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"Sanders, David"
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Affluence, austerity and electoral change in Britain
\"Investigates the political economy of party support for British political parties since Tony Blair led New Labour to power in 1997. Using valence politics models of electoral choice and marshalling an unprecedented wealth of survey data collected in the British Election Study's monthly Continuous Monitoring Surveys, the authors trace forces affecting support for New Labour during its 13 years in office\" --Provided by publisher.
Book
Nucleation landscape of biomolecular condensates
All structures within living cells must form at the right time and place. This includes condensates such as the nucleolus, Cajal bodies and stress granules, which form via liquid–liquid phase separation of biomolecules, particularly proteins enriched in intrinsically disordered regions (IDRs)
1
,
2
. In non-living systems, the initial stages of nucleated phase separation arise when thermal fluctuations overcome an energy barrier due to surface tension. This phenomenon can be modelled by classical nucleation theory (CNT), which describes how the rate of droplet nucleation depends on the degree of supersaturation, whereas the location at which droplets appear is controlled by interfacial heterogeneities
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,
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. However, it remains unknown whether this framework applies in living cells, owing to the multicomponent and highly complex nature of the intracellular environment, including the presence of diverse IDRs, whose specificity of biomolecular interactions is unclear
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. Here we show that despite this complexity, nucleation in living cells occurs through a physical process similar to that in inanimate materials, but the efficacy of nucleation sites can be tuned by their biomolecular features. By quantitatively characterizing the nucleation kinetics of endogenous and biomimetic condensates in living cells, we find that key features of condensate nucleation can be quantitatively understood through a CNT-like theoretical framework. Nucleation rates can be substantially enhanced by compatible biomolecular (IDR) seeds, and the kinetics of cellular processes can impact condensate nucleation rates and specificity of location. This quantitative framework sheds light on the intracellular nucleation landscape, and paves the way for engineering synthetic condensates precisely positioned in space and time.
Experiments using endogenous and biomimetic condensates in cells show that nucleation in cells resembles the physical process in inanimate materials, but is tuned by biomolecular features.
Journal Article
Revitalizing health for all : case studies of the struggle for comprehensive primary health care
\"The concept of Comprehensive Primary Health Care focuses on health system efforts to improve equity in health care access, community empowerment, participation of marginalized groups, and actions on the social determinants of health. Despite its existence since the late 1970s very few studies have been able to highlight the outcomes of this concept, until now. Revitalizing Health for All examines thirteen cases of efforts to implement CPHC reforms from around the globe including Australia, Brazil, Democratic Republic of Congo, Iran, South Africa, and more. The findings presented in this volume originate from an international action-research set of studies that utilized triads of senior and junior researchers and knowledge users from each country's public health system. Primary health care reform is an important policy discourse both at the national level in these countries and in the global conversations, and this volume reveals the similarities among CPHC projects in diverse national contexts. These similarities provide a rich evidence base from which future CPHC reform initiatives can draw, regardless of their country.\"-- Provided by publisher.
Book
Coeliac disease
Coeliac disease occurs in about 1% of people in most populations. Diagnosis rates are increasing, and this seems to be due to a true rise in incidence rather than increased awareness and detection. Coeliac disease develops in genetically susceptible individuals who, in response to unknown environmental factors, develop an immune response that is subsequently triggered by the ingestion of gluten. The disease has many clinical manifestations, ranging from severe malabsorption to minimally symptomatic or non-symptomatic presentations. Diagnosis requires the presence of duodenal villous atrophy, and most patients have circulating antibodies against tissue transglutaminase; in children, European guidelines allow a diagnosis without a duodenal biopsy provided that strict symptomatic and serological criteria are met. Although a gluten-free diet is an effective treatment in most individuals, a substantial minority develop persistent or recurrent symptoms. Difficulties adhering to a gluten-free diet have led to the development of non-dietary therapies, several of which are undergoing trials in human beings.
Journal Article
Composition-dependent thermodynamics of intracellular phase separation
Intracellular bodies such as nucleoli, Cajal bodies and various signalling assemblies represent membraneless organelles, or condensates, that form via liquid–liquid phase separation (LLPS)
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,
2
. Biomolecular interactions—particularly homotypic interactions mediated by self-associating intrinsically disordered protein regions—are thought to underlie the thermodynamic driving forces for LLPS, forming condensates that can facilitate the assembly and processing of biochemically active complexes, such as ribosomal subunits within the nucleolus. Simplified model systems
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have led to the concept that a single fixed saturation concentration is a defining feature of endogenous LLPS
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, and has been suggested as a mechanism for intracellular concentration buffering
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,
7
,
8
,
10
. However, the assumption of a fixed saturation concentration remains largely untested within living cells, in which the richly multicomponent nature of condensates could complicate this simple picture. Here we show that heterotypic multicomponent interactions dominate endogenous LLPS, and give rise to nucleoli and other condensates that do not exhibit a fixed saturation concentration. As the concentration of individual components is varied, their partition coefficients change in a manner that can be used to determine the thermodynamic free energies that underlie LLPS. We find that heterotypic interactions among protein and RNA components stabilize various archetypal intracellular condensates—including the nucleolus, Cajal bodies, stress granules and P-bodies—implying that the composition of condensates is finely tuned by the thermodynamics of the underlying biomolecular interaction network. In the context of RNA-processing condensates such as the nucleolus, this manifests in the selective exclusion of fully assembled ribonucleoprotein complexes, providing a thermodynamic basis for vectorial ribosomal RNA flux out of the nucleolus. This methodology is conceptually straightforward and readily implemented, and can be broadly used to extract thermodynamic parameters from microscopy images. These approaches pave the way for a deeper understanding of the thermodynamics of multicomponent intracellular phase behaviour and its interplay with the nonequilibrium activity that is characteristic of endogenous condensates.
Heterotypic multicomponent interactions are shown to dominate the liquid–liquid phase separation that enables the formation of intracellular condensates.
Journal Article
Size distributions of intracellular condensates reflect competition between coalescence and nucleation
Phase separation of biomolecules into condensates has emerged as a mechanism for intracellular organization and affects many intracellular processes, including reaction pathways through the clustering of enzymes and pathway intermediates. Precise and rapid spatiotemporal control of reactions by condensates requires tuning of their sizes. However, the physical processes that govern the distribution of condensate sizes remain unclear. Here we show that both native and synthetic condensates display an exponential size distribution, which is captured by Monte Carlo simulations of fast nucleation followed by coalescence. In contrast, pathological aggregates exhibit a power-law size distribution. These distinct behaviours reflect the relative importance of nucleation and coalescence kinetics. We demonstrate this by utilizing a combination of synthetic and native condensates to probe the underlying physical mechanisms determining condensate size. The appearance of exponential distributions for abrupt nucleation versus power-law distributions under continuous nucleation may reflect a general principle that determines condensate size distributions.Biomolecular condensates play a role in cellular processes and their size affects reaction pathways. The size distribution is connected to varying contributions of nucleation and coalescence.
Journal Article
Further research needed to determine first-line therapy for IBS in primary care
[...]a low FODMAP diet is a complex, restrictive diet that can lead to nutritional compromise, hence the importance of it being implemented and monitored by a specialist dietician.2 While the study tried to mitigate this issue by using a FODMAP-lowering diet, as opposed to a strict low FODMAP diet, the level of FODMAP reduction was not determined and nor were changes in macronutrient and micronutrient composition assessed. [...]the authors describe the FODMAP-lowering diet as being designed in combination with traditional dietary advice (TDA), the latter based on guidance provided by the National Institute for Health and Care Excellence and the British Dietetic Association.3 4 However, TDA in itself advises lowering FODMAPs (eg, through reducing common gas-producing foods like bread, beans, pulses, sweeteners) as well as adopting healthy, sensible eating patterns such as reducing the intake of rich fatty foods, spicy foods, alcohol, caffeine, fizzy drinks, etc.3–5 Hence, further clarity is needed to ascertain whether the FODMAP-lowering intervention used in this study was arguably TDA? [...]it should be borne in mind that, for some patients with IBS, a multi-integrated approach of combining treatments is more effective than choosing one therapy over another.9 In conclusion, we commend the authors for conducting a large novel trial of diet versus medication in primary care patients with IBS.
Journal Article
The Overlapping Area of Non-Celiac Gluten Sensitivity (NCGS) and Wheat-Sensitive Irritable Bowel Syndrome (IBS): An Update
Gluten-related disorders have recently been reclassified with an emerging scientific literature supporting the concept of non-celiac gluten sensitivity (NCGS). New research has specifically addressed prevalence, immune mechanisms, the recognition of non-immunoglobulin E (non-IgE) wheat allergy and overlap of NCGS with irritable bowel syndrome (IBS)-type symptoms. This review article will provide clinicians with an update that directly impacts on the management of a subgroup of their IBS patients whose symptoms are triggered by wheat ingestion.
Journal Article