Identification of the fructose transporter GLUT5 (SLC2A5) as a novel target of nuclear receptor LXR

Fructose has become a major constituent of our modern diet and is implicated as an underlying cause in the development of metabolic diseases. The fructose transporter GLUT5 (SLC2A5) is required for intestinal fructose absorption. GLUT5 expression is induced in the intestine and skeletal muscle of type 2 diabetes (T2D) patients and in certain cancers that are dependent on fructose metabolism, indicating that modulation of GLUT5 levels could have potential in the treatment of these diseases. Using an unbiased screen for transcriptional control of the human GLUT5 promoter we identified a strong and specific regulation by liver X receptor alpha (LXR alpha, NR1H3). Using promoter truncations and site-directed mutagenesis we identified a functional LXR response element (LXRE) in the human GLUT5 promoter, located at -385 bp relative to the transcriptional start site (TSS). Finally, mice treated with LXR agonist T0901317 showed an increase in Glut5 mRNA and protein levels in duodenum and adipose tissue, underscoring the in vivo relevance of its regulation by LXR. Together, our findings show that LXR alpha regulates GLUT5 in mice and humans. As a ligand-activated transcription factor, LXR alpha might provide novel pharmacologic strategies for the selective modulation of GLUT5 activity in the treatment of metabolic disease as well as cancer.</p

Effect of metabolosome encapsulation peptides on enzyme activity, co-aggregation, incorporation and bacterial microcompartment formation

Metabolosomes, catabolic bacterial microcompartments, are proteinaceous organelles that are associated with the breakdown of metabolites such as propanediol and ethanolamine. They are composed of an outer multi-component protein shell that encases a specific metabolic pathway. Protein cargo found within BMCs is directed by the presence of an encapsulation peptide that appears to trigger aggregation prior to the formation of the outer shell. We investigated the effect of three distinct encapsulation peptides on foreign cargo in a recombinant BMC system. Our data demonstrate that these peptides cause variation with respect to enzyme activity and protein aggregation. We observed that the level of protein aggregation generally correlates with the size of metabolosomes, while in the absence of cargo BMCs self-assemble into smaller compartments. The results agree with a flexible model for BMC formation based around the ability of the BMC shell to associate with an aggregate formed due to the interaction of encapsulation peptides

Prevalence of Livestock-Associated MRSA in Communities with High Pig-Densities in The Netherlands

Contains fulltext : 124345.pdf (publisher's version ) (Open Access)BACKGROUND: Recently, livestock-associated methicillin-resistant Staphylococcus aureus CC398 has been discovered in animals, livestock farmers and retail meat. This cross-sectional study aimed to determine the spread to persons not in direct contact with livestock in areas with a high density of pig farms. METHODOLOGY/PRINCIPAL FINDINGS: With a random mailing in 3 selected municipalities in The Netherlands, adult persons were asked to fill in a questionnaire and to take a nose swab. In total, complete information was obtained on 583 persons. Of the 534 persons without livestock-contact, one was positive for MRSA (0.2%; 95% confidence interval, <0.01-1.2). Of the 49 persons who did indicate to be working at or living on a livestock farm, 13 were positive for MRSA (26.5%; 95% confidence interval, 16.1-40.4). All spa-types belonged to CC398. CONCLUSIONS/SIGNIFICANCE: Livestock-associated MRSA has a high prevalence in people with direct contact with animals. At this moment it has not spread from the farms into the community

Cholestase bij pasgeborenen als gevolg van parenterale voeding

Toediening van totale parenterale voeding (TPN) aan pasgeborenen is geassocieerd met het ontstaan van cholestase. Ondanks intensief onderzoek zijn de pathofysiologische mechanismen slechts gedeeltelijk opgehelderd. In dit artikel wordt ingegaan op de huidige inzichten in de risicofactoren die geassocieerd zijn met TPN-cholestase bij pasgeborenen, de specifieke bestanddelen en deficiënties van TPN die cholestase kunnen veroorzaken, de mogelijke relatie met de ‘fysiologische cholestase van de pasgeborene’, die de pasgeborene kwetsbaarder maakt voor potentieel hepatotoxische stoffen, en de transportsystemen in de levercelmembraan die betrokken zijn bij galvorming. De hypothese dat ‘cholestatische galzuren’ een rol spelen in de etiologie van TPN-cholestase en de therapeutische mogelijkheden worden besproken.Administration of total parenteral nutrition (TPN) to neonates is associated with the occurrence of cholestasis. Despite intensive research, the pathophysiological mechanisms have not been elucidated. In this review we describe the present insights into the risk factors for the development of TPN-associated cholestasis, the specific components or lack of components (deficiencies) in TPN that can cause cholestasis, the possible correlation with 'physiologic cholestasis of the neonate', which makes the infant more susceptible for potentially hepatotoxic compounds, and the transport systems in the liver cell membrane which are involved in bile formation. The hypothesis that 'cholestatic bile salts' play a role in the etiology of TPN-related cholestasis and the therapeutic options will be discussed.</p

Smc5/6: a link between DNA repair and unidirectional replication?

Of the three structural maintenance of chromosome (SMC) complexes, two directly regulate chromosome dynamics. The third, Smc5/6, functions mainly in homologous recombination and in completing DNA replication. The literature suggests that Smc5/6 coordinates DNA repair, in part through post-translational modification of uncharacterized target proteins that can dictate their subcellular localization, and that Smc5/6 also functions to establish DNA-damage-dependent cohesion. A nucleolar-specific Smc5/6 function has been proposed because Smc5/6 yeast mutants display penetrant phenotypes of ribosomal DNA (rDNA) instability. rDNA repeats are replicated unidirectionally. Here, we propose that unidirectional replication, combined with global Smc5/6 functions, can explain the apparent rDNA specificity

De novo designed peptide and protein hairpins self‐assemble into sheets and nanoparticles

AFM, TEM, fluorescence microscopy image files and spectral data published in DOI:10.1002/smll.202100472. Preprint of this is available at bioRxiv DOI:10.1101/2020.08.14.25146

Engineered synthetic scaffolds for organizing proteins within the bacterial cytoplasm

We have developed a system for producing a supramolecular scaffold that permeates the entire Escherichia coli cytoplasm. This cytoscaffold is constructed from a three-component system comprising a bacterial microcompartment shell protein and two complementary de novo coiled-coil peptides. We show that other proteins can be targeted to this intracellular filamentous arrangement. Specifically, the enzymes pyruvate decarboxylase and alcohol dehydrogenase have been directed to the filaments, leading to enhanced ethanol production in these engineered bacterial cells compared to those that do not produce the scaffold. This is consistent with improved metabolic efficiency through enzyme colocation. Finally, the shell-protein scaffold can be directed to the inner membrane of the cell, demonstrating how synthetic cellular organization can be coupled with spatial optimization through in-cell protein design. The cytoscaffold has potential in the development of next-generation cell factories, wherein it could be used to organize enzyme pathways and metabolite transporters to enhance metabolic flux

The EASL–Lancet Liver Commission: protecting the next generation of Europeans against liver disease complications and premature mortality

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Consensus over Random Graph Processes: Network Borel-Cantelli Lemmas for Almost Sure Convergence

Distributed consensus computation over random graph processes is considered. The random graph process is defined as a sequence of random variables which take values from the set of all possible digraphs over the node set. At each time step, every node updates its state based on a Bernoulli trial, independent in time and among different nodes: either averaging among the neighbor set generated by the random graph, or sticking with its current state. Connectivity-independence and arc-independence are introduced to capture the fundamental influence of the random graphs on the consensus convergence. Necessary and/or sufficient conditions are presented on the success probabilities of the Bernoulli trials for the network to reach a global almost sure consensus, with some sharp threshold established revealing a consensus zero-one law. Convergence rates are established by lower and upper bounds of the $\epsilon$-computation time. We also generalize the concepts of connectivity/arc independence to their analogues from the $*$-mixing point of view, so that our results apply to a very wide class of graphical models, including the majority of random graph models in the literature, e.g., Erd\H{o}s-R\'{e}nyi, gossiping, and Markovian random graphs. We show that under $*$-mixing, our convergence analysis continues to hold and the corresponding almost sure consensus conditions are established. Finally, we further investigate almost sure finite-time convergence of random gossiping algorithms, and prove that the Bernoulli trials play a key role in ensuring finite-time convergence. These results add to the understanding of the interplay between random graphs, random computations, and convergence probability for distributed information processing.Comment: IEEE Transactions on Information Theory, In Pres