist for each of the three main ?-synucleinopathies, with these phenotypes differing in the dynamic distribution of their underlying neuropathologies. Identifying the factors involved in causing different ?-synuclein phenotypes may ultimately lead to more targeted therapeutics as well as more accurate clinical prognosis.
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Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies.
Hum. Mol. Genet.
PUBLISHED: 06-27-2014
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Clinical and neuropathological similarities between dementia with Lewy bodies (DLB), Parkinson's and Alzheimer's diseases (PD and AD, respectively) suggest that these disorders may share etiology. To test this hypothesis, we have performed an association study of 54 genomic regions, previously implicated in PD or AD, in a large cohort of DLB cases and controls. The cohort comprised 788 DLB cases and 2624 controls. To minimize the issue of potential misdiagnosis, we have also performed the analysis including only neuropathologically proven DLB cases (667 cases). The results show that the APOE is a strong genetic risk factor for DLB, confirming previous findings, and that the SNCA and SCARB2 loci are also associated after a study-wise Bonferroni correction, although these have a different association profile than the associations reported for the same loci in PD. We have previously shown that the p.N370S variant in GBA is associated with DLB, which, together with the findings at the SCARB2 locus, suggests a role for lysosomal dysfunction in this disease. These results indicate that DLB has a unique genetic risk profile when compared with the two most common neurodegenerative diseases and that the lysosome may play an important role in the etiology of this disorder. We make all these data available.
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Frontotemporal dementia and its subtypes: a genome-wide association study.
Raffaele Ferrari, Dena G Hernandez, Michael A Nalls, Jonathan D Rohrer, Adaikalavan Ramasamy, John B J Kwok, Carol Dobson-Stone, William S Brooks, Peter R Schofield, Glenda M Halliday, John R Hodges, Olivier Piguet, Lauren Bartley, Elizabeth Thompson, Eric Haan, Isabel Hernández, Agustin Ruíz, Mercè Boada, Barbara Borroni, Alessandro Padovani, Carlos Cruchaga, Nigel J Cairns, Luisa Benussi, Giuliano Binetti, Roberta Ghidoni, Gianluigi Forloni, Daniela Galimberti, Chiara Fenoglio, Maria Serpente, Elio Scarpini, Jordi Clarimón, Alberto Lleó, Rafael Blesa, Maria Landqvist Waldö, Karin Nilsson, Christer Nilsson, Ian R A Mackenzie, Ging-Yuek R Hsiung, David M A Mann, Jordan Grafman, Christopher M Morris, Johannes Attems, Timothy D Griffiths, Ian G McKeith, Alan J Thomas, P Pietrini, Edward D Huey, Eric M Wassermann, Atik Baborie, Evelyn Jaros, Michael C Tierney, Pau Pastor, Cristina Razquin, Sara Ortega-Cubero, Elena Alonso, Robert Perneczky, Janine Diehl-Schmid, Panagiotis Alexopoulos, Alexander Kurz, Innocenzo Rainero, Elisa Rubino, Lorenzo Pinessi, Ekaterina Rogaeva, Peter St George-Hyslop, Giacomina Rossi, Fabrizio Tagliavini, Giorgio Giaccone, James B Rowe, Johannes C M Schlachetzki, James Uphill, John Collinge, Simon Mead, Adrian Danek, Vivianna M Van Deerlin, Murray Grossman, John Q Trojanowski, Julie van der Zee, William Deschamps, Tim Van Langenhove, Marc Cruts, Christine Van Broeckhoven, Stefano F Cappa, Isabelle Le Ber, Didier Hannequin, Véronique Golfier, Martine Vercelletto, Alexis Brice, Benedetta Nacmias, Sandro Sorbi, Silvia Bagnoli, Irene Piaceri, Jørgen E Nielsen, Lena E Hjermind, Matthias Riemenschneider, Manuel Mayhaus, Bernd Ibach, Gilles Gasparoni, Sabrina Pichler, Wei Gu, Martin N Rossor, Nick C Fox, Jason D Warren, Maria Grazia Spillantini, Huw R Morris, Patrizia Rizzu, Peter Heutink, Julie S Snowden, Sara Rollinson, Anna Richardson, Alexander Gerhard, Amalia C Bruni, Raffaele Maletta, Francesca Frangipane, Chiara Cupidi, Livia Bernardi, Maria Anfossi, Maura Gallo, Maria Elena Conidi, Nicoletta Smirne, Rosa Rademakers, Matt Baker, Dennis W Dickson, Neill R Graff-Radford, Ronald C Petersen, David Knopman, Keith A Josephs, Bradley F Boeve, Joseph E Parisi, William W Seeley, Bruce L Miller, Anna M Karydas, Howard Rosen, John C van Swieten, Elise G P Dopper, Harro Seelaar, Yolande A L Pijnenburg, Philip Scheltens, Giancarlo Logroscino, Rosa Capozzo, Valeria Novelli, Annibale A Puca, Massimo Franceschi, Alfredo Postiglione, Graziella Milan, Paolo Sorrentino, Mark Kristiansen, Huei-Hsin Chiang, Caroline Graff, Florence Pasquier, Adeline Rollin, Vincent Deramecourt, Florence Lebert, Dimitrios Kapogiannis, Luigi Ferrucci, Stuart Pickering-Brown, Andrew B Singleton, John Hardy, Parastoo Momeni.
Lancet Neurol
PUBLISHED: 06-20-2014
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Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72--have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.
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Spinal Clear Cell Meningioma in a 3-Year-Old: A Case Report.
Pediatr Neurosurg
PUBLISHED: 06-15-2014
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Clear cell meningioma (CCM) is an aggressive meningioma variant with a tendency to early recurrence posing a challenge to its treatment. Although spinal meningiomas are uncommon in children, this rare entity has been described as the most common variant of spinal meningiomas in the pediatric age group. We present the case of a 3-year-old with a confirmed lumbar spine CCM and discuss the problems encountered in the management of this disease. © 2014 S. Karger AG, Basel.
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The HY5-PIF regulatory module coordinates light and temperature control of photosynthetic gene transcription.
PLoS Genet.
PUBLISHED: 06-01-2014
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The ability to interpret daily and seasonal alterations in light and temperature signals is essential for plant survival. This is particularly important during seedling establishment when the phytochrome photoreceptors activate photosynthetic pigment production for photoautotrophic growth. Phytochromes accomplish this partly through the suppression of phytochrome interacting factors (PIFs), negative regulators of chlorophyll and carotenoid biosynthesis. While the bZIP transcription factor long hypocotyl 5 (HY5), a potent PIF antagonist, promotes photosynthetic pigment accumulation in response to light. Here we demonstrate that by directly targeting a common promoter cis-element (G-box), HY5 and PIFs form a dynamic activation-suppression transcriptional module responsive to light and temperature cues. This antagonistic regulatory module provides a simple, direct mechanism through which environmental change can redirect transcriptional control of genes required for photosynthesis and photoprotection. In the regulation of photopigment biosynthesis genes, HY5 and PIFs do not operate alone, but with the circadian clock. However, sudden changes in light or temperature conditions can trigger changes in HY5 and PIFs abundance that adjust the expression of common target genes to optimise photosynthetic performance and growth.
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Tracing the fate of limbal epithelial progenitor cells in the murine cornea.
Stem Cells
PUBLISHED: 05-21-2014
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Stem cell (SC) division, deployment and differentiation are processes that contribute to corneal epithelial renewal. Until now studying the destiny of these cells in a living mammal has not been possible. However, the advent of inducible multicolor genetic tagging and powerful imaging technologies has rendered this achievable in the translucent and readily accessible murine cornea. K14CreER(T2) -Confetti mice which harbor two copies of the Brainbow 2.1 cassette, yielding up to ten colors from the stochastic recombination of fluorescent proteins, were used to monitor K-14(+) progenitor cell dynamics within the corneal epithelium in live animals. Multicolored columns of cells emerged from the basal limbal epithelium as they expanded and migrated linearly at a rate of 10.8 µm/day towards the central cornea. Moreover, the permanent expression of fluorophores, passed on from progenitor to progeny, assisted in discriminating individual clones as spectrally distinct streaks containing over 1000 cells within the illuminated area. The centripetal clonal expansion is suggestive that a single progenitor cell is responsible for maintaining a narrow corridor of corneal epithelial cells. Our data are in agreement with the limbus as the repository for SC as opposed to SC being distributed throughout the central cornea. This is the first report describing stem/progenitor cell fate determination in the murine cornea using multicolor genetic tracing. This model represents a powerful new resource to monitor SC kinetics and fate choice under homeostatic conditions, and may assist in assessing clonal evolution during corneal development, aging, wound-healing, disease and following transplantation. Stem Cells 2014.
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Beyond the temporal pole: limbic memory circuit in the semantic variant of primary progressive aphasia.
Brain
PUBLISHED: 05-19-2014
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Despite accruing evidence for relative preservation of episodic memory in the semantic variant of primary progressive aphasia (previously semantic dementia), the neural basis for this remains unclear, particularly in light of their well-established hippocampal involvement. We recently investigated the Papez network of memory structures across pathological subtypes of behavioural variant frontotemporal dementia and demonstrated severe degeneration of all relay nodes, with the anterior thalamus in particular emerging as crucial for intact episodic memory. The present study investigated the status of key components of Papez circuit (hippocampus, mammillary bodies, anterior thalamus, cingulate cortex) and anterior temporal cortex using volumetric and quantitative cell counting methods in pathologically-confirmed cases with semantic variant of primary progressive aphasia (n = 8; 61-83 years; three males), behavioural variant frontotemporal dementia with TDP pathology (n = 9; 53-82 years; six males) and healthy controls (n = 8, 50-86 years; four males). Behavioural variant frontotemporal dementia cases with TDP pathology were selected because of the association between the semantic variant of primary progressive aphasia and TDP pathology. Our findings revealed that the semantic variant of primary progressive aphasia and behavioural variant frontotemporal dementia show similar degrees of anterior thalamic atrophy. The mammillary bodies and hippocampal body and tail were preserved in the semantic variant of primary progressive aphasia but were significantly atrophic in behavioural variant frontotemporal dementia. Importantly, atrophy in the anterior thalamus and mild progressive atrophy in the body of the hippocampus emerged as the main memory circuit regions correlated with increasing dementia severity in the semantic variant of primary progressive aphasia. Quantitation of neuronal populations in the cingulate cortices confirmed the selective loss of anterior cingulate von Economo neurons in behavioural variant frontotemporal dementia. We also show that by end-stage these neurons selectively degenerate in the semantic variant of primary progressive aphasia with preservation of neurons in the posterior cingulate cortex. Overall, our findings demonstrate for the first time, severe atrophy, although not necessarily neuronal loss, across all relay nodes of Papez circuit with the exception of the mammillary bodies and hippocampal body and tail in the semantic variant of primary progressive aphasia. Despite the longer disease course in the semantic variant of primary progressive aphasia compared with behavioural variant frontotemporal dementia, we suggest here that the neural preservation of crucial memory relays (hippocampal?mammillary bodies and posterior cingulate?hippocampus) likely reflects the conservation of specific episodic memory components observed in most patients with semantic variant of primary progressive aphasia.
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Glucocerebrosidase deficits in sporadic Parkinson disease.
Autophagy
PUBLISHED: 05-15-2014
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Parkinson disease (PD) is a progressive neurodegenerative movement disorder characterized pathologically by abnormal SNCA/?-synuclein protein inclusions in neurons. Impaired lysosomal autophagic degradation of cellular proteins is implicated in PD pathogenesis and progression. Heterozygous GBA mutations, encoding lysosomal GBA/glucocerebrosidase (glucosidase, ?, acid), are the greatest genetic risk factor for PD, and reduced GBA and SNCA accumulation are related in PD models. Here we review our recent human brain tissue study demonstrating that GBA deficits in sporadic PD are related to the early accumulation of SNCA, and dysregulation of chaperone-mediated autophagy (CMA) pathways and lipid metabolism.
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Altered ceramide acyl chain length and ceramide synthase gene expression in Parkinson’s disease.
Mov. Disord.
PUBLISHED: 05-14-2014
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Genetic studies have provided increasing evidence that ceramide homeostasis plays a role in neurodegenerative diseases including Parkinson’s disease (PD). It is known that the relative amounts of different ceramide molecular species, as defined by their fatty acyl chain length, regulate ceramide function in lipid membranes and in signaling pathways. In the present study we used a comprehensive sphingolipidomic case-control approach to determine the effects of PD on ceramide composition in postmortem brain tissue from the anterior cingulate cortex (a region with significant PD pathology) and the occipital cortex (spared in PD), also assessing mRNA expression of the major ceramide synthase genes that regulate ceramide acyl chain composition in the same tissue using quantitative PCR. In PD anterior cingulate cortex but not occipital cortex, total ceramide and sphingomyelin levels were reduced from control levels by 53% (P < 0.001) and 42% (P < 0.001), respectively. Of the 13 ceramide and 15 sphingomyelin molecular lipid species identified and quantified, there was a significant shift in the ceramide acyl chain composition toward shorter acyl chain length in the PD anterior cingulate cortex. This PD-associated change in ceramide acyl chain composition was accompanied by an upregulation of ceramide synthase-1 gene expression, which we consider may represent a response to reduced ceramide levels. These data suggest a significant shift in ceramide function in lipid membranes and signaling pathways occurs in regions with PD pathology. Identifying the regulatory mechanisms precipitating this change may provide novel targets for future therapeutics.
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The role of transcriptional control in multiple system atrophy.
Neurobiol. Aging
PUBLISHED: 05-07-2014
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Multiple system atrophy (MSA) is an ?-synucleinopathy that is clinically characterized by varying degrees of parkinsonian, autonomic, and cerebellar features. Unlike other ?-synucleinopathies such as Parkinson's disease, MSA is unique in that the principal ?-synuclein lesions, called glial cytoplasmic inclusions, occur in oligodendroglia rather than neurons, with significantly more ?-synuclein accumulating in MSA brain compared with Parkinson's disease. Although well defined clinically, the molecular pathophysiology of MSA has barely been investigated. In particular, there have been no systematic studies of the perturbation of the brain transcriptome during the onset and progression of this disease. Interestingly, measurements of ?-synuclein gene (SNCA) expression in MSA brain tissue have not revealed overexpression of this gene in oligodendroglia or neurons. It has therefore become clear that other genes and gene networks, both directly as noncoding RNAs or through protein products, contribute to the accumulation of the ?-synuclein protein in the brain. This review provides a summary of current developments in the investigation of the transcriptional causes of MSA and outlines perspectives for future research toward the elucidation of the molecular pathology of MSA-specific neurodegeneration.
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CNS-PNETs with C19MC amplification and/or LIN28 expression comprise a distinct histogenetic diagnostic and therapeutic entity.
Acta Neuropathol.
PUBLISHED: 05-02-2014
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Amplification of the C19MC oncogenic miRNA cluster and high LIN28 expression has been linked to a distinctly aggressive group of cerebral CNS-PNETs (group 1 CNS-PNETs) arising in young children. In this study, we sought to evaluate the diagnostic specificity of C19MC and LIN28, and the clinical and biological spectra of C19MC amplified and/or LIN28+ CNS-PNETs. We interrogated 450 pediatric brain tumors using FISH and IHC analyses and demonstrate that C19MC alteration is restricted to a sub-group of CNS-PNETs with high LIN28 expression; however, LIN28 immunopositivity was not exclusive to CNS-PNETs but was also detected in a proportion of other malignant pediatric brain tumors including rhabdoid brain tumors and malignant gliomas. C19MC amplified/LIN28+ group 1 CNS-PNETs arose predominantly in children <4 years old; a majority arose in the cerebrum but 24 % (13/54) of tumors had extra-cerebral origins. Notably, group 1 CNS-PNETs encompassed several histologic classes including embryonal tumor with abundant neuropil and true rosettes (ETANTR), medulloepithelioma, ependymoblastoma and CNS-PNETs with variable differentiation. Strikingly, gene expression and methylation profiling analyses revealed a common molecular signature enriched for primitive neural features, high LIN28/LIN28B and DNMT3B expression for all group 1 CNS-PNETs regardless of location or tumor histology. Our collective findings suggest that current known histologic categories of CNS-PNETs which include ETANTRs, medulloepitheliomas, ependymoblastomas in various CNS locations, comprise a common molecular and diagnostic entity and identify inhibitors of the LIN28/let7/PI3K/mTOR axis and DNMT3B as promising therapeutics for this distinct histogenetic entity.
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In vivo radiation response of proneural glioma characterized by protective p53 transcriptional program and proneural-mesenchymal shift.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 03-24-2014
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Glioblastoma is the most common adult primary brain tumor and has a dismal median survival. Radiation is a mainstay of treatment and significantly improves survival, yet recurrence is nearly inevitable. Better understanding the radiation response of glioblastoma will help improve strategies to treat this devastating disease. Here, we present a comprehensive study of the in vivo radiation response of glioma cells in a mouse model of proneural glioblastoma. These tumors are a heterogeneous mix of cell types with differing radiation sensitivities. To explicitly study the gene expression changes comprising the radiation response of the Olig2(+) tumor bulk cells, we used translating ribosome affinity purification (TRAP) from Olig2-TRAP transgenic mice. Comparing both ribosome-associated and total pools of mRNA isolated from Olig2(+) cells indicated that the in vivo gene expression response to radiation occurs primarily at the total transcript level. Genes related to apoptosis and cell growth were significantly altered. p53 and E2F were implicated as major regulators of the radiation response, with p53 activity needed for the largest gene expression changes after radiation. Additionally, radiation induced a marked shift away from a proneural expression pattern toward a mesenchymal one. This shift occurs in Olig2(+) cells within hours and in multiple genetic backgrounds. Targets for Stat3 and CEBPB, which have been suggested to be master regulators of a mesenchymal shift, were also up-regulated by radiation. These data provide a systematic description of the events following radiation and may be of use in identifying biological processes that promote glioma radioresistance.
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Time to redefine PD? Introductory statement of the MDS Task Force on the definition of Parkinson's disease.
Mov. Disord.
PUBLISHED: 03-11-2014
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With advances in knowledge disease, boundaries may change. Occasionally, these changes are of such a magnitude that they require redefinition of the disease. In recognition of the profound changes in our understanding of Parkinson's disease (PD), the International Parkinson and Movement Disorders Society (MDS) commissioned a task force to consider a redefinition of PD. This review is a discussion article, intended as the introductory statement of the task force. Several critical issues were identified that challenge current PD definitions. First, new findings challenge the central role of the classical pathologic criteria as the arbiter of diagnosis, notably genetic cases without synuclein deposition, the high prevalence of incidental Lewy body (LB) deposition, and the nonmotor prodrome of PD. It remains unclear, however, whether these challenges merit a change in the pathologic gold standard, especially considering the limitations of alternate gold standards. Second, the increasing recognition of dementia in PD challenges the distinction between diffuse LB disease and PD. Consideration might be given to removing dementia as an exclusion criterion for PD diagnosis. Third, there is increasing recognition of disease heterogeneity, suggesting that PD subtypes should be formally identified; however, current subtype classifications may not be sufficiently robust to warrant formal delineation. Fourth, the recognition of a nonmotor prodrome of PD requires that new diagnostic criteria for early-stage and prodromal PD should be created; here, essential features of these criteria are proposed. Finally, there is a need to create new MDS diagnostic criteria that take these changes in disease definition into consideration.
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Interaction of light and temperature signalling.
J. Exp. Bot.
PUBLISHED: 02-25-2014
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Light and temperature are arguably two of the most important signals regulating the growth and development of plants. In addition to their direct energetic effects on plant growth, light and temperature provide vital immediate and predictive cues for plants to ensure optimal development both spatially and temporally. While the majority of research to date has focused on the contribution of either light or temperature signals in isolation, it is becoming apparent that an understanding of how the two interact is essential to appreciate fully the complex and elegant ways in which plants utilize these environmental cues. This review will outline the diverse mechanisms by which light and temperature signals are integrated and will consider why such interconnected systems (as opposed to entirely separate light and temperature pathways) may be evolutionarily favourable.
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Developing programs for African families, by African families: engaging African migrant families in Melbourne in health promotion interventions.
Fam Community Health
PUBLISHED: 02-20-2014
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Obesity is an emerging problem for African migrants in Australia, but few prevention programs incorporate their cultural beliefs and values. This study reports on the application of community capacity-building and empowerment principles in 4 workshops with Sudanese families in Australia. Workshop participants prioritized health behaviors, skill and knowledge gaps, and environments for change to identify culturally centered approaches to health promotion. The workshops highlighted a need for culturally and age-appropriate interventions that build whole-of-family skills and knowledge around the positive effects of physical activity and nutrition to improve health within communities while reducing intergenerational and gender role family conflicts.
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The neurobiological basis of cognitive impairment in Parkinson's disease.
Mov. Disord.
PUBLISHED: 02-08-2014
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The recent formalization of clinical criteria for Parkinson's disease with dementia (PDD) codifies many studies on this topic, including those assessing biological correlates. These studies show that the emergence of PDD occurs on the background of severe dopamine deficits with, the main pathological drivers of cognitive decline being a synergistic effect between alpha-synuclein and Alzheimer's disease pathology. The presence of these pathologies correlates with a marked loss of limbic and cortically projecting dopamine, noradrenaline, serotonin, and acetylcholine neurons, although the exact timing of these relationships remains to be determined. Genetic factors, such as triplications in the ?-synuclein gene, lead to a clear increased risk of PDD, whereas others, such as parkin mutations, are associated with a reduced risk of PDD. The very recent formalization of clinical criteria for PD with mild cognitive impairment (PD-MCI) allows only speculation on its biological and genetic bases. Critical assessment of animal models shows that chronic low-dose MPTP treatment in primates recapitulates PD-MCI over time, enhancing the current biological concept of PD-MCI as having enhanced dopamine deficiency in frontostriatal pathways as well as involvement of other neurotransmitter systems. Data from other animal models support multiple transmitter involvement in cognitive impairment in PD. Whereas dopamine dysfunction has been highlighted because of its obvious role in PD, the role of the other neurotransmitter systems, neurodegenerative pathologies, and genetic factors in PD-MCI remains to be fully elucidated.
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Arabidopsis cell expansion is controlled by a photothermal switch.
Nat Commun
PUBLISHED: 02-04-2014
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In Arabidopsis, the seedling hypocotyl has emerged as an exemplar model system to study light and temperature control of cell expansion. Light sensitivity of this organ is epitomized in the fluence rate response where suppression of hypocotyl elongation increases incrementally with light intensity. This finely calibrated response is controlled by the photoreceptor, phytochrome B, through the deactivation and proteolytic destruction of phytochrome-interacting factors (PIFs). Here we show that this classical light response is strictly temperature dependent: a shift in temperature induces a dramatic reversal of response from inhibition to promotion of hypocotyl elongation by light. Applying an integrated experimental and mathematical modelling approach, we show how light and temperature coaction in the circuitry drives a molecular switch in PIF activity and control of cell expansion. This work provides a paradigm to understand the importance of signal convergence in evoking different or non-intuitive alterations in molecular signalling.
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Lipid dysfunction and pathogenesis of multiple system atrophy.
Acta Neuropathol Commun
PUBLISHED: 02-03-2014
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Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by the accumulation of ?-synuclein protein in the cytoplasm of oligodendrocytes, the myelin-producing support cells of the central nervous system (CNS). The brain is the most lipid-rich organ in the body and disordered metabolism of various lipid constituents is increasingly recognized as an important factor in the pathogenesis of several neurodegenerative diseases. ?-Synuclein is a 17 kDa protein with a close association to lipid membranes and biosynthetic processes in the CNS, yet its precise function is a matter of speculation, particularly in oligodendrocytes. ?-Synuclein aggregation in neurons is a well-characterized feature of Parkinson's disease and dementia with Lewy bodies. Epidemiological evidence and in vitro studies of ?-synuclein molecular dynamics suggest that disordered lipid homeostasis may play a role in the pathogenesis of ?-synuclein aggregation. However, MSA is distinct from other ?-synucleinopathies in a number of respects, not least the disparate cellular focus of ?-synuclein pathology. The recent identification of causal mutations and polymorphisms in COQ2, a gene encoding a biosynthetic enzyme for the production of the lipid-soluble electron carrier coenzyme Q10 (ubiquinone), puts membrane transporters as central to MSA pathogenesis, although how such transporters are involved in the early myelin degeneration observed in MSA remains unclear. The purpose of this review is to bring together available evidence to explore the potential role of membrane transporters and lipid dyshomeostasis in the pathogenesis of ?-synuclein aggregation in MSA. We hypothesize that dysregulation of the specialized lipid metabolism involved in myelin synthesis and maintenance by oligodendrocytes underlies the unique neuropathology of MSA.
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Mathematical models light up plant signaling.
Plant Cell
PUBLISHED: 01-30-2014
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Plants respond to changes in the environment by triggering a suite of regulatory networks that control and synchronize molecular signaling in different tissues, organs, and the whole plant. Molecular studies through genetic and environmental perturbations, particularly in the model plant Arabidopsis thaliana, have revealed many of the mechanisms by which these responses are actuated. In recent years, mathematical modeling has become a complementary tool to the experimental approach that has furthered our understanding of biological mechanisms. In this review, we present modeling examples encompassing a range of different biological processes, in particular those regulated by light. Current issues and future directions in the modeling of plant systems are discussed.
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Tricks of the mind: Visual hallucinations as disorders of attention.
Prog. Neurobiol.
PUBLISHED: 01-29-2014
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Visual hallucinations are common across a number of disorders but to date, a unifying pathophysiology underlying these phenomena has not been described. In this manuscript, we combine insights from neuropathological, neuropsychological and neuroimaging studies to propose a testable common neural mechanism for visual hallucinations. We propose that 'simple' visual hallucinations arise from disturbances within regions responsible for the primary processing of visual information, however with no further modulation of perceptual content by attention. In contrast, 'complex' visual hallucinations reflect dysfunction within and between the Attentional Control Networks, leading to the inappropriate interpretation of ambiguous percepts. The incorrect information perceived by hallucinators is often differentially interpreted depending on the time-course and the neuroarchitecture underlying the interpretation. Disorders with 'complex' hallucinations without retained insight are proposed to be associated with a reduction in the activity within the Dorsal Attention Network. The review concludes by showing that a variety of pathological processes can ultimately manifest in any of these three categories, depending on the precise location of the impairment.
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Reduced glucocerebrosidase is associated with increased ?-synuclein in sporadic Parkinson's disease.
Brain
PUBLISHED: 01-28-2014
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Heterozygous mutations in GBA1, the gene encoding lysosomal glucocerebrosidase, are the most frequent known genetic risk factor for Parkinson's disease. Reduced glucocerebrosidase and ?-synuclein accumulation are directly related in cell models of Parkinson's disease. We investigated relationships between Parkinson's disease-specific glucocerebrosidase deficits, glucocerebrosidase-related pathways, and ?-synuclein levels in brain tissue from subjects with sporadic Parkinson's disease without GBA1 mutations. Brain regions with and without a Parkinson's disease-related increase in ?-synuclein levels were assessed in autopsy samples from subjects with sporadic Parkinson's disease (n = 19) and age- and post-mortem delay-matched controls (n = 10). Levels of glucocerebrosidase, ?-synuclein and related lysosomal and autophagic proteins were assessed by western blotting. Glucocerebrosidase enzyme activity was measured using a fluorimetric assay, and glucocerebrosidase and ?-synuclein messenger RNA expression determined by quantitative polymerase chain reaction. Related sphingolipids were analysed by mass spectrometry. Multivariate statistical analyses were performed to identify differences between disease groups and regions, with non-parametric correlations used to identify relationships between variables. Glucocerebrosidase protein levels and enzyme activity were selectively reduced in the early stages of Parkinson's disease in regions with increased ?-synuclein levels although limited inclusion formation, whereas GBA1 messenger RNA expression was non-selectively reduced in Parkinson's disease. The selective loss of lysosomal glucocerebrosidase was directly related to reduced lysosomal chaperone-mediated autophagy, increased ?-synuclein and decreased ceramide. Glucocerebrosidase deficits in sporadic Parkinson's disease are related to the abnormal accumulation of ?-synuclein and are associated with substantial alterations in lysosomal chaperone-mediated autophagy pathways and lipid metabolism. Our data suggest that the early selective Parkinson's disease changes are likely a result of the redistribution of cellular membrane proteins leading to a chronic reduction in lysosome function in brain regions vulnerable to Parkinson's disease pathology.
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The microanatomic basis of finger clubbing - a high-resolution magnetic resonance imaging study.
J. Rheumatol.
PUBLISHED: 01-15-2014
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Hypervascularization in finger clubbing is recognized, but its microanatomical basis remains unclear. This pilot descriptive study used magnetic resonance imaging (MRI) to explore this further.
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New criteria for frontotemporal dementia syndromes: clinical and pathological diagnostic implications.
J. Neurol. Neurosurg. Psychiatr.
PUBLISHED: 01-13-2014
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To assess the impact of new clinical diagnostic criteria for frontotemporal dementia (FTD) syndromes, including primary progressive aphasias (PPA), on prior clinical diagnosis and to explore clinicopathological correlations.
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Brm inhibits the proliferative response of keratinocytes and corneal epithelial cells to ultraviolet radiation-induced damage.
PLoS ONE
PUBLISHED: 01-01-2014
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Ultraviolet radiation (UV) from sunlight is the primary cause of skin and ocular neoplasia. Brahma (BRM) is part of the SWI/SNF chromatin remodeling complex. It provides energy for rearrangement of chromatin structure. Previously we have found that human skin tumours have a hotspot mutation in BRM and that protein levels are substantially reduced. Brm-/- mice have enhanced susceptibility to photocarcinogenesis. In these experiments, Brm-/- mice, with both or a single Trp53 allele were exposed to UV for 2 or 25 weeks. In wild type mice the central cornea and stroma became atrophic with increasing time of exposure while the peripheral regions became hyperplastic, presumably as a reparative process. Brm-/-, Trp53+/-, and particularly the Brm-/- Trp53+/- mice had an exaggerated hyperplastic regeneration response in the corneal epithelium and stroma so that the central epithelial atrophy or stromal loss was reduced. UV induced hyperplasia of the epidermis and corneal epithelium, with an increase in the number of dividing cells as determined by Ki-67 expression. This response was considerably greater in both the Brm-/- Trp53+/+ and Brm-/- Trp53+/- mice indicating that Brm protects from UV-induced enhancement of cell division, even with loss of one Trp53 allele. Cell division was disorganized in Brm-/- mice. Rather than being restricted to the basement membrane region, dividing cells were also present in the suprabasal regions of both tissues. Brm appears to be a tumour suppressor gene that protects from skin and ocular photocarcinogenesis. These studies indicate that Brm protects from UV-induced hyperplastic growth in both cutaneous and corneal keratinocytes, which may contribute to the ability of Brm to protect from photocarcinogenesis.
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Parkinson's disease-implicated kinases in the brain; insights into disease pathogenesis.
Front Mol Neurosci
PUBLISHED: 01-01-2014
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Substantial evidence implicates abnormal protein kinase function in various aspects of Parkinson's disease (PD) etiology. Elevated phosphorylation of the PD-defining pathological protein, ?-synuclein, correlates with its aggregation and toxic accumulation in neurons, whilst genetic missense mutations in the kinases PTEN-induced putative kinase 1 and leucine-rich repeat kinase 2, increase susceptibility to PD. Experimental evidence also links kinases of the phosphoinositide 3-kinase and mitogen-activated protein kinase signaling pathways, amongst others, to PD. Understanding how the levels or activities of these enzymes or their substrates change in brain tissue in relation to pathological states can provide insight into disease pathogenesis. Moreover, understanding when and where kinase dysfunction occurs is important as modulation of some of these signaling pathways can potentially lead to PD therapeutics. This review will summarize what is currently known in regard to the expression of these PD-implicated kinases in pathological human postmortem brain tissue.
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Revisiting bistability in the lysis/lysogeny circuit of bacteriophage lambda.
PLoS ONE
PUBLISHED: 01-01-2014
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The lysis/lysogeny switch of bacteriophage lambda serves as a paradigm for binary cell fate decision, long-term maintenance of cellular state and stimulus-triggered switching between states. In the literature, the system is often referred to as "bistable." However, it remains unclear whether this term provides an accurate description or is instead a misnomer. Here we address this question directly. We first quantify transcriptional regulation governing lysogenic maintenance using a single-cell fluorescence reporter. We then use the single-cell data to derive a stochastic theoretical model for the underlying regulatory network. We use the model to predict the steady states of the system and then validate these predictions experimentally. Specifically, a regime of bistability, and the resulting hysteretic behavior, are observed. Beyond the steady states, the theoretical model successfully predicts the kinetics of switching from lysogeny to lysis. Our results show how the physics-inspired concept of bistability can be reliably used to describe cellular phenotype, and how an experimentally-calibrated theoretical model can have accurate predictive power for cell-state switching.
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Strengths and limitations of period estimation methods for circadian data.
PLoS ONE
PUBLISHED: 01-01-2014
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A key step in the analysis of circadian data is to make an accurate estimate of the underlying period. There are many different techniques and algorithms for determining period, all with different assumptions and with differing levels of complexity. Choosing which algorithm, which implementation and which measures of accuracy to use can offer many pitfalls, especially for the non-expert. We have developed the BioDare system, an online service allowing data-sharing (including public dissemination), data-processing and analysis. Circadian experiments are the main focus of BioDare hence performing period analysis is a major feature of the system. Six methods have been incorporated into BioDare: Enright and Lomb-Scargle periodograms, FFT-NLLS, mFourfit, MESA and Spectrum Resampling. Here we review those six techniques, explain the principles behind each algorithm and evaluate their performance. In order to quantify the methods' accuracy, we examine the algorithms against artificial mathematical test signals and model-generated mRNA data. Our re-implementation of each method in Java allows meaningful comparisons of the computational complexity and computing time associated with each algorithm. Finally, we provide guidelines on which algorithms are most appropriate for which data types, and recommendations on experimental design to extract optimal data for analysis.
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Comparison of bacterial communities in sands and water at beaches with bacterial water quality violations.
PLoS ONE
PUBLISHED: 01-01-2014
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Recreational water quality, as measured by culturable fecal indicator bacteria (FIB), may be influenced by persistent populations of these bacteria in local sands or wrack, in addition to varied fecal inputs from human and/or animal sources. In this study, pyrosequencing was used to generate short sequence tags of the 16S hypervariable region ribosomal DNA from shallow water samples and from sand samples collected at the high tide line and at the intertidal water line at sites with and without FIB exceedance events. These data were used to examine the sand and water bacterial communities to assess the similarity between samples, and to determine the impact of water quality exceedance events on the community composition. Sequences belonging to a group of bacteria previously identified as alternative fecal indicators were also analyzed in relationship to water quality violation events. We found that sand and water samples hosted distinctly different overall bacterial communities, and there was greater similarity in the community composition between coastal water samples from two distant sites. The dissimilarity between high tide and intertidal sand bacterial communities, although more similar to each other than to water, corresponded to greater tidal range between the samples. Within the group of alternative fecal indicators greater similarity was observed within sand and water from the same site, likely reflecting the anthropogenic contribution at each beach. This study supports the growing evidence that community-based molecular tools can be leveraged to identify the sources and potential impact of fecal pollution in the environment, and furthermore suggests that a more diverse bacterial community in beach sand and water may reflect a less contaminated site and better water quality.
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Increased Ndfip1 in the substantia nigra of parkinsonian brains is associated with elevated iron levels.
PLoS ONE
PUBLISHED: 01-01-2014
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Iron misregulation is a central component in the neuropathology of Parkinson's disease. The iron transport protein DMT1 is known to be increased in Parkinson's brains linking functional transport mechanisms with iron accumulation. The regulation of DMT1 is therefore critical to the management of iron uptake in the disease setting. We previously identified post-translational control of DMT1 levels through a ubiquitin-mediated pathway led by Ndfip1, an adaptor for Nedd4 family of E3 ligases. Here we show that loss of Ndfip1 from mouse dopaminergic neurons resulted in misregulation of DMT1 levels and increased susceptibility to iron induced death. We report that in human Parkinson's brains increased iron concentrations in the substantia nigra are associated with upregulated levels of Ndfip1 in dopaminergic neurons containing ?-synuclein deposits. Additionally, Ndfip1 was also found to be misexpressed in astrocytes, a cell type normally devoid of this protein. We suggest that in Parkinson's disease, increased iron levels are associated with increased Ndfip1 expression for the regulation of DMT1, including abnormal Ndfip1 activation in non-neuronal cell types such as astrocytes.
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HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENES1 Is Required for Circadian Periodicity through the Promotion of Nucleo-Cytoplasmic mRNA Export in Arabidopsis.
Plant Cell
PUBLISHED: 11-19-2013
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Cold acclimation has been shown to be attenuated by the degradation of the INDUCER OF CBF EXPRESSION1 protein by the E3 ubiquitin ligase HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENES1 (HOS1). However, recent work has suggested that HOS1 may have a wider range of roles in plants than previously appreciated. Here, we show that hos1 mutants are affected in circadian clock function, exhibiting a long-period phenotype in a wide range of temperature and light environments. We demonstrate that hos1 mutants accumulate polyadenylated mRNA in the nucleus and that the circadian defect in hos1 is shared by multiple mutants with aberrant mRNA export, but not in a mutant attenuated in nucleo-cytoplasmic transport of microRNAs. As revealed by RNA sequencing, hos1 exhibits gross changes to the transcriptome with genes in multiple functional categories being affected. In addition, we show that hos1 and other previously described mutants with altered mRNA export affect cold signaling in a similar manner. Our data support a model in which altered mRNA export is important for the manifestation of hos1 circadian clock defects and suggest that HOS1 may indirectly affect cold signaling through disruption of the circadian clock.
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Prodegenerative I?B? expression in oligodendroglial ?-synuclein models of multiple system atrophy.
Neurobiol. Dis.
PUBLISHED: 11-01-2013
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Multiple system atrophy is a progressive, neurodegenerative disease characterized by parkinsonism, ataxia, autonomic dysfunction, and accumulation of ?-synuclein in oligodendrocytes. To understand how ?-synuclein aggregates impact oligodendroglial homeostasis, we investigated an oligodendroglial cell model of ?-synuclein dependent degeneration and identified responses linked to the NF-?B transcription factor stress system. Coexpression of human ?-synuclein and the oligodendroglial protein p25? increased the expression of I?B? mRNA and protein early during the degenerative process and this was dependent on both aggregation and Ser129 phosphorylation of ?-synuclein. This response was prodegenerative because blocking I?B? expression by siRNA rescued the cells. I?B? is an inhibitor of NF-?B and acts by binding and retaining NF-?B p65 in the cytoplasm. The protection obtained by silencing I?B? was accompanied by a strong increase in nuclear p65 translocation indicating that NF-?B activation protects against ?-synuclein aggregate stress. In the cellular model, two different phenotypes were observed; degenerating cells retracting their microtubules and resilient cells tolerating the coexpression of ?-synuclein and p25?. The resilient cells displayed a significant higher nuclear translocation of p65 and activation of the NF-?B system relied on stress elicited by aggregated and Ser129 phosphorylated ?-synuclein. To validate the relationship between oligodendroglial ?-synuclein expression and I?B?, we analyzed two different lines of transgenic mice expressing human ?-synuclein under the control of the oligodendrocytic MBP promotor (intermediate-expresser line 1 and high-expresser line 29). I?B? mRNA expression was increased in both lines and immunofluorescence microscopy and in situ hybridization revealed that I?B? mRNA and protein is expressed in oligodendrocytes. I?B? mRNA expression was demonstrated prior to activation of microglia and astrocytes in line 1. Human brain tissue affected by MSA displayed increased expression of I?B? and NF-?B p65 in some oligodendrocytes containing glial cytoplasmic inclusions. Our data suggest that oligodendroglial I?B? expression and NF-?B are activated early in the course of MSA and their balance contributes to the decision of cellular demise. Favoring oligodendroglial NF-?B activation may represent a therapeutic strategy for this devastating disease.
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Danon Disease Due to a Novel LAMP2 Microduplication.
JIMD Rep
PUBLISHED: 09-14-2013
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Danon disease is a rare X-linked disorder comprising hypertrophic cardiomyopathy, skeletal myopathy, intellectual disability, and retinopathy; mutations of the lysosome-associated membrane protein gene LAMP2 are responsible. Most affected persons exhibit "private" point mutations; small locus rearrangements have recently been reported in four cases. Here, we describe the clinical, pathologic, and molecular features of a male proband and his affected mother with Danon disease and a small LAMP2 microduplication. The proband presented at age 12 years with exercise intolerance, hypertrophic cardiomyopathy, and increased creatine kinase. Endomyocardial biopsy findings were nonspecific, showing myocyte hypertrophy and reactive mitochondrial changes. Quadriceps muscle biopsy demonstrated the characteristic autophagic vacuoles with sarcolemma-like features. LAMP2 tissue immunostaining was absent; however, LAMP2 sequencing was normal. Deletion/duplication testing by multiplex ligation-dependent probe amplification (MLPA) assay revealed a 1.5kb microduplication containing LAMP2 exons 4 and 5. RT-PCR studies were consistent with the inclusion of these two duplicated exons in the final spliced transcript, resulting in a frameshift. The probands mother, who had died following cardiac transplantation due to suspected myocarditis at age 35, was reviewed and was shown to be affected upon immunostaining of banked myocardial tissue. This case constitutes the second report of a pathogenic microduplication in Danon disease, and illustrates a number of potential diagnostic pitfalls. Firstly, given the imperfect sensitivity of LAMP2 sequencing, tissue immunostaining and/or MLPA should be considered as a diagnostic adjunct in the workup for this disorder. Secondly, the pathological findings in myocardium may be falsely indicative of relatively common conditions such as myocarditis.
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Disease duration and the integrity of the nigrostriatal system in Parkinsons disease.
Brain
PUBLISHED: 07-26-2013
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The pace of nigrostriatal degeneration, both with regards to striatal denervation and loss of melanin and tyrosine hydroxylase-positive neurons, is poorly understood especially early in the Parkinsons disease process. This study investigated the extent of nigrostriatal degeneration in patients with Parkinsons disease at different disease durations from time of diagnosis. Brains of patients with Parkinsons disease (n=28) with post-diagnostic intervals of 1-27 years and normal elderly control subjects (n=9) were examined. Sections of the post-commissural putamen and substantia nigra pars compacta were processed for tyrosine hydroxylase and dopamine transporter immunohistochemistry. The post-commissural putamen was selected due to tissue availability and the fact that dopamine loss in this region is associated with motor disability in Parkinsons disease. Quantitative assessments of putaminal dopaminergic fibre density and stereological estimates of the number of melanin-containing and tyrosine hydroxylase-immunoreactive neurons in the substantia nigra pars compacta (both in total and in subregions) were performed by blinded investigators in cases where suitable material was available (n=17). Dopaminergic markers in the dorsal putamen showed a modest loss at 1 year after diagnosis in the single case available for study. There was variable (moderate to marked) loss, at 3 years. At 4 years post-diagnosis and thereafter, there was virtually complete loss of staining in the dorsal putamen with only an occasional abnormal dopaminergic fibre detected. In the substantia nigra pars compacta, there was a 50-90% loss of tyrosine hydroxylase-positive neurons from the earliest time points studied with only marginal additional loss thereafter. There was only a ?10% loss of melanized neurons in the one case evaluated 1 year post-diagnosis, and variable (30 to 60%) loss during the first several years post-diagnosis with more gradual and subtle loss in the second decade. At all time points, there were more melanin-containing than tyrosine hydroxylase-positive cells. Loss of dopaminergic markers in the dorsal putamen occurs rapidly and is virtually complete by 4 years post-diagnosis. Loss of melanized nigral neurons lags behind the loss of dopamine markers. These findings have important implications for understanding the nature of Parkinsons disease neurodegeneration and for studies of putative neuroprotective/restorative therapies.
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Characterization of a novel RNA polymerase mutant that alters DksA activity.
J. Bacteriol.
PUBLISHED: 07-12-2013
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The auxiliary factor DksA is a global transcription regulator and, with the help of ppGpp, controls the nutritional stress response in Escherichia coli. Although the consequences of its modulation of RNA polymerase (RNAP) are becoming better explained, it is still not fully understood how the two proteins interact. We employed a series of genetic suppressor selections to find residues in RNAP that alter its sensitivity to DksA. Our approach allowed us to identify and genetically characterize in vivo three single amino acid substitutions: ? E677G, ? V146F, and ? G534D. We demonstrate that the mutation ? E677G affects the activity of both DksA and its homolog, TraR, but does not affect the action of other secondary interactors, such as GreA or GreB. Our mutants provide insight into how different auxiliary transcription factors interact with RNAP and contribute to our understanding of how different stages of transcription are regulated through the secondary channel of RNAP in vivo.
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DNA methylation of the MAPT gene in Parkinsons disease cohorts and modulation by vitamin E In Vitro.
Mov. Disord.
PUBLISHED: 07-09-2013
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Parkinsons disease (PD) is a neurodegenerative disorder for which environmental factors influence disease risk and may act via an epigenetic mechanism. The microtubule-associated protein tau (MAPT) is a susceptibility gene for idiopathic PD. Methylation levels were determined by pyrosequencing of bisulfite-treated DNA in a leukocyte cohort (358 PD patients and 1084 controls) and in two brain cohorts (Brain1, comprising 69 cerebellum controls; and Brain2, comprising 3 brain regions from 28 PD patients and 12 controls). In vitro assays involved the transfection of methylated promoter-luciferase constructs or treatment with an exogenous micronutrient. In normal leukocytes, the MAPT H1/H2 diplotype and sex were predictors of MAPT methylation. Haplotype-specific pyrosequencing confirmed that the H1 haplotype had higher methylation than the H2 haplotype in normal leukocytes and brain tissues. MAPT methylation was negatively associated with MAPT expression in the Brain1 cohort and in transfected cells. Methylation levels differed between three normal brain regions (Brain2 cohort, putamen?
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Endogenous progesterone levels and frontotemporal dementia: modulation of TDP-43 and Tau levels in vitro and treatment of the A315T TARDBP mouse model.
Dis Model Mech
PUBLISHED: 06-20-2013
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Frontotemporal dementia (FTD) is associated with motor neurone disease (FTD-MND), corticobasal syndrome (CBS) and progressive supranuclear palsy syndrome (PSPS). Together, this group of disorders constitutes a major cause of young-onset dementia. One of the three clinical variants of FTD is progressive nonfluent aphasia (PNFA), which is focused on in this study. The steroid hormone progesterone (PROG) is known to have an important role as a neurosteroid with potent neuroprotective and promyelination properties. In a case-control study of serum samples (39 FTD, 91 controls), low serum PROG was associated with FTD overall. In subgroup analysis, low PROG levels were significantly associated with FTD-MND and CBS, but not with PSPS or PNFA. PROG levels of >195 pg/ml were significantly correlated with lower disease severity (frontotemporal dementia rating scale) for individuals with CBS. In the human neuroblastoma SK-N-MC cell line, exogenous PROG (9300-93,000 pg/ml) had a significant effect on overall Tau and nuclear TDP-43 levels, reducing total Tau levels by ?1.5-fold and increasing nuclear TDP-43 by 1.7- to 2.0-fold. Finally, elevation of plasma PROG to a mean concentration of 5870 pg/ml in an Ala315Thr (A315T) TARDBP transgenic mouse model significantly reduced the rate of loss of locomotor control in PROG-treated, compared with placebo, mice. The PROG treatment did not significantly increase survival of the mice, which might be due to the limitation of the transgenic mouse to accurately model TDP-43-mediated neurodegeneration. Together, our clinical, cellular and animal data provide strong evidence that PROG could be a valid therapy for specific related disorders of FTD.
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Differential control of seed primary dormancy in Arabidopsis ecotypes by the transcription factor SPATULA.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 06-10-2013
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Freshly matured seeds exhibit primary dormancy, which prevents germination until environmental conditions are favorable. The establishment of dormancy occurs during seed development and involves both genetic and environmental factors that impact on the ratio of two antagonistic phytohormones: abscisic acid (ABA), which promotes dormancy, and gibberellic acid, which promotes germination. Although our understanding of dormancy breakage in mature seeds is well advanced, relatively little is known about the mechanisms involved in establishing dormancy during seed maturation. We previously showed that the SPATULA (SPT) transcription factor plays a key role in regulating seed germination. Here we investigate its role during seed development and find that, surprisingly, it has opposite roles in setting dormancy in Landsberg erecta and Columbia Arabidopsis ecotypes. We also find that SPT regulates expression of five transcription factor encoding genes: ABA-INSENSITIVE4 (ABI4) and ABI5, which mediate ABA signaling; REPRESSOR-OF-GA (RGA) and RGA-LIKE3 involved in gibberellic acid signaling; and MOTHER-OF-FT-AND-TFL1 (MFT) that we show here promotes Arabidopsis seed dormancy. Although ABI4, RGA, and MFT are repressed by SPT, ABI5 and RGL3 are induced. Furthermore, we show that RGA, MFT, and ABI5 are direct targets of SPT in vivo. We present a model in which SPT drives two antagonistic "dormancy-repressing" and "dormancy-promoting" routes that operate simultaneously in freshly matured seeds. Each of these routes has different impacts and this in turn explains the opposite effect of SPT on seed dormancy of the two ecotypes analyzed here.
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Classification of FTLD-TDP cases into pathological subtypes using antibodies against phosphorylated and non-phosphorylated TDP43.
Acta Neuropathol Commun
PUBLISHED: 06-06-2013
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Two commercially available TDP43 antibodies (phosphorylated or pTDP43, non-phosphorylated or iTDP43) are currently in use for the neuropathological classification of FTLD-TDP cases into pathological subtypes. To date, no studies have performed direct comparisons between these TDP43 antibodies to determine if they identify the same FTLD-TDP subtypes. The reliability of subtype classification with the use of either of these antibodies has also not been investigated. The present study compares the severity of pathological lesions identified with pTDP43 and iTDP43 in a cohort of 14 FTLD-TDP cases, and assesses the accuracy and inter-observer reliability found with either of these antibodies.
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Heritable change caused by transient transcription errors.
PLoS Genet.
PUBLISHED: 06-01-2013
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Transmission of cellular identity relies on the faithful transfer of information from the mother to the daughter cell. This process includes accurate replication of the DNA, but also the correct propagation of regulatory programs responsible for cellular identity. Errors in DNA replication (mutations) and protein conformation (prions) can trigger stable phenotypic changes and cause human disease, yet the ability of transient transcriptional errors to produce heritable phenotypic change (epimutations) remains an open question. Here, we demonstrate that transcriptional errors made specifically in the mRNA encoding a transcription factor can promote heritable phenotypic change by reprogramming a transcriptional network, without altering DNA. We have harnessed the classical bistable switch in the lac operon, a memory-module, to capture the consequences of transient transcription errors in living Escherichia coli cells. We engineered an error-prone transcription sequence (A9 run) in the gene encoding the lac repressor and show that this slippery sequence directly increases epigenetic switching, not mutation in the cell population. Therefore, one altered transcript within a multi-generational series of many error-free transcripts can cause long-term phenotypic consequences. Thus, like DNA mutations, transcriptional epimutations can instigate heritable changes that increase phenotypic diversity, which drives both evolution and disease.
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Pharmacologically Antagonizing the CXCR4-CXCL12 Chemokine Pathway with AMD3100 Inhibits Sunlight-Induced Skin Cancer.
J. Invest. Dermatol.
PUBLISHED: 05-09-2013
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One way sunlight causes skin cancer is by suppressing anti-tumor immunity. A major mechanism involves altering mast cell migration via the C-X-C motif chemokine receptor 4-C-X-C motif chemokine ligand 12 (CXCR4-CXCL12) chemokine pathway. We have discovered that pharmacologically blocking this pathway with the CXCR4 antagonist AMD3100 prevents both UV radiation-induced immune suppression and skin cancer. The majority of control mice receiving UV-only developed histopathologically confirmed squamous cell carcinomas. In contrast, skin tumor incidence and burden was significantly lower in AMD3100-treated mice. Perhaps most striking was that AMD3100 completely prevented the outgrowth of latent tumors that occurred once UV irradiation ceased. AMD3100 protection from UV immunosuppression and skin cancer was associated with reduced mast cell infiltration into the skin, draining lymph nodes, and the tumor itself. Thus a major target of CXCR4 antagonism was the mast cell. Our results indicate that interfering with UV-induced CXCL12 by antagonizing CXCR4 significantly inhibits skin tumor development by blocking UV-induced effects on mast cells. Hence, the CXCR4-CXCL12 chemokine pathway is a novel therapeutic target in the prevention of UV-induced skin cancer.Journal of Investigative Dermatology advance online publication, 14 November 2013; doi:10.1038/jid.2013.424.
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The pathogenesis of cingulate atrophy in behavioral variant frontotemporal dementia and Alzheimers disease.
Acta Neuropathol Commun
PUBLISHED: 04-18-2013
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Early atrophy of the cingulate cortex is a feature of both behavioral variant frontotemporal dementia (bvFTD) and Alzheimers disease (AD), with degeneration of the anterior cingulate region increasingly recognized as a strong predictor of bvFTD. The total number of neurons in this region, rather than the density of neurons, is associated with mood disturbance in other dementias, although there are no data on the extent and magnitude of neuronal loss in patients with bvFTD. While the density of small populations of neurons in this region has been assessed, it is unlikely that the degree of atrophy of the cingulate cortex seen in bvFTD can be explained by the loss of these subpopulations. This suggests that there is more generalized degeneration of neurons in this region in bvFTD.The present study assesses total neuronal number, as well as characteristic pathologies, in the anterior and posterior cingulate cortices of pathologically confirmed bvFTD (N?=?11) and AD (N?=?9) patients compared with age-matched controls (N?=?14). The bvFTD cohort comprised 5 cases with tau pathology (Picks disease), and 6 with TDP-43 pathology.
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Copper pathology in vulnerable brain regions in Parkinsons disease.
Neurobiol. Aging
PUBLISHED: 04-15-2013
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Synchrotron-based x-ray fluorescence microscopy, immunofluorescence, and Western blotting were used to investigate changes in copper (Cu) and Cu-associated pathways in the vulnerable substantia nigra (SN) and locus coeruleus (LC) and in nondegenerating brain regions in cases of Parkinsons disease (PD) and appropriate healthy and disease controls. In PD and incidental Lewy body disease, levels of Cu and Cu transporter protein 1, were significantly reduced in surviving neurons in the SN and LC. Specific activity of the cuproprotein superoxide dismutase 1 was unchanged in the SN in PD but was enhanced in the parkinsonian anterior cingulate cortex, a region with ?-synuclein pathology, normal Cu, and limited cell loss. These data suggest that regions affected by ?-synuclein pathology may display enhanced vulnerability and cell loss if Cu-dependent protective mechanisms are compromised. Additional investigation of copper pathology in PD may identify novel targets for the development of protective therapies for this disorder.
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ABCA8 stimulates sphingomyelin production in oligodendrocytes.
Biochem. J.
PUBLISHED: 04-09-2013
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Members of the ABCA (ATP-binding cassette subfamily A) family are characterized by their ability to transport lipids across cellular membranes and regulate lipid homoeostasis in the brain and peripheral tissues. ABCA8 is a little-known member of this subfamily that was originally cloned from human brain libraries and has no known function. In an effort to elucidate the role of ABCA8 in the brain we first undertook a comprehensive analysis of its expression in the human brain. ABCA8 was differentially expressed in multiple regions of adult human brains with significantly higher expression in oligodendrocyte-enriched white matter regions compared with grey matter cortical regions. We then assessed the impact of ABCA8 on sphingomyelin production in oligodendrocyte and showed that ABCA8 was able to significantly stimulate both sphingomyelin synthase 1 expression and sphingomyelin production. Furthermore, ABCA8 expression in the prefrontal cortex across the human life span correlated strongly with age-associated myelination, and the myelinating gene p25? was significantly up-regulated with ABCA8. The present study represents the first extensive expression and functional study of ABCA8 in the human brain and the results strongly suggest that ABCA8 regulates lipid metabolism in oligodendrocytes and potentially plays a role in myelin formation and maintenance.
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Primary conjunctival anaplastic large cell lymphoma in a child.
J AAPOS
PUBLISHED: 04-04-2013
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Conjunctival tumors in children are uncommon and behave differently from those in adults. The vast majority of tumors are benign. Of the malignant lesions in this age group, lymphoma and melanoma are most commonly reported. Most lymphoid tumors in children represent lymphoid hyperplasia, not lymphoma. Clinical differentiation of these two entities is not possible and biopsy is required to establish the diagnosis. We present an unusual case of primary anaplastic large cell lymphoma of the conjunctiva in a young boy.
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The role of dysfunctional attentional control networks in visual misperceptions in Parkinsons disease.
Hum Brain Mapp
PUBLISHED: 04-01-2013
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Visual misperceptions and hallucinations represent a problematic symptom of Parkinsons disease. The pathophysiological mechanisms underlying these symptoms remain poorly understood, however, a recent hypothesis has suggested that visual misperceptions and hallucinations may arise from disrupted processing across attentional networks. To test the specific predictions of this hypothesis, 22 patients with Parkinsons disease underwent 3T fMRI while performing the Bistable Percept Paradigm, a task that has previously been shown to identify patients with hallucinations. Subjects are required to study a battery of randomly assigned "monostable" and "bistable" monochromatic images for the presence or absence of a bistable percept. Those patients who scored a high percentage of misperceptions and missed images on the task were less able to activate frontal and parietal hubs of the putative Dorsal Attention Network. Furthermore, poor performance on the task was significantly correlated with the degree of decreased activation in a number of these hubs. At the group level, the difference between processing a bistable versus a monostable cue was associated with increased recruitment of the anterior insula. In addition, those patients with impaired performance on the paradigm displayed decreased resting state functional connectivity between hubs of the Ventral and Dorsal Attention Networks. These same patients had significantly decreased gray matter in the insula bilaterally. In addition, a combined analysis of the separate neuroimaging approaches revealed significant relationships across the impaired networks. These findings are consistent with specific predictions from a recently proposed hypothesis that implicates dysfunction within attentional networks in Parkinsonian hallucinations. Hum Brain Mapp, 2013. © 2013 Wiley Periodicals, Inc.
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Variability in neuronal expression of dopamine receptors and transporters in the substantia nigra.
Mov. Disord.
PUBLISHED: 04-01-2013
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Parkinsons disease (PD) patients have increased susceptibility to impulse control disorders. Recent studies have suggested that alterations in dopamine receptors in the midbrain underlie impulsive behaviors and that more impulsive individuals, including patients with PD, exhibit increased occupancy of their midbrain dopamine receptors. The cellular location of dopamine receptor subtypes and transporters within the human midbrain may therefore have important implications for the development of impulse control disorders in PD. The localization of the dopamine receptors (D1-D5) and dopamine transporter proteins in the upper brain stems of elderly adult humans (n = 8) was assessed using single immunoperoxidase and double immunofluorescence (with tyrosine hydroxylase to identify dopamine neurons). The relative amount of protein expressed in dopamine neurons from different regions was assessed by comparing their relative immunofluorescent intensities. The midbrain dopamine regions associated with impulsivity (medial nigra and ventral tegmental area [VTA]) expressed less dopamine transporter on their neurons than other midbrain dopamine regions. Medial nigral dopamine neurons expressed significantly greater amounts of D1 and D2 receptors and vesicular monoamine transporter than VTA dopamine neurons. The heterogeneous pattern of dopamine receptors and transporters in the human midbrain suggests that the effects of dopamine and dopamine agonists are likely to be nonuniform. The expression of excitatory D1 receptors on nigral dopamine neurons in midbrain regions associated with impulsivity, and their variable loss as seen in PD, may be of particular interest for impulse control.
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ATP13A2 (PARK9) protein levels are reduced in brain tissue of cases with Lewy bodies.
Acta Neuropathol Commun
PUBLISHED: 03-25-2013
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ATP13A2 (PARK9) loss of function mutations are a genetic cause of an early-onset form of Parkinsons disease (PD), with in vitro studies showing that ATP13A2 deficits lead to lysosomal and mitochondrial dysfunction and ?-synuclein accumulation, while elevated ATP13A2 expression reduces ?-synuclein toxicity. The three human brain tissue studies assessing changes in ATP13A2 expression in PD produced divergent results; mRNA is increased while protein levels were observed to be either increased or decreased. This apparent conflict in protein levels might have arisen from examining Lewy body disease cases with coexisting Alzheimer-type pathologies.To assess whether ATP13A2 levels in Lewy body disease are modified by Alzheimer-type ?-amyloid deposition, we evaluated cases of pure PD and pure dementia with Lewy bodies (DLB) for changes in ATP13A2, ?-synuclein and ?-amyloid protein levels in cortical regions with and without Lewy bodies.
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Characterisation of retinoblastomas without RB1 mutations: genomic, gene expression, and clinical studies.
Lancet Oncol.
PUBLISHED: 03-13-2013
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Retinoblastoma is the childhood retinal cancer that defined tumour-suppressor genes. Previous work shows that mutation of both alleles of the RB1 retinoblastoma suppressor gene initiates disease. We aimed to characterise non-familial retinoblastoma tumours with no detectable RB1 mutations.
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Favourable IL28B polymorphisms are associated with a marked increase in baseline viral load in hepatitis C virus subtype 3a infection and do not predict a sustained virological response after 24 weeks of therapy.
J. Gen. Virol.
PUBLISHED: 03-13-2013
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IL28B host genetic make-up is known to play a critical role in the outcome of genotype 1 hepatitis C virus (HCV) infection in the context of both primary infection and therapy. However, the role of IL28B in subtype 3a infection remains unclear, and has not yet been assessed in the UK population where subtype 3a is dominant. In this study, we evaluated the role of the IL28B single-nucleotide polymorphism rs8099917 in 201 patients recruited from two well-defined cohorts (from Nottingham and Oxford), treated with the standard-of-care therapy of pegylated interferon and ribavirin for 24 weeks. We showed that the favourable IL28B gene was associated with a rapid virological response to therapy at 4 weeks (P<0.0001), but not with a sustained virological response to therapy. The median viral load at baseline, before therapy, was markedly increased in people with the favourable IL28B genotype [median viral load for the TT allele, 925,961 IU ml(-1) (range 2200-21,116,965 IU ml(-1)), and for the GT or GG allele, 260,284 IU ml(-1) (range 740-7,560,000 IU ml(-1)); P = 0.0010]. Our results suggest that the host genetic response plays an important role in early viral clearance of subtype 3a virus from the blood. However, significant reservoirs of infection must persist, as viral relapse is common, even in those with the favourable host genotype.
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Retrosplenial cortex (BA 29) volumes in behavioral variant frontotemporal dementia and Alzheimers disease.
Dement Geriatr Cogn Disord
PUBLISHED: 02-09-2013
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The retrosplenial cortex (RSC) is a crucial transit region between the hippocampus and cingulate cortex and has been implicated in spatial navigation and memory. Importantly, RSC atrophy is a predilection site of Alzheimers (AD) pathology, but there have been no studies assessing structural changes in the RSC in behavioral variant frontotemporal dementia (bvFTD).
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Network balance via CRY signalling controls the Arabidopsis circadian clock over ambient temperatures.
Mol. Syst. Biol.
PUBLISHED: 01-28-2013
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Circadian clocks exhibit temperature compensation, meaning that they show only small changes in period over a broad temperature range. Several clock genes have been implicated in the temperature-dependent control of period in Arabidopsis. We show that blue light is essential for this, suggesting that the effects of light and temperature interact or converge upon common targets in the circadian clock. Our data demonstrate that two cryptochrome photoreceptors differentially control circadian period and sustain rhythmicity across the physiological temperature range. In order to test the hypothesis that the targets of light regulation are sufficient to mediate temperature compensation, we constructed a temperature-compensated clock model by adding passive temperature effects into only the light-sensitive processes in the model. Remarkably, this model was not only capable of full temperature compensation and consistent with mRNA profiles across a temperature range, but also predicted the temperature-dependent change in the level of LATE ELONGATED HYPOCOTYL, a key clock protein. Our analysis provides a systems-level understanding of period control in the plant circadian oscillator.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.