Increased Expression of M1 and M2 Phenotypic Markers in Isolated Microglia After Four-Day Binge Alcohol Exposure in Male Rats

Microglia activation and neuroinflammation are common features of neurodegenerative conditions, including alcohol use disorders (AUDs). When activated, microglia span a continuum of diverse phenotypes ranging from classically activated, pro-inflammatory (M1) microglia/macrophages to alternatively activated, growth-promoting (M2) microglia/macrophages. Identifying microglia phenotypes is critical for understanding the role of microglia in the pathogenesis of AUDs. Therefore, male rats were gavaged with 25% (w/v) ethanol or isocaloric control diet every 8 h for 4 days and sacrificed at 0, 2, 4, and 7 days after alcohol exposure (e.g., T0, T2, etc.). Microglia were isolated from hippocampus and entorhinal cortices by Percoll density gradient centrifugation. Cells were labeled with microglia surface antigens and analyzed by flow cytometry. Consistent with prior studies, isolated cells yielded a highly enriched population of brain macrophages/microglia (\u3e 95% pure), evidenced by staining for the macrophage/microglia antigen CD11b. Polarization states of CD11b+CD45low microglia were evaluated by expression of M1 surface markers, major histocompatibility complex (MHC) II, CD32, CD86, and M2 surface marker, CD206 (mannose receptor). Ethanol-treated animals begin to show increased expression of M1 and M2 markers at T0 (p = n.s.), with significant changes at the T2 time point. At T2, expression of M1 markers, MHC-II, CD86, and CD32 were increased (p \u3c 0.05) in hippocampus and entorhinal cortices, while M2 marker, CD206, was increased significantly only in entorhinal cortices (p \u3c 0.05). All effects resolved to control levels by T4. In summary, four-day binge alcohol exposure produces a transient increase in both M1 (MHC-II, CD32, and CD86) and M2 (CD206) populations of microglia isolated from the entorhinal cortex and hippocampus. Thus, these findings that both pro-inflammatory and potentially beneficial, recovery-promoting microglia phenotypes can be observed after a damaging exposure of alcohol are critically important to our understanding of the role of microglia in the pathogenesis of AUDs

The Renormalization Group and Singular Perturbations: Multiple-Scales, Boundary Layers and Reductive Perturbation Theory

Perturbative renormalization group theory is developed as a unified tool for global asymptotic analysis. With numerous examples, we illustrate its application to ordinary differential equation problems involving multiple scales, boundary layers with technically difficult asymptotic matching, and WKB analysis. In contrast to conventional methods, the renormalization group approach requires neither {\it ad hoc\/} assumptions about the structure of perturbation series nor the use of asymptotic matching. Our renormalization group approach provides approximate solutions which are practically superior to those obtained conventionally, although the latter can be reproduced, if desired, by appropriate expansion of the renormalization group approximant. We show that the renormalization group equation may be interpreted as an amplitude equation, and from this point of view develop reductive perturbation theory for partial differential equations describing spatially-extended systems near bifurcation points, deriving both amplitude equations and the center manifold.Comment: 44 pages, 2 Postscript figures, macro \uiucmac.tex available at macro archives or at ftp://gijoe.mrl.uiuc.edu/pu

Renormalization Group Theory for Global Asymptotic Analysis

We show with several examples that renormalization group (RG) theory can be used to understand singular and reductive perturbation methods in a unified fashion. Amplitude equations describing slow motion dynamics in nonequilibrium phenomena are RG equations. The renormalized perturbation approach may be simpler to use than other approaches, because it does not require the use of asymptotic matching, and yields practically superior approximations.Comment: 13 pages, plain tex + uiucmac.tex (available from babbage.sissa.it), one PostScript figure appended at end. Or (easier) get compressed postscript file by anon ftp from gijoe.mrl.uiuc.edu (128.174.119.153), file /pub/rg_sing_prl.ps.

An ANGPTL4-ceramide-protein kinase Cζ axis mediates chronic glucocorticoid exposure-induced hepatic steatosis and hypertriglyceridemia in mice.

Chronic or excess glucocorticoid exposure causes lipid disorders such as hypertriglyceridemia and hepatic steatosis. Angptl4 (angiopoietin-like 4), a primary target gene of the glucocorticoid receptor in hepatocytes and adipocytes, is required for hypertriglyceridemia and hepatic steatosis induced by the synthetic glucocorticoid dexamethasone. Angptl4 has also been shown to be required for dexamethasone-induced hepatic ceramide production. Here, we further examined the role of ceramide-mediated signaling in hepatic dyslipidemia caused by chronic glucocorticoid exposure. Using a stable isotope-labeling technique, we found that dexamethasone treatment induced the rate of hepatic de novo lipogenesis and triglyceride synthesis. These dexamethasone responses were compromised in Angptl4-null mice (Angptl4-/-). Treating mice with myriocin, an inhibitor of the rate-controlling enzyme of de novo ceramide synthesis, serine palmitoyltransferase long-chain base subunit 1 (SPTLC1)/SPTLC2, decreased dexamethasone-induced plasma and liver triglyceride levels in WT but not Angptl4-/- mice. We noted similar results in mice infected with adeno-associated virus-expressing small hairpin RNAs targeting Sptlc2. Protein phosphatase 2 phosphatase activator (PP2A) and protein kinase Cζ (PKCζ) are two known downstream effectors of ceramides. We found here that mice treated with an inhibitor of PKCζ, 2-acetyl-1,3-cyclopentanedione (ACPD), had lower levels of dexamethasone-induced triglyceride accumulation in plasma and liver. However, small hairpin RNA-mediated targeting of the catalytic PP2A subunit (Ppp2ca) had no effect on dexamethasone responses on plasma and liver triglyceride levels. Overall, our results indicate that chronic dexamethasone treatment induces an ANGPTL4-ceramide-PKCζ axis that activates hepatic de novo lipogenesis and triglyceride synthesis, resulting in lipid disorders

Exponentially Improving the Complexity of Simulating the Weisfeiler-Lehman Test with Graph Neural Networks

Recent work shows that the expressive power of Graph Neural Networks (GNNs) in distinguishing non-isomorphic graphs is exactly the same as that of the Weisfeiler-Lehman (WL) graph test. In particular, they show that the WL test can be simulated by GNNs. However, those simulations involve neural networks for the 'combine' function of size polynomial or even exponential in the number of graph nodes $n$, as well as feature vectors of length linear in $n$. We present an improved simulation of the WL test on GNNs with \emph{exponentially} lower complexity. In particular, the neural network implementing the combine function in each node has only a polylogarithmic number of parameters in $n$, and the feature vectors exchanged by the nodes of GNN consists of only $O(\log n)$ bits. We also give logarithmic lower bounds for the feature vector length and the size of the neural networks, showing the (near)-optimality of our construction.Comment: 22 pages,5 figures, accepted at NeurIPS 202

Novel components of the Toxoplasma inner membrane complex revealed by BioID.

UNLABELLED:The inner membrane complex (IMC) of Toxoplasma gondii is a peripheral membrane system that is composed of flattened alveolar sacs that underlie the plasma membrane, coupled to a supporting cytoskeletal network. The IMC plays important roles in parasite replication, motility, and host cell invasion. Despite these central roles in the biology of the parasite, the proteins that constitute the IMC are largely unknown. In this study, we have adapted a technique named proximity-dependent biotin identification (BioID) for use in T. gondii to identify novel components of the IMC. Using IMC proteins in both the alveoli and the cytoskeletal network as bait, we have uncovered a total of 19 new IMC proteins in both of these suborganellar compartments, two of which we functionally evaluate by gene knockout. Importantly, labeling of IMC proteins using this approach has revealed a group of proteins that localize to the sutures of the alveolar sacs that have been seen in their entirety in Toxoplasma species only by freeze fracture electron microscopy. Collectively, our study greatly expands the repertoire of known proteins in the IMC and experimentally validates BioID as a strategy for discovering novel constituents of specific cellular compartments of T. gondii. IMPORTANCE:The identification of binding partners is critical for determining protein function within cellular compartments. However, discovery of protein-protein interactions within membrane or cytoskeletal compartments is challenging, particularly for transient or unstable interactions that are often disrupted by experimental manipulation of these compartments. To circumvent these problems, we adapted an in vivo biotinylation technique called BioID for Toxoplasma species to identify binding partners and proximal proteins within native cellular environments. We used BioID to identify 19 novel proteins in the parasite IMC, an organelle consisting of fused membrane sacs and an underlying cytoskeleton, whose protein composition is largely unknown. We also demonstrate the power of BioID for targeted discovery of proteins within specific compartments, such as the IMC cytoskeleton. In addition, we uncovered a new group of proteins localizing to the alveolar sutures of the IMC. BioID promises to reveal new insights on protein constituents and interactions within cellular compartments of Toxoplasma

S-matrix for magnons in the D1-D5 system

We show that integrability and symmetries of the near horizon geometry of the D1-D5 system determine the S-matrix for the scattering of magnons with polarizations in AdS3 $\times$ S3 completely up to a phase. Using semi-classical methods we evaluate the phase to the leading and to the one-loop approximation in the strong coupling expansion. We then show that the phase obeys the unitarity constraint implied by the crossing relations to the one-loop order. We also verify that the dispersion relation obeyed by these magnons is one-loop exact at strong coupling which is consistent with their BPS nature.Comment: 40 pages, Latex, Role of Virasoro constraints clarified, version matches with published versio