Does proteolysis explain glutamine release from the septic brain?

Berg and colleagues report on amino acid exchange across the human brain during endotoxin infusion. Lipopolysaccharide infusion induced a decrease in the ratio between branched chain amino acids and aromatic amino acids, increased unidirectional phenylalanine uptake, and increased net brain glutamine release. Cerebral proteolysis is suggested to play a role, but the question is whether this is the case and why this would happen

Cell cycle dependent expression of the CCK2 receptor by gastrointestinal myofibroblasts: putative role in determining cell migration.

The well-known action of the gastric hormone gastrin in stimulating gastric acid secretion is mediated by activation of cholecystokinin-2 receptors (CCK2R). The latter are expressed by a variety of cell types suggesting that gastrin is implicated in multiple functions. During wound healing in the stomach CCK2R may be expressed by myofibroblasts. We have now characterized CCK2R expression in cultured myofibroblasts. Immunocytochemistry showed that a relatively small proportion (1-6%) of myofibroblasts expressed the receptor regardless of the region of the gut from which they were derived, or whether from cancer or control tissue. Activation of CCK2R by human heptadecapeptide gastrin (hG17) increased intracellular calcium concentrations in a small subset of myofibroblasts indicating the presence of a functional receptor. Unexpectedly, we found over 80% of cells expressing CCK2R were also labeled with 5-ethynyl-2'-deoxyuridine (EdU) which is incorporated into DNA during S-phase of the cell cycle. hG17 did not stimulate EdU incorporation but increased migration of both EdU-labeled and unlabelled myofibroblasts; the migratory response was inhibited by a CCK2R antagonist and by an inhibitor of IGF receptor tyrosine kinase; hG17 also increased IGF-2 transcript abundance. The data suggest myofibroblasts express CCK2R in a restricted period of the cell cycle during S-phase, and that gastrin accelerates migration of these cells; it also stimulates migration of adjacent cells probably through paracrine release of IGF. Together with previous findings, the results raise the prospect that gastrin controls the position of dividing myofibroblasts which may be relevant in wound healing and cancer progression in the gastrointestinal tract

Assessing the impact of beach nourishment on the intertidal food web through the development of a mechanistic-envelope model

1. Beach nourishment, the placement of sand onto a sediment-starved stretch of coast, is widely applied as a soft coastal protection measure because of its reduced ecological impact relative to hard coastal protection. In order to predict effects on the intertidal sandy beach ecosystem, we developed a simulation model that integrates species envelope-based projections for the dominant macrobenthos species and mechanistic food web modules for higher trophic levels. 2. Species envelopes were estimated by using Bayesian inference of species’ biomass relationships according to the three determining abiotic variables: intertidal elevation, median grain size and total organic matter, obtained from multiple sampling campaigns along the Belgian coast. Maximum potential abundance of higher trophic levels represented by birds, shrimp and flatfish were estimated based on their derived trophic relationship with macrobenthos. 3. After validation, we demonstrated that unlike nourishment slope, sediment grain size strongly determines beach-level species richness and production, with strong deterioration in species richness after nourishment with coarse sediment (>300 lm). Patterns for higher trophic levels do not follow the changes in macrobenthos abundance and biomass. 4. Synthesis and applications. The optimal grain size range for nourishment of fine-grained beaches is 200–300 lm. This modelling approach shows that the impact assessment of beach nourishment needs to include the evaluation of different species richness and biomass variables. Focusing solely on the potential abundance of species from higher trophic levels might lead to deceptive conclusions due to the dominance of opportunistic prey species

Electronic transport in polycrystalline graphene

Most materials in available macroscopic quantities are polycrystalline. Graphene, a recently discovered two-dimensional form of carbon with strong potential for replacing silicon in future electronics, is no exception. There is growing evidence of the polycrystalline nature of graphene samples obtained using various techniques. Grain boundaries, intrinsic topological defects of polycrystalline materials, are expected to dramatically alter the electronic transport in graphene. Here, we develop a theory of charge carrier transmission through grain boundaries composed of a periodic array of dislocations in graphene based on the momentum conservation principle. Depending on the grain boundary structure we find two distinct transport behaviours - either high transparency, or perfect reflection of charge carriers over remarkably large energy ranges. First-principles quantum transport calculations are used to verify and further investigate this striking behaviour. Our study sheds light on the transport properties of large-area graphene samples. Furthermore, purposeful engineering of periodic grain boundaries with tunable transport gaps would allow for controlling charge currents without the need of introducing bulk band gaps in otherwise semimetallic graphene. The proposed approach can be regarded as a means towards building practical graphene electronics.Comment: accepted in Nature Material

Haploinsufficient Bmp4 ocular phenotypes include anterior segment dysgenesis with elevated intraocular pressure

BACKGROUND: Glaucoma is a blinding disease usually associated with high intraocular pressure (IOP). In some families, abnormal anterior segment development contributes to glaucoma. The genes causing anterior segment dysgenesis and glaucoma in most of these families are not identified and the affected developmental processes are poorly understood. Bone morphogenetic proteins (BMPs) participate in various developmental processes. We tested the importance of Bmp4 gene dosage for ocular development and developmental glaucoma. RESULTS: Bmp4(+/-) mice have anterior segment abnormalities including malformed, absent or blocked trabecular meshwork and Schlemm's canal drainage structures. Mice with severe drainage structure abnormalities, over 80% or more of their angle's extent, have elevated IOP. The penetrance and severity of abnormalities is strongly influenced by genetic background, being most severe on the C57BL/6J background and absent on some other backgrounds. On the C57BL/6J background there is also persistence of the hyaloid vasculature, diminished numbers of inner retinal cells, and absence of the optic nerve. CONCLUSIONS: We demonstrate that heterozygous deficiency of BMP4 results in anterior segment dysgenesis and elevated IOP. The abnormalities are similar to those in human patients with developmental glaucoma. Thus, BMP4 is a strong candidate to contribute to Axenfeld-Rieger anomaly and other developmental conditions associated with human glaucoma. BMP4 also participates in posterior segment development and wild-type levels are usually critical for optic nerve development on the C57BL/6J background. Bmp4(+/-) mice are useful for studying various components of ocular development, and may allow identification of strain specific modifiers affecting a variety of ocular phenotypes

Impaired brain glymphatic flow in experimental hepatic encephalopathy

Background & Aims: Neuronal function is exquisitely sensitive to alterations in the extracellular environment. In patients with hepatic encephalopathy (HE), accumulation of metabolic waste products and noxious substances in the interstitial fluid of the brain is thought to result from liver disease and may contribute to neuronal dysfunction and cognitive impairment. This study was designed to test the hypothesis that the accumulation of these substances, such as bile acids, may result from reduced clearance from the brain. Methods: In a rat model of chronic liver disease with minimal HE (the bile duct ligation [BDL] model), we used emerging dynamic contrast-enhanced MRI and mass-spectroscopy techniques to assess the efficacy of the glymphatic system, which facilitates clearance of solutes from the brain. Immunofluorescence of aquaporin-4 (AQP4) and behavioural experiments were also performed. Results: We identified discrete brain regions (olfactory bulb, prefrontal cortex and hippocampus) of altered glymphatic clearance in BDL rats, which aligned with cognitive/behavioural deficits. Reduced AQP4 expression was observed in the olfactory bulb and prefrontal cortex in HE, which could contribute to the pathophysiological mechanisms underlying the impairment in glymphatic function in BDL rats. Conclusions: This study provides the first experimental evidence of impaired glymphatic flow in HE, potentially mediated by decreased AQP4 expression in the affected regions. Lay summary: The 'glymphatic system' is a newly discovered brain-wide pathway that facilitates clearance of various sub-stances that accumulate in the brain due to its activity. This study evaluated whether the function of this system is altered in a model of brain dysfunction that occurs in cirrhosis. For the first time, we identified that the clearance of substances from the brain in cirrhosis is reduced because this clearance system is defective. This study proposes a new mechanism of brain dysfunction in patients with cirrhosis and provides new targets for therapy

