α-Synuclein expression in response to bacterial ligands and metabolites in gut enteroendocrine cells: an in vitro proof of concept study

Caudo-rostral migration of pathological forms of α-synuclein from the gut to the brain is proposed as an early feature in Parkinson’s disease pathogenesis, but the underlying mechanisms remain unknown. Intestinal epithelial enteroendocrine cells sense and respond to numerous luminal signals, including bacterial factors, and transmit this information to the brain via the enteric nervous system and vagus nerve. There is evidence that gut bacteria composition and their metabolites change in Parkinson’s disease patients, and these alterations can trigger α-synuclein pathology in animal models of the disorder. Here, we investigated the effect of toll-like receptor and free fatty acid receptor agonists on the intracellular level of α-synuclein and its release using mouse secretin tumour cell line 1 enteroendocrine cells. Secretin tumour cell line 1 enteroendocrine cells were treated for 24 or 48 h with toll-like receptor agonists (toll-like receptor 4 selective lipopolysaccharide; toll-like receptor 2 selective Pam3CysSerLys4) and the free fatty acid receptor 2/3 agonists butyrate, propionate and acetate. The effect of selective receptor antagonists on the agonists’ effects after 24 hours was also investigated. The level of α-synuclein protein was measured in cell lysates and cell culture media by western blot and enzyme-linked immunosorbent assay. The level of α-synuclein and tumour necrosis factor messenger RNA was measured by quantitative reverse transcription real-time polymerase chain reaction. Stimulation of secretin tumour cell line 1 enteroendocrine cells for 24 and 48 hours with toll-like receptor and free fatty acid receptor agonists significantly increased the amount of intracellular α-synuclein and the release of α-synuclein from the cells into the culture medium. Both effects were significantly reduced by antagonists selective for each receptor. Toll-like receptor and free fatty acid receptor agonists also significantly increased tumour necrosis factor transcription, and this was effectively inhibited by corresponding antagonists. Elevated intracellular α-synuclein increases the likelihood of aggregation and conversion to toxic forms. Factors derived from bacteria induce α-synuclein accumulation in secretin tumour cell line 1 enteroendocrine cells. Here, we provide support for a mechanism by which exposure of enteroendocrine cells to specific bacterial factors found in Parkinson’s disease gut dysbiosis might facilitate accumulation of α-synuclein pathology in the gut

The impact of high functional connectivity network hub resection on language task performance in adult low- and high-grade glioma.

ObjectiveGliomas are intrinsic brain tumors with the hallmark of diffuse white matter infiltration, resulting in short- and long-range network dysfunction. Preoperative magnetoencephalography (MEG) can assist in maximizing the extent of resection while minimizing morbidity. While MEG has been validated in motor mapping, its role in speech mapping remains less well studied. The authors assessed how the resection of intraoperative electrical stimulation (IES)-negative, high functional connectivity (HFC) network sites, as identified by MEG, impacts language performance.MethodsResting-state, whole-brain MEG recordings were obtained from 26 patients who underwent perioperative language evaluation and glioma resection that was guided by awake language and IES mapping. The functional connectivity of an individual voxel was determined by the imaginary coherence between the index voxel and the rest of the brain, referenced to its contralesional pair. The percentage of resected HFC voxels was correlated with postoperative language outcomes in tasks of increasing complexity: text reading, 4-syllable repetition, picture naming, syntax (SYN), and auditory stimulus naming (AN).ResultsOverall, 70% of patients (14/20) in whom any HFC tissue was resected developed an early postoperative language deficit (mean 2.3 days, range 1-8 days), compared to 33% of patients (2/6) in whom no HFC tissue was resected (p = 0.16). When bifurcated by the amount of HFC tissue that was resected, 100% of patients (3/3) with an HFC resection > 25% displayed deficits in AN, compared to 30% of patients (6/20) with an HFC resection < 25% (p = 0.04). Furthermore, there was a linear correlation between the severity of AN and SYN decline with percentage of HFC sites resected (p = 0.02 and p = 0.04, respectively). By 2.2 months postoperatively (range 1-6 months), the correlation between HFC resection and both AN and SYN decline had resolved (p = 0.94 and p = 1.00, respectively) in all patients (9/9) except two who experienced early postoperative tumor progression or stroke involving inferior frontooccipital fasciculus.ConclusionsImaginary coherence measures of functional connectivity using MEG are able to identify HFC network sites within and around low- and high-grade gliomas. Removal of IES-negative HFC sites results in early transient postoperative decline in AN and SYN, which resolved by 3 months in all patients without stroke or early tumor progression. Measures of functional connectivity may therefore be a useful means of counseling patients about postoperative risk and assist with preoperative surgical planning

On the Location of the Gamma-ray Emission in the 2008 Outburst in the BL Lacertae Object AO 0235+164 through Observations across the Electromagnetic Spectrum

We present observations of a major outburst at centimeter, millimeter, optical, X-ray, and gamma-ray wavelengths of the BL Lacertae object AO 0235+164. We analyze the timing of multi-waveband variations in the flux and linear polarization, as well as changes in Very Long Baseline Array (VLBA) images at 7mm with 0.15 milliarcsecond resolution. The association of the events at different wavebands is confirmed at high statistical significance by probability arguments and Monte-Carlo simulations. A series of sharp peaks in optical linear polarization, as well as a pronounced maximum in the 7 mm polarization of a superluminal jet knot, indicate rapid fluctuations in the degree of ordering of the magnetic field. These results lead us to conclude that the outburst occurred in the jet both in the quasi-stationary "core" and in the superluminal knot, both parsecs downstream of the supermassive black hole. We interpret the outburst as a consequence of the propagation of a disturbance, elongated along the line of sight by light-travel time delays, that passes through a standing recollimation shock in the core and propagates down the jet to create the superluminal knot. The multi-wavelength light curves vary together on long time-scales (months/years), but the correspondence is poorer on shorter time-scales. This, as well as the variability of the polarization and the dual location of the outburst, agrees with the expectations of a multi-zone emission model in which turbulence plays a major role in modulating the synchrotron and inverse Compton fluxes.Comment: Accepted for Publication in the Astrophysical Journal Letters. 7 pages (including 5 figures). Minor corrections with regard to previous version, as proposed by the refere

Extensive Variation in Chromatin States Across Humans

The majority of disease-associated variants lie outside protein-coding regions, suggesting a link between variation in regulatory regions and disease predisposition. We studied differences in chromatin states using five histone modifications, cohesin, and CTCF in lymphoblastoid lines from 19 individuals of diverse ancestry. We found extensive signal variation in regulatory regions, which often switch between active and repressed states across individuals. Enhancer activity is particularly diverse among individuals, whereas gene expression remains relatively stable. Chromatin variability shows genetic inheritance in trios, correlates with genetic variation and population divergence, and is associated with disruptions of transcription factor binding motifs. Overall, our results provide insights into chromatin variation among humans

Methods for Population-Adjusted Indirect Comparisons in Health Technology Appraisal

Standard methods for indirect comparisons and network meta-analysis are based on aggregate data, with the key assumption that there is no difference between the trials in the distribution of effect-modifying variables. Methods which relax this assumption are becoming increasingly common for submissions to reimbursement agencies such as NICE. These use individual patient data from a subset of trials to form population-adjusted indirect comparisons between treatments, in a specific target population. Recently proposed population adjustment methods include the Matching-Adjusted Indirect Comparison (MAIC) and the Simulated Treatment Comparison (STC). Despite increasing popularity, MAIC and STC remain largely untested. Furthermore, there is a lack of clarity about exactly how and when they should be applied in practice, and even whether the results are relevant to the decision problem. There is therefore a real and present risk that the assumptions being made in one submission to a reimbursement agency are fundamentally different to – or even incompatible with – the assumptions being made in another for the same indication. We describe the assumptions required for population-adjusted indirect comparisons, and demonstrate how these may be used to generate comparisons in any given target population. We distinguish between anchored and unanchored comparisons according to whether a common comparator arm is used or not. Unanchored comparisons make much stronger assumptions which are widely regarded as infeasible. We provide recommendations on how and when population adjustment methods should be used, and the supporting analyses that are required, in order to provide statistically valid, clinically meaningful, transparent and consistent results for the purposes of health technology appraisal. Simulation studies are needed to examine the properties of population adjustment methods and their robustness to breakdown of assumptions

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

Do público e do privado: uma perspectiva de género sobre uma dicotomia moderna

Neste texto propomos uma interpretação crítica da dicotomia histórica entre público e privado como dinâmica fundamental da modernidade. A partir de uma perspectiva de género, discutimos as fronteiras construídas entre espaço coletivo de cidadania e de sociabilidade e espaço individual de intimidade e desigualdade. Argumentamos a favor de uma relação de cumplicidade, ainda que tensa, entre as duas esferas, observando que a vida privada foi, em grande medida, moldada pelas mudanças operadas na vida pública. Recorrendo a diferentes definições de "público", notamos que, à medida que as sociabilidades tradicionais, essencialmente masculinas, estudadas entre outros por Ariès ou Sennett, sofriam uma erosão, crescia o sentimento de intimidade, aumentando igualmente a inclusão do privado no público através do alargamento da cidadania, em consequência das lutas travadas na esfera pública por vários movimentos de emancipação, como o operário ou o feminista. À medida que a pessoa era retirada da comunidade, do clã, do grupo de parentesco, em que eram "naturais" as desigualdades, no sentido aristotélico do termo, ia-se reencontrando progressivamente como indivíduo portador de cidadania. Se o espaço privado se tornou central na definição de uma identidade, ele é também crescentemente atravessado por mecanismos públicos de regulação. Nesse sentido, o movimento de ascensão do privado, que nas últimas décadas tem ocupado espaço de debate, deve ser cuidadosamente reinterpretado

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy