Summary
The distal gut harbours ∼1013 bacteria, representing the most densely populated ecosystem known. The functional diversity expressed by these communities is enormous and relatively unexplored. ...The past decade of research has unveiled the profound influence that the resident microbial populations bestow to host immunity and metabolism. The evolution of these communities from birth generates a highly adapted and highly personalized microbiota that is stable in healthy individuals. Immune homeostasis is achieved and maintained due in part to the extensive interplay between the gut microbiota and host mucosal immune system. Imbalances of gut microbiota may lead to a number of pathologies such as obesity, type I and type II diabetes, inflammatory bowel disease (IBD), colorectal cancer (CRC) and inflammaging/immunosenscence in the elderly. In‐depth understanding of the underlying mechanisms that control homeostasis and dysbiosis of the gut microbiota represents an important step in our ability to reliably modulate the gut microbiota with positive clinical outcomes. The potential of microbiome‐based therapeutics to treat epidemic human disease is of great interest. New therapeutic paradigms, including second‐generation personalized probiotics, prebiotics, narrow spectrum antibiotic treatment and faecal microbiome transplantation, may provide safer and natural alternatives to traditional clinical interventions for chronic diseases. This review discusses host–microbiota homeostasis, consequences of its perturbation and the associated challenges in therapeutic developments that lie ahead.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
In pugilistic parlance, the one-two punch is a devastating combination of blows, with the first punch setting the stage and the second delivering the knock-out. This analogy can be extended to ...molecularly targeted cancer therapies, with oncogene addiction serving to set the stage for tumor cell killing by a targeted therapeutic agent. While in vitro and in vivo examples abound documenting the existence of this phenomenon, the mechanistic underpinnings that govern oncogene addiction are just beginning to emerge. Our current inability to fully exploit this weakness of cancer cells stems from an incomplete understanding of oncogene addiction, which nonetheless represents one of the rare chinks in the formidable armor of cancer cells.
A crossover from a non-Gaussian to Gaussian subdiffusion has been observed ubiquitously in various polymeric and molecular glassformers. We have developed a framework that generalizes the fractional ...Brownian motion model to incorporate non-Gaussian features by introducing a jump kernel. We illustrate that the non-Gaussian fractional Brownian motion model accurately characterizes the subdiffusion crossover. From the solutions of the non-Gaussian fractional Brownian motion model, we gain insights into the nature of van Hove self-correlation in non-Gaussian subdiffusive regime, which is found to exhibit exponential tails, providing first such experimental evidence in molecular glassformers. The validity of the model is supported by comparison with incoherent quasielastic neutron scattering data obtained from several molecular and polymeric glassformers.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UL, UM
Deep eutectic solvents (DESs) have become ubiquitous in a variety of industrial and pharmaceutical applications since their discovery. However, the fundamental understanding of their physicochemical ...properties and their emergence from the microscopic features is still being explored fervently. Particularly, the knowledge of transport mechanisms in DESs is essential to tune their properties, which shall aid in expanding the territory of their applications. This perspective presents the current state of understanding of the bulk/macroscopic transport properties and microscopic relaxation processes in DESs. The dependence of these properties on the components and composition of the DES is explored, highlighting the role of hydrogen bonding (H-bonding) interactions. Modulation of these interactions by water and other additives, and their subsequent effect on the transport mechanisms, is also discussed. Various models (
e.g.
hole theory, free volume theory,
etc.
) have been proposed to explain the macroscopic transport phenomena from a microscopic origin. But the formation of H-bond networks and clusters in the DES reveals the insufficiency of these models, and establishes an antecedent for dynamic heterogeneity. Even significantly above the glass transition, the microscopic relaxation processes in DESs are rife with temporal and spatial heterogeneity, which causes a substantial decoupling between the viscosity and microscopic diffusion processes. However, we propose that a thorough understanding of the structural relaxation associated to the H-bond dynamics in DESs will provide the necessary framework to interpret the emergence of bulk transport properties from their microscopic counterparts.
A thorough understanding of the structural relaxation associated to the H-bond dynamics in DESs will provide the necessary framework to interpret the emergence of bulk transport properties from their microscopic counterparts.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely prescribed for their antipyretic, anti-inflammatory, and painkiller actions despite a wide spectrum of side effects. The mechanisms involved ...in their therapeutic actions and side-effects have not been clearly understood yet. The assertion that effects of NSAIDs are related to their action at cellular membrane level has stimulated the investigation of interaction between NSAIDs and membranes. Here, we report effects of two different NSAIDs, ibuprofen and indomethacin, on the thermotropic phase behaviour and the dynamics of DMPC membrane as studied using neutron scattering techniques. Elastic intensity scan measurements showed that both drugs substantially alter the phase behaviour of the membrane. However, the effects of these drugs are found to differ quantitatively, which is correlated with their respective interactions with phospholipid membrane. Quasielastic neutron scattering measurements showed that in the ordered phase, both drugs enhance the dynamics of the membrane, but the drugs' effects on the membrane dynamics differ in the fluid phase. Indomethacin suppresses the dynamics of the membrane, whereas ibuprofen does not show significant effect at the same molar concentration. We have also investigated the effect of concentration of ibuprofen on the dynamics of the membrane. Our measurements provide clear evidence that interaction of NSAID with the membrane depends on both the physical state of the membrane and the nature and concentration of NSAID. Hence, one must investigate each NSAID independently while analysing its action mechanism. Better understanding of NSAID-membrane interaction can pave the way for designing more effective NSAID with reduced side effects.
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•Effects of ibuprofen and indomethacin on motions of the membrane lipids are probed.•NSAID-membrane interaction depends on membrane phase state and drug concentration.•NSAIDs broaden the main phase transition and shift it towards a lower temperature.•In ordered phase, ibuprofen and indomethacin enhance the dynamics of the membrane.•In fluid phase, indomethacin, but not ibuprofen, suppresses the membrane dynamics.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Efforts to discover new cancer drugs and predict their clinical activity are limited by the fact that laboratory models to test drug efficacy do not faithfully recapitulate this complex disease. One ...important model system for evaluating candidate anticancer agents is human tumour-derived cell lines. Although cultured cancer cells can exhibit distinct properties compared with their naturally growing counterparts, recent technologies that facilitate the parallel analysis of large panels of such lines, together with genomic technologies that define their genetic constitution, have revitalized efforts to use cancer cell lines to assess the clinical utility of new investigational cancer drugs and to discover predictive biomarkers.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Accumulating evidence implicates heterogeneity within cancer cell populations in the response to stressful exposures, including drug treatments. While modeling the acute response to various ...anticancer agents in drug-sensitive human tumor cell lines, we consistently detected a small subpopulation of reversibly “drug-tolerant” cells. These cells demonstrate >100-fold reduced drug sensitivity and maintain viability via engagement of IGF-1 receptor signaling and an altered chromatin state that requires the histone demethylase RBP2/KDM5A/Jarid1A. This drug-tolerant phenotype is transiently acquired and relinquished at low frequency by individual cells within the population, implicating the dynamic regulation of phenotypic heterogeneity in drug tolerance. The drug-tolerant subpopulation can be selectively ablated by treatment with IGF-1 receptor inhibitors or chromatin-modifying agents, potentially yielding a therapeutic opportunity. Together, these findings suggest that cancer cell populations employ a dynamic survival strategy in which individual cells transiently assume a reversibly drug-tolerant state to protect the population from eradication by potentially lethal exposures.
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► Human cancer cell lines harbor a subpopulation of “drug-tolerant” cells ► The drug-tolerant state can emerge de novo and is transiently maintained ► The emergence of drug tolerance requires IGF-1R signaling ► Drug tolerance involves distinct chromatin states that can be disrupted
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The plasma membrane is one of the principal structural components of the cell and, therefore, one of the key components of the cellular life. Because the membrane's dynamics links the membrane's ...structure and function, the complexity and the broad range of the membrane's motions are essential for the enormously diverse functionality of the cell membrane. Even for the main membrane component, the lipid bilayer, considered alone, the range and complexity of the lipid motions are remarkable. Spanning the time scale from sub-picosecond to minutes and hours, the lipid motion in a bilayer is challenging to study even when a broad array of dynamic measurement techniques is employed. Neutron scattering plays a special role among such dynamic measurement techniques, particularly, because it involves the energy transfers commensurate with the typical intra- and inter- molecular dynamics and the momentum transfers commensurate with intra- and inter-molecular distances. Thus, using neutron scattering-based techniques, the spatial and temporal information on the lipid motion can be obtained and analysed simultaneously. Protium vs. deuterium sensitivity and non-destructive character of the neutron probe add to the remarkable prowess of neutron scattering for elucidating the lipid dynamics. Herein we present an overview of the neutron scattering-based studies of lipid dynamics in model membranes, with a discussion of the direct relevance and implications to the real-life cell membranes. The latter are much more complex systems than simple model membranes, consisting of heterogeneous non-stationary domains composed of lipids, proteins, and other small molecules, such as carbohydrates. Yet many fundamental aspects of the membrane behavior and membrane interactions with other molecules can be understood from neutron scattering measurements of the model membranes. For example, such studies can provide a great deal of information on the interactions of antimicrobial compounds with the lipid matrix of a pathogen membrane, or the interactions of drug molecules with the plasma membrane. Finally, we briefly discuss the recently emerging field of neutron scattering membrane studies with a reach far beyond the model membrane systems.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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