Nonlinear control of transcription through enhancer-promoter interactions.

Chromosome structure in mammals is thought to regulate transcription by modulating three-dimensional interactions between enhancers and promoters, notably through CTCF-mediated loops and topologically associating domains (TADs)1-4. However, how chromosome interactions are actually translated into transcriptional outputs remains unclear. Here, to address this question, we use an assay to position an enhancer at large numbers of densely spaced chromosomal locations relative to a fixed promoter, and measure promoter output and interactions within a genomic region with minimal regulatory and structural complexity. A quantitative analysis of hundreds of cell lines reveals that the transcriptional effect of an enhancer depends on its contact probabilities with the promoter through a nonlinear relationship. Mathematical modelling suggests that nonlinearity might arise from transient enhancer-promoter interactions being translated into slower promoter bursting dynamics in individual cells, therefore uncoupling the temporal dynamics of interactions from those of transcription. This uncovers a potential mechanism of how distal enhancers act from large genomic distances, and of how topologically associating domain boundaries block distal enhancers. Finally, we show that enhancer strength also determines absolute transcription levels as well as the sensitivity of a promoter to CTCF-mediated transcriptional insulation. Our measurements establish general principles for the context-dependent role of chromosome structure in long-range transcriptional regulation

CD4+ Regulatory and Effector/Memory T Cell Subsets Profile Motor Dysfunction in Parkinson’s Disease

Animal models and clinical studies have linked the innate and adaptive immune system to the pathology of Parkinson’s disease (PD). Despite such progress, the specific immune responses that influence disease progression have eluded investigators. Herein, we assessed relationships between T cell phenotype and function with PD progression. Peripheral blood lymphocytes from two separate cohorts, a discovery cohort and a validation cohort, totaling 113 PD patients and 96 age- and environment-matched caregivers were examined by flow cytometric analysis and T cell proliferation assays. Increased effector/memory T cells (Tem), defined as CD45RO+ and FAS+ CD4+ T cells and decreased CD31+ and α4β7+ CD4+ T cells were associated with progressive Unified Parkinson’s Disease Rating Scale III scores. However, no associations were seen between immune biomarkers and increased age or disease duration. Impaired abilities of regulatory T cells (Treg) from PD patients to suppress effector T cell function was observed. These data support the concept that chronic immune stimulation, notably Tem activation and Treg dysfunction is linked to PD pathobiology and disease severity, but not disease duration. The association of T cell phenotypes with motor symptoms provides fresh avenues for novel biomarkers and therapeutic designs

Supercritical fluid chromatography – Mass spectrometry in metabolomics: Past, present, and future perspectives

Metabolomics, which consists of the comprehensive analysis of metabolites within a biological system, has been playing a growing role in the implementation of personalized medicine in modern healthcare. A wide range of analytical approaches are used in metabolomics, notably mass spectrometry (MS) combined to liquid chromatography (LC), gas chromatography (GC), or capillary electrophoresis (CE). However, none of these methods enable a comprehensive analysis of the metabolome, due to its extreme complexity and the large differences in physico-chemical properties between metabolite classes. In this context, supercritical fluid chromatography (SFC) represents a promising alternative approach to improve the metabolome coverage, while further increasing the analysis throughput. SFC, which uses supercritical CO2 as mobile phase, leads to numerous advantages such as improved kinetic performance and lower environmental impact. This chromatographic technique has gained a significant interest since the introduction of advanced instrumentation, together with the introduction of dedicated interfaces for hyphenating SFC to MS. Moreover, new developments in SFC column chemistry (including sub-2 µm particles), as well as the use of large amounts of organic modifiers and additives in the CO2-based mobile phase, significantly extended the application range of SFC, enabling the simultaneous analysis of a large diversity of metabolites. Over the last years, several applications have been reported in metabolomics using SFC-MS – from lipophilic compounds, such as steroids and other lipids, to highly polar compounds, such as carbohydrates, amino acids, or nucleosides. With all these advantages, SFC-MS is promised to a bright future in the field of metabolomics

Closing the mass budget of a tidewater glacier : the example of Kronebreen, Svalbard

In this study, we combine remote sensing, in situ and model-derived datasets from 1966 to 2014 to calculate the mass-balance components of Kronebreen, a fast-flowing tidewater glacier in Svalbard. For the well-surveyed period 2009-2014, we are able to close the glacier mass budget within the prescribed errors. During these 5 years, the glacier geodetic mass balance was -0.69 +/- 0.12 m w.e. a(-1), while the mass budget method led to a total mass balance of -0.92 +/- 0.16 m w.e. a(-1), as a consequence of a strong frontal ablation (-0.78 +/- 0.11 m w.e. a(-1) ), and a slightly negative climatic mass balance (-0.14 +/- 0.11 m w.e. a(-1) ). The trend towards more negative climatic mass balance between 1966-1990 (+0.20 +/- 0.05 m w.e. a(-1) ) and 2009-2014 is not reflected in the geodetic mass balance trend. Therefore, we suspect a reduction in ice-discharge in the most recent period. Yet, these multidecadal changes in ice-discharge cannot be measured from the available observations and thus are only estimated with relatively large errors as a residual of the mass continuity equation. Our study presents the multidecadal evolution of the dynamics and mass balance of a tidewater glacier and illustrates the errors introduced by inferring one unmeasured mass-balance component from the others

Managing marine socio-ecological systems: picturing the future

What do you get when a lawyer, a modeller, an economist, a social scientist and an ecologist talk about the ocean? Besides an interesting conversation, it is likely there will be some consideration of how to solve many of the problems facing marine ecosystems around the world. That is precisely what the MSEAS 2016 symposium on understanding marine socio-ecological systems aimed to do. From 30 May to 3 June in Brest, France, the symposium gathered over 230 participants from around the world and from multiple disciplines to discuss the challenge of explicitly considering the human component in producing synoptic assessments of marine social-ecological systems. The symposium fostered dynamic debates on the inter-disciplinary collaborations needed to support management of ongoing and anticipated growth in multiple ocean uses, with particular consideration of the triple bottom line of ecological, economic and social sustainability. Building on the illustrations produced by a professional cartoonist during the meeting, this graphic novel summarizes the key challenges ahead in understanding marine socio-ecological systems and draws a path for future research endeavours in this domain

Sialic acid linkage differentiation of glycopeptides using capillary electrophoresis – electrospray ionization – mass spectrometry

Sialylation is a glycosylation feature that occurs in different linkages at the non-reducing end of a glycan moiety, the linkage isomers are often differentially associated with various biological processes.Due to very similar physico-chemical properties, the separation of isomeric sialylated glycopeptides remains challenging but of utmost importance in the biomedicine and biotechnology, including biomarker discovery, glyco-engineering and biopharmaceutical characterization. This study presents the implementation of a high-resolution separation platform based on capillary electrophoresis – mass spectrometry (CE–MS) allowing for the selective analysis of α2,3- and α2,6-sialylated glycopeptides. These differentially linked glycopeptides showed an identical fragmentation pattern (collision induced dissociation) but different electrophoretic mobilities, allowing for baseline separation of the different linkages without the need for an extensive sample preparation. The different migration behavior between the two moieties was found to correlate with differences in pKa values. Using a novel methodology adapted from the so-called internal standard CE approach, a relative difference of 3.4·10−2 in pKa unit was determined. This approach was applied for the analysis of tryptic glycopeptides of prostate specific antigen, which shows highly complex and heterogeneous glycosylation. The developed platform therefore appears attractive for the identification of differentially linked sialic acids that may be related to pathological conditions