Breaking through an epigenetic wall: Re-activation ofOct4by KRAB-containing designer zinc finger transcription factors

The gene Oct4 encodes a transcription factor critical for the maintenance of pluripotency and self-renewal in embryonic stem cells. In addition, improper re-activation of Oct4 contributes to oncogenic processes. Herein, we describe a novel designer zinc finger protein (ZFP) capable of upregulating the endogenous Oct4 promoter in a panel of breast and ovarian cell lines carrying a silenced gene. In some ovarian tumor lines, the ZFP triggered a strong reactivation of Oct4, with levels of expression comparable with exogenous Oct4 cDNA delivery. Surprisingly, the reactivation of Oct4 required a KRAB domain for effective upregulation of the endogenous gene. While KRAB-containing ZFPs are traditionally described as transcriptional repressors, our results suggest that these proteins could, in certain genomic contexts, function as potent activators and, thus, outline an emerging novel function of KRAB-ZFPs. In addition, we document a novel ZFP that could be used for the epigenetic reprograming of cancer cells

The iron law of democratic socialism: British and Austrian influences on the young Karl Polanyi

This article has been made available through the Brunel Open Access Publishing Fund.A central thesis of Karl Polanyi's The great transformation concerns the tensions between capitalism and democracy: the former embodies the principle of inequality, while democracy represents that of equality. This paper explores the intellectual heritage of this thesis, in the ‘functional theory’ of G.D.H. Cole and Otto Bauer and in the writings of Eduard Bernstein. It scrutinizes Polanyi's relationship with Bernstein's ‘evolutionary socialism’ and charts his ‘double movement’ vis-à-vis Marxist philosophy: in the 1910s he reacted sharply against Marxism's deterministic excesses, but he then, in the 1920s, engaged in sympathetic dialogue with Austro-Marxist thinkers. The latter, like Bernstein, disavowed economic determinism and insisted upon the importance and autonomy of ethics. Yet they simultaneously predicted a law-like expansion of democracy from the political to the economic arena. Analysis of this contradiction provides the basis for a concluding discussion that reconsiders the deterministic threads in Polanyi's oeuvre. Whereas for some Polanyi scholars these attest to his residual attraction to Marxism, I argue that matters are more complex. While Polanyi did repudiate the more rigidly deterministic of currents in Marxist philosophy, those to which he was attracted, notably Bernstein's ‘revision’ and Austro-Marxism, incorporated a deterministic fatalism of their own, in respect of democratization. Herein lies a more convincing explanation of Polanyi's incomplete escape from a deterministic philosophy of history, as exemplified in his masterwork, The great transformation

Social democracy, embeddedness and decommodification: On the conceptual innovations and intellectual affiliations of Karl Polanyi

Of the several debates that revolve around the work of the economic historian and political economist Karl Polanyi, one that continues to exercise minds concerns his analysis of, and political attitudes toward, post-war capitalism and the welfare state. Simplified a little, it is a debate with two sides. To borrow Iván Szelényi's terms, one side constructs a ‘hard’ Karl Polanyi, the other a ‘soft’ one. The former advocated a socialist mixed economy dominated by redistributive mechanisms. He was a radical socialist for whom the market should never be the dominant mechanism of economic coordination. His ‘soft’ alter ego insisted that the market system remain essentially intact but be complemented by redistributive mechanisms. The ‘double movement’ – the central thesis of his ‘Great Transformation’ – acts, in this reading, as a self-correcting mechanism that moderates the excesses of market fundamentalism; its author was positioned within the social-democratic mainstream for which the only realistic desirable goal is a regulated form of capitalism. In terms of textual evidence there is much to be said for both interpretations. In this article I suggest a different approach, one that focuses upon the meaning of Polanyi's concepts in relation to their socio-political and intellectual environment

TGFβ pathway limits dedifferentiation following WNT and MAPK pathway activation to suppress intestinal tumourigenesis

Recent studies have suggested increased plasticity of differentiated cells within the intestine to act both as intestinal stem cells (ISCs) and tumour-initiating cells. However, little is known of the processes that regulate this plasticity. Our previous work has shown that activating mutations of Kras or the NF-κB pathway can drive dedifferentiation of intestinal cells lacking Apc. To investigate this process further, we profiled both cells undergoing dedifferentiation in vitro and tumours generated from these cells in vivo by gene expression analysis. Remarkably, no clear differences were observed in the tumours; however, during dedifferentiation in vitro we found a marked upregulation of TGFβ signalling, a pathway commonly mutated in colorectal cancer (CRC). Genetic inactivation of TGFβ type 1 receptor (Tgfbr1/Alk5) enhanced the ability of KrasG12D/+ mutation to drive dedifferentiation and markedly accelerated tumourigenesis. Mechanistically this is associated with a marked activation of MAPK signalling. Tumourigenesis from differentiated compartments is potently inhibited by MEK inhibition. Taken together, we show that tumours arising in differentiated compartments will be exposed to different suppressive signals, for example, TGFβ and blockade of these makes tumourigenesis more efficient from this compartment

Restraint of appetite and reduced regional brain volumes in anorexia nervosa: a voxel-based morphometric study

<p>Abstract</p> <p>Background</p> <p>Previous Magnetic Resonance Imaging (MRI) studies of people with anorexia nervosa (AN) have shown differences in brain structure. This study aimed to provide preliminary extensions of this data by examining how different levels of appetitive restraint impact on brain volume.</p> <p>Methods</p> <p>Voxel based morphometry (VBM), corrected for total intracranial volume, age, BMI, years of education in 14 women with AN (8 RAN and 6 BPAN) and 21 women (HC) was performed. Correlations between brain volume and dietary restraint were done using Statistical Package for the Social Sciences (SPSS).</p> <p>Results</p> <p>Increased right dorsolateral prefrontal cortex (DLPFC) and reduced right anterior insular cortex, bilateral parahippocampal gyrus, left fusiform gyrus, left cerebellum and right posterior cingulate volumes in AN compared to HC. RAN compared to BPAN had reduced left orbitofrontal cortex, right anterior insular cortex, bilateral parahippocampal gyrus and left cerebellum. Age negatively correlated with right DLPFC volume in HC but not in AN; dietary restraint and BMI predicted 57% of variance in right DLPFC volume in AN.</p> <p>Conclusions</p> <p>In AN, brain volume differences were found in appetitive, somatosensory and top-down control brain regions. Differences in regional GMV may be linked to levels of appetitive restraint, but whether they are state or trait is unclear. Nevertheless, these discrete brain volume differences provide candidate brain regions for further structural and functional study in people with eating disorders.</p

Pathogenic copy number variants and SCN1A mutations in patients with intellectual disability and childhood-onset epilepsy

Background Copy number variants (CNVs) have been linked to neurodevelopmental disorders such as intellectual disability (ID), autism, epilepsy and psychiatric disease. There are few studies of CNVs in patients with both ID and epilepsy. Methods We evaluated the range of rare CNVs found in 80 Welsh patients with ID or developmental delay (DD), and childhood-onset epilepsy. We performed molecular cytogenetic testing by single nucleotide polymorphism array or microarray-based comparative genome hybridisation. Results 8.8 % (7/80) of the patients had at least one rare CNVs that was considered to be pathogenic or likely pathogenic. The CNVs involved known disease genes (EHMT1, MBD5 and SCN1A) and imbalances in genomic regions associated with neurodevelopmental disorders (16p11.2, 16p13.11 and 2q13). Prompted by the observation of two deletions disrupting SCN1A we undertook further testing of this gene in selected patients. This led to the identification of four pathogenic SCN1A mutations in our cohort. Conclusions We identified five rare de novo deletions and confirmed the clinical utility of array analysis in patients with ID/DD and childhood-onset epilepsy. This report adds to our clinical understanding of these rare genomic disorders and highlights SCN1A mutations as a cause of ID and epilepsy, which can easily be overlooked in adults

Active multiple myeloma suppresses and typically eliminates coexisting MGUS

Background: Myeloma is consistently preceded by premalignant monoclonal gammopathy of undetermined significance (MGUS). In >5% of MGUS patients there is a second MGUS clone (biclonal gammopathy of undetermined significance; BGUS), yet, at myeloma diagnosis, presentation of biclonal gammopathy myeloma (BGMy) is considered less frequent, implying that myeloma eradicates coexisting MGUS. Methods: In the largest study of its kind, we assessed BGMy frequency amongst 6399 newly diagnosed myeloma patients enrolled in recent UK clinical trials. Results: Compared to expected prevalence (i.e., >5% of MGUS have BGUS), only 58 of 6399 (0.91%) newly diagnosed myeloma patients had BGMy, indicating myeloma typically eliminates coexistent MGUS. In these 58 BGMy cases, the MGUS plasma cell clone was greatly suppressed in size compared to typical levels observed in conventional MGUS; contrarily, the MGUS clone did not inhibit the myeloma plasma cell clone in BGMy. Conclusion: Myeloma eliminates the majority of competing MGUS, and when it does not, the MGUS clone is substantially reduced in size

Upper limit map of a background of gravitational waves

We searched for an anisotropic background of gravitational waves using data from the LIGO S4 science run and a method that is optimized for point sources. This is appropriate if, for example, the gravitational wave background is dominated by a small number of distinct astrophysical sources. No signal was seen. Upper limit maps were produced assuming two different power laws for the source strain power spectrum. For an f^-3 power law and using the 50 Hz to 1.8 kHz band the upper limits on the source strain power spectrum vary between 1.2e-48 Hz^-1 (100 Hz/f)^3 and 1.2e-47 Hz^-1 (100 Hz /f)^3, depending on the position in the sky. Similarly, in the case of constant strain power spectrum, the upper limits vary between 8.5e-49 Hz^-1 and 6.1e-48 Hz^-1. As a side product a limit on an isotropic background of gravitational waves was also obtained. All limits are at the 90% confidence level. Finally, as an application, we focused on the direction of Sco-X1, the closest low-mass X-ray binary. We compare the upper limit on strain amplitude obtained by this method to expectations based on the X-ray luminosity of Sco-X1.Comment: 11 pages, 9 figures, 2 table

Upper limit map of a background of gravitational waves

We searched for an anisotropic background of gravitational waves using data from the LIGO S4 science run and a method that is optimized for point sources. This is appropriate if, for example, the gravitational wave background is dominated by a small number of distinct astrophysical sources. No signal was seen. Upper limit maps were produced assuming two different power laws for the source strain power spectrum. For an f^-3 power law and using the 50 Hz to 1.8 kHz band the upper limits on the source strain power spectrum vary between 1.2e-48 Hz^-1 (100 Hz/f)^3 and 1.2e-47 Hz^-1 (100 Hz /f)^3, depending on the position in the sky. Similarly, in the case of constant strain power spectrum, the upper limits vary between 8.5e-49 Hz^-1 and 6.1e-48 Hz^-1. As a side product a limit on an isotropic background of gravitational waves was also obtained. All limits are at the 90% confidence level. Finally, as an application, we focused on the direction of Sco-X1, the closest low-mass X-ray binary. We compare the upper limit on strain amplitude obtained by this method to expectations based on the X-ray luminosity of Sco-X1.Comment: 11 pages, 9 figures, 2 table

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio