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

Preliminary study of light-cured hydrogel for endodontic drug delivery vehicle

AIM: Direct pulp capping is the treatment of an exposed vital pulp with a dental material to facilitate the formation of reparative dentin and maintenance of vital pulp. A bioengineered drug delivery vehicle has the potential to increase the success rate of pulp capping. The aim of this study was to develop an injectable and light-curing drug delivery vehicle for endodontic treatment including direct pulp capping.METHODS: Polyethylene glycol-maleate-citrate (PEGMC) hydrogel was synthesized as a drug delivery vehicle that is composed of PEGMC (45% w/v), acrylic acid (AA) (5% w/v), 2,2'-azobis(2-methylpropionamidine) dihydrochloride (AAPH) (0.1% w/v), and deionized water. The association between prehydrogel-solution volume and visible light-curing was examined. The cytotoxicity of the hydrogel was tested using L929 cells in a cell culture system. Ca(2+) release from the hydrogel was determined using calcium hydroxide as the incorporated medicine.RESULTS: The results showed that the light-curing time for hydrogel is comparable to composite resin. The hydrogel had cell toxicity similar to adhesive systems. Moreover, controlled Ca(2+) release was obtained from the calcium hydroxide incorporated hydrogel.CONCLUSIONS: The data suggest that hydrogel should be explored further as a promising drug delivery vehicle for vital pulp therapy and regenerative endodontics

Improved Dynamical Constraints on the Masses of the Central Black Holes in Nearby Low-mass Early-type Galactic Nuclei And the First Black Hole Determination for NGC 205

We improve the dynamical black hole (BH) mass estimates in three nearby low-mass early-type galaxies--NGC 205, NGC 5102, and NGC 5206. We use new \hst/STIS spectroscopy to fit the star formation histories of the nuclei in these galaxies, and use these measurements to create local color--mass-to-light ratio (\ml) relations. We then create new mass models from \hst~imaging and combined with adaptive optics kinematics, we use Jeans dynamical models to constrain their BH masses. The masses of the central BHs in NGC 5102 and NGC 5206 are both below one million solar masses and are consistent with our previous estimates, $9.12_{-1.53}^{+1.84}\times10^5$\Msun~and $6.31_{-2.74}^{+1.06}\times10^5$\Msun~(3$\sigma$ errors), respectively. However, for NGC 205, the improved models suggest the presence of a BH for the first time, with a best-fit mass of $6.8_{-6.7}^{+95.6}\times10^3$\Msun~(3$\sigma$ errors). This is the least massive central BH mass in a galaxy detected using any method. We discuss the possible systematic errors of this measurement in detail. Using this BH mass, the existing upper limits of both X-ray, and radio emissions in the nucleus of NGC 205 suggest an accretion rate $\lesssim$$10^{-5}$ of the Eddington rate. We also discuss the color--\mleff~relations in our nuclei and find that the slopes of these vary significantly between nuclei. Nuclei with significant young stellar populations have steeper color--\mleff~relations than some previously published galaxy color--\mleff~relations.Comment: 31 pages, 19 figures, 6 tables, Accepted to Ap

Clinical significance of VEGF-A, -C and -D expression in esophageal malignancies

Vascular endothelial growth factors ( VEGF)- A, - C and - D are members of the proangiogenic VEGF family of glycoproteins. VEGF-A is known to be the most important angiogenic factor under physiological and pathological conditions, while VEGF-C and VEGF-D are implicated in the development and sprouting of lymphatic vessels, so called lymphangiogenesis. Local tumor progression, lymph node metastases and hematogenous tumor spread are important prognostic factors for esophageal carcinoma ( EC), one of the most lethal malignancies throughout the world. We found solid evidence in the literature that VEGF expression contributes to tumor angiogenesis, tumor progression and lymph node metastasis in esophageal squamous cell carcinoma ( SCC), and many authors could show a prognostic value for VEGF-assessment. In adenocarcinoma (AC) of the esophagus angiogenic properties are acquired in early stages, particularly in precancerous lesions like Barrett's dysplasia. However, VEGF expression fails to give prognostic information in AC of the esophagus. VEGF-C and VEGF-D were detected in SCC and dysplastic lesions, but not in normal mucosa of the esophagus. VEGF-C expression might be associated with lymphatic tumor invasion, lymph node metastases and advanced disease in esophageal SCC and AC. Therapeutic interference with VEGF signaling may prove to be a promising way of anti-angiogenic co-treatment in esophageal carcinoma. However, concrete clinical data are still pending

