Diabetes Aggravates Periodontitis by Limiting Repair Through Enhanced Inflammation

Periodontitis is the most common lytic bone disease and one of the first clinical manifestations of diabetes. Diabetes increases the risk of periodontitis. The aim of the present study was to examine mechanisms by which diabetes aggravates periodontitis. Ligature-induced periodontitis was examined in Goto-Kakizaki rats with type 2 diabetes. A tumor necrosis factor (TNF)-specificinhibitor, pegsunercept, was applied to diabetic rats after the onset of periodontal disease. Interferon-γ (IFN-γ), TNF-α, interleukin-1 β (IL-1β), fibroblast growth factor-2 (FGF-2), transforming growth factor beta-1 (TGFβ-1), bone morphogenetic protein-2 (BMP-2), and BMP-6 were measured by real-time RT-PCR, and histological sections were examined for leukocyte infiltration and several parameters related to bone resorption and formation. Inflammation was prolonged in diabetic rats and was reversed by the TNF inhibitor, which reduced cytokine mRNA levels, leukocyte infiltration, and osteoclasts. In contrast, new bone and osteoid formation and osteoblast numbers were increased significantly vs. untreated diabetic animals. TNF inhibition in diabetic animals also reduced apoptosis, increased proliferation of bone-lining cells, and increased mRNA levels of FGF-2, TGFβ-1, BMP-2, and BMP-6. Thus, diabetes prolongs inflammation and osteoclastogenesis in periodontitis and through TNF limits the normal reparative process by negatively modulating factors that regulate bone. © FASEB

Transient receptor potential canonical 5 channels plays an essential role in hepatic dyslipidemia associated with cholestasis.

Transient receptor potential canonical 5 (TRPC5), a calcium-permeable, non-selective cation channel is expressed in the periphery, but there is limited knowledge of its regulatory roles in vivo. Endogenous modulators of TRPC5 include a range of phospholipids that have an established role in liver disease, including lysophosphatidylcholine (LPC). Cholestasis is characterized by impairment of excretion of bile acids, leading to elevation of hepatic bile acids. We investigated the contribution of TRPC5 in a murine model of cholestasis. Wild-type (WT) and TRPC5 knock-out (KO) mice were fed a diet supplemented with 0.5% cholic acid (CA) for 21 days. CA-diet supplementation resulted in enlargement of the liver in WT mice, which was ameliorated in TRPC5 KO mice. Hepatic bile acid and lipid content was elevated in WT mice, with a reduction observed in TRPC5 KO mice. Consistently, liver enzymes were significantly increased in cholestatic WT mice and significantly blunted in TRPC5 KO mice. Localized dyslipidaemia, secondary to cholestasis, was investigated utilizing a selected lipid analysis. This revealed significant perturbations in the lipid profile following CA-diet feeding, with increased cholesterol, triglycerides and phospholipids, in WT, but not TRPC5 KO mice. Our results suggest that activation of TRPC5 contributes to the development of cholestasis and associated dyslipidemia. Modulation of TRPC5 activity may present as a novel therapeutic target for liver disease

NF-κB perturbation reveals unique immunomodulatory functions in Prx1 + Fibroblasts that Promote Development of Atopic Dermatitis

Skin is composed of diverse cell populations that cooperatively maintain homeostasis. Up-regulation of the nuclear factor кB (NF-кB) pathway may lead to the development of chronic inflammatory disorders of the skin, but its role during the early events remains unclear. Through analysis of single-cell RNA sequencing data via iterative random forest leave one out prediction, an explainable artificial intelligence method, we identified an immunoregulatory role for a unique paired related homeobox-1 (Prx1)+ fibroblast subpopulation. Disruption of Ikkb-NF-кB under homeostatic conditions in these fibroblasts paradoxically induced skin inflammation due to the overexpression of C-C motif chemokine ligand 11 (CCL11; or eotaxin-1) characterized by eosinophil infiltration and a subsequent TH2 immune response. Because the inflammatory phenotype resembled that seen in human atopic dermatitis (AD), we examined human AD skin samples and found that human AD fibroblasts also overexpressed CCL11 and that perturbation of Ikkb-NF-кB in primary human dermal fibroblasts up-regulated CCL11. Monoclonal antibody treatment against CCL11 was effective in reducing the eosinophilia and TH2 inflammation in a mouse model. Together, the murine model and human AD specimens point to dysregulated Prx1+ fibroblasts as a previously unrecognized etiologic factor that may contribute to the pathogenesis of AD and suggest that targeting CCL11 may be a way to treat AD-like skin lesions. © 2022 The Authors, some rights reserve

A (Running) Bolt for New Reasons

We construct a four-parameter family of smooth, horizonless, stationary solutions of ungauged five-dimensional supergravity by using the four-dimensional Euclidean Schwarzschild metric as a base space and "magnetizing" its bolt. We then generalize this to a five-parameter family based upon the Euclidean Kerr-Taub-Bolt. These "running Bolt" solutions are necessarily non-static. They also have the same charges and mass as a non-extremal black hole with a classically-large horizon area. Moreover, in a certain regime their mass can decrease as their charges increase. The existence of these solutions supports the idea that the singularities of non-extremal black holes are resolved by low-mass modes that correct the singularity of the classical black hole solution on large (horizon-sized) scales.Comment: 25 pages, 3 figures, LaTeX; v2: minor changes, references adde

Multi-Center non-BPS Black Holes - the Solution

We construct multi-center, non-supersymmetric four-dimensional solutions describing a rotating anti-D6-D2 black hole and an arbitrary number of D4-D2-D0 black holes in a line. These solutions correspond to an arbitrary number of extremal non-BPS black rings in a Taub-NUT space with a rotating three-charge black hole in the middle. The positions of the centers are determined by solving a set of "bubble" or "integrability" equations that contain cubic polynomials of the inter-center distance, and that allow scaling solutions even when the total four-dimensional angular momentum of the scaling centers is non-zero.Comment: 16 pages, LaTe

Non-extremal Black Hole Microstates: Fuzzballs of Fire or Fuzzballs of Fuzz ?

We construct the first family of microstate geometries of near-extremal black holes, by placing metastable supertubes inside certain scaling supersymmetric smooth microstate geometries. These fuzzballs differ from the classical black hole solution macroscopically at the horizon scale, and for certain probes the fluctuations between various fuzzballs will be visible as thermal noise far away from the horizon. We discuss whether these fuzzballs appear to infalling observers as fuzzballs of fuzz or as fuzzballs of fire. The existence of these solutions suggests that the singularity of non-extremal black holes is resolved all the way to the outer horizon and this "backwards in time" singularity resolution can shed light on the resolution of spacelike cosmological singularities.Comment: 34 pages, 10 figure

New instability of non-extremal black holes: spitting out supertubes

We search for stable bound states of non-extremal rotating three-charge black holes in five dimensions (Cvetic-Youm black holes) and supertubes. We do this by studying the potential of supertube probes in the non-extremal black hole background and find that generically the marginally bound state of the supersymmetric limit becomes metastable and disappears with non-extremality (higher temperature). However near extremality there is a range of parameters allowing for stable bound states, which have lower energy than the supertube-black hole merger. Angular momentum is crucial for this effect. We use this setup in the D1-D5 decoupling limit to map a thermodynamic instability of the CFT (a new phase which is entropically dominant over the black hole phase) to a tunneling instability of the black hole towards the supertube-black hole bound state. This generalizes the results of ArXiv:1108.0411 [hep-th], which mapped an entropy enigma in the bulk to the dual CFT in a supersymmetric setup.Comment: 28 pages + appendix, 15 figures, v2: References added, typos corrected. Version published in JHE

Limits of Life and the Habitability of Mars: The ESA Space Experiment BIOMEX on the ISS

BIOMEX (BIOlogy and Mars EXperiment) is an ESA/Roscosmos space exposure experiment housed within the exposure facility EXPOSE-R2 outside the Zvezda module on the International Space Station (ISS). The design of the multiuser facility supports—among others—the BIOMEX investigations into the stability and level of degradation of space-exposed biosignatures such as pigments, secondary metabolites, and cell surfaces in contact with a terrestrial and Mars analog mineral environment. In parallel, analysis on the viability of the investigated organisms has provided relevant data for evaluation of the habitability of Mars, for the limits of life, and for the likelihood of an interplanetary transfer of life (theory of lithopanspermia). In this project, lichens, archaea, bacteria, cyanobacteria, snow/permafrost algae, meristematic black fungi, and bryophytes from alpine and polar habitats were embedded, grown, and cultured on a mixture of martian and lunar regolith analogs or other terrestrial minerals. The organisms and regolith analogs and terrestrial mineral mixtures were then exposed to space and to simulated Mars-like conditions by way of the EXPOSE-R2 facility. In this special issue, we present the first set of data obtained in reference to our investigation into the habitability of Mars and limits of life. This project was initiated and implemented by the BIOMEX group, an international and interdisciplinary consortium of 30 institutes in 12 countries on 3 continents. Preflight tests for sample selection, results from ground-based simulation experiments, and the space experiments themselves are presented and include a complete overview of the scientific processes required for this space experiment and postflight analysis. The presented BIOMEX concept could be scaled up to future exposure experiments on the Moon and will serve as a pretest in low Earth orbit

Excitations in the deformed D1D5 CFT

We perform some simple computations for the first order deformation of the D1D5 CFT off its orbifold point. It had been shown earlier that under this deformation the vacuum state changes to a squeezed state (with the further action of a supercharge). We now start with states containing one or two initial quanta and write down the corresponding states obtained under the action of deformation operator. The result is relevant to the evolution of an initial excitation in the CFT dual to the near extremal D1D5 black hole: when a left and a right moving excitation collide in the CFT, the deformation operator spreads their energy over a larger number of quanta, thus evolving the state towards the infrared.Comment: 26 pages, Latex, 4 figure

Deforming the D1D5 CFT away from the orbifold point

The D1D5 brane bound state is believed to have an `orbifold point' in its moduli space which is the analogue of the free Yang Mills theory for the D3 brane bound state. The supergravity geometry generated by D1 and D5 branes is described by a different point in moduli space, and in moving towards this point we have to deform the CFT by a marginal operator: the `twist' which links together two copies of the CFT. In this paper we find the effect of this deformation operator on the simplest physical state of the CFT -- the Ramond vacuum. The twist deformation leads to a final state that is populated by pairs of excitations like those in a squeezed state. We find the coefficients characterizing the distribution of these particle pairs (for both bosons and fermions) and thus write this final state in closed form.Comment: 30 pages, 4 figures, Late