The fasting polypeptide FGF21 can enter brain from blood

FGF21 recently has been proposed as a missing link in the biology of fasting, raising the question of whether it directly reaches the brain. We used multiple time-regression analysis to quantify the influx rate of this polypeptide across the blood–brain barrier (BBB), size-exclusion chromatography to examine degradation, capillary depletion to differentiate entry into brain parenchyma from retention in the microvasculature, and measurement of efflux rate to determine a possible confounding effect on measurement of entry. FGF21 was 94% intact in serum and 75% in brain 10 min after intravenous bolus delivery. Its influx rate was 0.23 ± 0.12 μl/g-min, nearly four times faster than that of the vascular marker albumin. At 10 min, about 0.5% of the administered FGF21 was present in a gram of brain tissue. Of this, 70% reached the parenchyma of the brain. Co-injection of excess FGF21 failed to inhibit the influx, showing a lack of saturation. Efflux, which occurred at the same rate as the bulk reabsorption of cerebrospinal fluid, also was not saturable. In summary, FGF21 shows significant, non-saturable, unidirectional influx across the BBB.     

Drosophila gastrulation: identification of a missing link

Drosophila gastrulation serves as a model system to elucidate the genetic and molecular mechanisms involved in morphogenetic movements. The ligand of the FGF receptor Heartless, which is involved in mesoderm movement, has now been isolated and shown to be a link between a morphogen gradient and cell behavior.     

Here come the SUNs: a nucleocytoskeletal missing link

The nuclear envelope has traditionally been thought of as a barrier that separates the nucleoplasm from the cytoplasm in eukaryotic cells. Increasing evidence shows that the nuclear envelope also links the inside of the nucleus to the cytoskeleton. Here we discuss recent papers showing that this link occurs through complexes of lamins on the inner aspect of the inner nuclear membrane, transmembrane proteins of the inner nuclear membrane called SUNs and large nesprin isoforms localized specifically to the outer nuclear membrane. These discoveries have implications for nuclear positioning, nuclear migration and pathogenesis of inherited diseases that are caused by mutations in nuclear envelope proteins.     

FGF21 attenuates lipolysis in human adipocytes - a possible link to improved insulin sensitivity

Fibroblast growth factor 21 (FGF21) is active in murine adipocytes and has beneficial metabolic effects in animal models of type 2 diabetes mellitus. We assessed whether FGF21 influences lipolysis in human adipocytes and 3T3-L1 cells. FGF21 had no short-time effect (h) while a 3-day incubation with FGF21 attenuated hormone-stimulated lipolysis. FGF21 did not influence the mRNA expression of genes involved in regulating lipolysis, but significantly reduced the expression of the lipid droplet-associated phosphoprotein perilipin without affecting differentiation. Via reduced release of fatty acids into the circulation, the anti-lipolytic effect could be a mechanism through which FGF21 promotes insulin sensitivity in man.     

Mixotrophy: the missing link in consumer-resource-based ecologies

Theoretical Ecology - The classical separate treatments of competition and predation and difficulties in providing a sensible theoretical basis for mutualism attest to the inability of traditional...     

FTO and obesity: the missing link

The field of vascular molecular imaging is searching for the "holy grail" of an imaging technique that will quantitatively and reliably assess vulnerable coronary plaques. Fluorescence imaging with indocyanine green specifically identifies lipid-rich plaques in rabbits and in humans and represents a promising, though invasive, approach.     

The cholinergic anti-inflammatory pathway: a missing link in neuroimmunomodulation

This review outlines the mechanisms underlying the interaction between the nervous and immune systems of the host in response to an immune challenge. The main focus is the cholinergic anti-inflammatory pathway, which we recently described as a novel function of the efferent vagus nerve. This pathway plays a critical role in controlling the inflammatory response through interaction with peripheral a7 subunit-containing nicotinic acetylcholine receptors expressed on macrophages. We describe the modulation of systemic and local inflammation by the cholinergic anti-inflammatory pathway and its function as an interface between the brain and the immune system. The clinical implications of this novel mechanism also are discussed.     

Programmed cell death: a missing link is found

Two families of proteins have advanced our understanding of the molecular basis of programmed cell death (PCD) in animal cells - the caspases and Bcl-2-related proteins. While caspases lie at the heart of the death programme, Bcl-2-related proteins act as key intracellular regulators. Although there has been considerable progress in elucidating the biochemical functions of caspases, how Bcl-2-related proteins regulate caspase activation and thereby PCD, has remained a mystery. One key to resolving this mystery seems to lie with a new third family of proteins related to the Caenorhabditis elegans cell-death protein CED-4, which connects Bcl-2-related proteins to caspases. An important step in defining this new family has been made by the identification of a human CED-4 homologue.     

Chromosome segregation: a kinetochore missing link is found

During mitosis the kinetochore assembles on centromeric chromatin. The component that connects the chromatin-associated inner domain to the microtubule-binding outer domain has eluded researchers. Two new studies identify a conserved molecular linkage between the inner and outer kinetochore.     

Bifunctional isocitrate-homoisocitrate dehydrogenase: a missing link in the evolution of beta-decarboxylating dehydrogenase

Beta-decarboxylating dehydrogenases comprise 3-isopropylmalate dehydrogenase, isocitrate dehydrogenase, and homoisocitrate dehydrogenase. They share a high degree of amino acid sequence identity and occupy equivalent positions in the amino acid biosynthetic pathways for leucine, glutamate, and lysine, respectively. Therefore, not only the enzymes but also the whole pathways should have evolved from a common ancestral pathway. In Pyrococcus horikoshii, only one pathway of the three has been identified in the genomic sequence, and PH1722 is the sole beta-decarboxylating dehydrogenase gene. The organism does not require leucine, glutamate, or lysine for growth; the single pathway might play multiple (i.e., ancestral) roles in amino acid biosynthesis. The PH1722 gene was cloned and expressed in Escherichia coli and the substrate specificity of the recombinant enzyme was investigated. It exhibited activities on isocitrate and homoisocitrate at near equal efficiency, but not on 3-isopropylmalate. PH1722 is thus a novel, bifunctional beta-decarboxylating dehydrogenase, which likely plays a dual role in glutamate and lysine biosynthesis in vivo.     

Small molecules: the missing link in the central dogma

Small molecules have critical roles at all levels of biological complexity and yet remain orphans of the central dogma. Chemical biologists, working with small molecules, expand our understanding of these central elements of life.     

Glycolytic breakdown of sulfoquinovose in bacteria: a missing link in the sulfur cycle

Sulfoquinovose (6-deoxy-6-sulfo-D-glucopyranose), formed by the hydrolysis of the plant sulfolipid, is a major component of the biological sulfur cycle. However, pathways for its catabolism are poorly delineated. We examined the hypothesis that mineralization of sulfoquinovose to inorganic sulfate is initiated by reactions of the glycolytic and/or Entner-Doudoroff pathways in bacteria. Metabolites of [U-(13)C]sulfoquinovose were identified by (13)C-nuclear magnetic resonance (NMR) in strains of Klebsiella and Agrobacterium previously isolated for their ability to utilize sulfoquinovose as a sole source of carbon and energy for growth, and cell extracts were analyzed for enzymes diagnostic for the respective pathways. Klebsiella sp. strain ABR11 grew rapidly on sulfoquinovose, with major accumulations of sulfopropandiol (2,3-dihydroxypropanesulfonate) but no detectable release of sulfate. Later, when sulfoquinovose was exhausted and growth was very slow, sulfopropandiol disappeared and inorganic sulfate and small amounts of sulfolactate (2-hydroxy-3-sulfopropionate) were formed. In Agrobacterium sp. strain ABR2, growth and sulfoquinovose disappearance were again coincident, though slower than that in Klebsiella sp. Release of sulfate was still late but was faster than that in Klebsiella sp., and no metabolites were detected by (13)C-NMR. Extracts of both strains grown on sulfoquinovose contained phosphofructokinase activities that remained unchanged when fructose 6-phosphate was replaced in the assay mixture with either glucose 6-phosphate or sulfoquinovose. The results were consistent with the operation of the Embden-Meyerhoff-Parnas (glycolysis) pathway for catabolism of sulfoquinovose. Extracts of Klebsiella but not Agrobacterium also contained an NAD(+)-dependent sulfoquinovose dehydrogenase activity, indicating that the Entner-Doudoroff pathway might also contribute to catabolism of sulfoquinovose.     

Ant behaviour and seed morphology: a missing link of myrmecochory

Seed dispersal by ants (myrmecochory) is mediated by the presence of a lipid-rich appendage (elaiosome) on the seed that induces a variety of ants to collect the diaspores. When seeds mature or fall onto the ground, these ant species transport them to their nest. After eating the elaiosome, the seed is discarded in nest galleries or outside, in the midden or farther away, where seeds can potentially germinate. The final location of seeds with their elaiosomes removed was evaluated to assess the importance of possible handles (structures that ants can grasp to carry) in transporting ants during re-dispersal experiments of seeds from nests of six species of ants. The results indicate that seeds remained within the nest because the ants were not able to transport them out of the nest. As a consequence of the elaiosome being removed, small ant species could not take Euphorbia characias seeds out of their nests. Only large ant species could remove E. characias seeds from their nests. Attaching an artificial handle to E. characias seeds allowed small ant species to redistribute the seeds from their nests. On the other hand, Rhamnus alaternus seeds that have a natural handle after the elaiosome removal were removed from the nests by both groups of ant species. If a seed has an element that acts as a handle, it will eventually get taken out of the nest. The ants’ size and their mandible gap can determine the outcome of the interaction (i.e. the pattern of the final seed shadow) and as a consequence, could influence the events that take place after the dispersal process.