Stage-Specific Inhibition of MHC Class I Presentation by the Epstein-Barr Virus BNLF2a Protein during Virus Lytic Cycle

gamma-herpesvirus Epstein-Barr virus (EBV) persists for life in infected individuals despite the presence of a strong immune response. During the lytic cycle of EBV many viral proteins are expressed, potentially allowing virally infected cells to be recognized and eliminated by CD8+ T cells. We have recently identified an immune evasion protein encoded by EBV, BNLF2a, which is expressed in early phase lytic replication and inhibits peptide- and ATP-binding functions of the transporter associated with antigen processing. Ectopic expression of BNLF2a causes decreased surface MHC class I expression and inhibits the presentation of indicator antigens to CD8+ T cells. Here we sought to examine the influence of BNLF2a when expressed naturally during EBV lytic replication. We generated a BNLF2a-deleted recombinant EBV (ΔBNLF2a) and compared the ability of ΔBNLF2a and wild-type EBV-transformed B cell lines to be recognized by CD8+ T cell clones specific for EBV-encoded immediate early, early and late lytic antigens. Epitopes derived from immediate early and early expressed proteins were better recognized when presented by ΔBNLF2a transformed cells compared to wild-type virus transformants. However, recognition of late antigens by CD8+ T cells remained equally poor when presented by both wild-type and ΔBNLF2a cell targets. Analysis of BNLF2a and target protein expression kinetics showed that although BNLF2a is expressed during early phase replication, it is expressed at a time when there is an upregulation of immediate early proteins and initiation of early protein synthesis. Interestingly, BNLF2a protein expression was found to be lost by late lytic cycle yet ΔBNLF2a-transformed cells in late stage replication downregulated surface MHC class I to a similar extent as wild-type EBV-transformed cells. These data show that BNLF2a-mediated expression is stage-specific, affecting presentation of immediate early and early proteins, and that other evasion mechanisms operate later in the lytic cycle

Stochastic population growth in spatially heterogeneous environments

Classical ecological theory predicts that environmental stochasticity increases extinction risk by reducing the average per-capita growth rate of populations. To understand the interactive effects of environmental stochasticity, spatial heterogeneity, and dispersal on population growth, we study the following model for population abundances in $n$ patches: the conditional law of $X_{t+dt}$ given $X_t=x$ is such that when $dt$ is small the conditional mean of $X_{t+dt}^i-X_t^i$ is approximately $[x^i\mu_i+\sum_j(x^j D_{ji}-x^i D_{ij})]dt$, where $X_t^i$ and $\mu_i$ are the abundance and per capita growth rate in the $i$-th patch respectivly, and $D_{ij}$ is the dispersal rate from the $i$-th to the $j$-th patch, and the conditional covariance of $X_{t+dt}^i-X_t^i$ and $X_{t+dt}^j-X_t^j$ is approximately $x^i x^j \sigma_{ij}dt$. We show for such a spatially extended population that if $S_t=(X_t^1+...+X_t^n)$ is the total population abundance, then $Y_t=X_t/S_t$, the vector of patch proportions, converges in law to a random vector $Y_\infty$ as $t\to\infty$, and the stochastic growth rate $\lim_{t\to\infty}t^{-1}\log S_t$ equals the space-time average per-capita growth rate \sum_i\mu_i\E[Y_\infty^i] experienced by the population minus half of the space-time average temporal variation \E[\sum_{i,j}\sigma_{ij}Y_\infty^i Y_\infty^j] experienced by the population. We derive analytic results for the law of $Y_\infty$, find which choice of the dispersal mechanism $D$ produces an optimal stochastic growth rate for a freely dispersing population, and investigate the effect on the stochastic growth rate of constraints on dispersal rates. Our results provide fundamental insights into "ideal free" movement in the face of uncertainty, the persistence of coupled sink populations, the evolution of dispersal rates, and the single large or several small (SLOSS) debate in conservation biology.Comment: 47 pages, 4 figure