Where to from here? A quality improvement project investigating burns treatment and rehabilitation practices in India

Abstract Objective To describe the capacity of the Indian healthcare system in providing appropriate and effective burns treatment and rehabilitation services. Results Health professionals involved in burns treatment or rehabilitation at seven hospitals from four states in India were invited to participate in consultative meetings. Existing treatment and rehabilitation strategies, barriers and enablers to patient flow across the continuum of care and details on inpatient and outpatient rehabilitation were discussed during the meetings. Seventeen health professionals from various clinical backgrounds were involved in the consultation process. Key themes highlighted (a) a lack of awareness on burn first aid at the community level, (b) a lack of human resource to treat burn injuries in hospital settings, (c) a gap in burn care training for medical staff, (d) poor hospital infrastructure and (e) a variation in treatment practices and rehabilitation services available between hospitals. A number of opportunities exist to improve burns treatment and rehabilitation in India. Improvements would most effectively be achieved through promoting multidisciplinary care across a number of facilities and service providers. Further research is required to develop context-specific burn care models, determining how these can be integrated into the Indian healthcare system

Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi's sarcoma

Emerging evidence suggests that both human stem cells and mature stromal cells can play an important role in the development and growth of human malignancies. In contrast to these tumor-promoting properties, we observed that in an in vivo model of Kaposi's sarcoma (KS), intravenously (i.v.) injected human mesenchymal stem cells (MSCs) home to sites of tumorigenesis and potently inhibit tumor growth. We further show that human MSCs can inhibit the in vitro activation of the Akt protein kinase within some but not all tumor and primary cell lines. The inhibition of Akt activity requires the MSCs to make direct cell–cell contact and can be inhibited by a neutralizing antibody against E-cadherin. We further demonstrate that in vivo, Akt activation within KS cells is potently down-regulated in areas adjacent to MSC infiltration. Finally, the in vivo tumor-suppressive effects of MSCs correlates with their ability to inhibit target cell Akt activity, and KS tumors engineered to express a constitutively activated Akt construct are no longer sensitive to i.v. MSC administration. These results suggest that in contrast to other stem cells or normal stromal cells, MSCs possess intrinsic antineoplastic properties and that this stem cell population might be of particular utility for treating those human malignancies characterized by dysregulated Akt

Nearby Early-type Galactic Nuclei at High Resolution: Dynamical Black Hole and Nuclear Star Cluster Mass Measurements

We present a detailed study of the nuclear star clusters (NSCs) and massive black holes (BHs) of four of the nearest low-mass early-type galaxies: M32, NGC 205, NGC 5102, and NGC 5206. We measure the dynamical masses of both the BHs and NSCs in these galaxies using Gemini/NIFS or VLT/SINFONI stellar kinematics, Hubble Space Telescope (HST) imaging, and Jeans anisotropic models. We detect massive BHs in M32, NGC 5102, and NGC 5206, while in NGC 205, we find only an upper limit. These BH mass estimates are consistent with previous measurements in M32 and NGC 205, while those in NGC 5102 and NGC 5206 are estimated for the first time and both found to be <106 M ⊙. This adds to just a handful of galaxies with dynamically measured sub-million M ⊙ central BHs. Combining these BH detections with our recent work on NGC 404's BH, we find that 80% (4/5) of nearby, low-mass ({10}^{9}\mbox{--}{10}^{10} M ⊙; {\sigma }_{\star }\sim 20\mbox{--}70 km s−1) early-type galaxies host BHs. Such a high occupation fraction suggests that the BH seeds formed in the early epoch of cosmic assembly likely resulted in abundant seeds, favoring a low-mass seed mechanism of the remnants, most likely from the first generation of massive stars. We find dynamical masses of the NSCs ranging from 2 to 73 × 106 M ⊙ and compare these masses to scaling relations for NSCs based primarily on photometric mass estimates. Color gradients suggest that younger stellar populations lie at the centers of the NSCs in three of the four galaxies (NGC 205, NGC 5102, and NGC 5206), while the morphology of two are complex and best fit with multiple morphological components (NGC 5102 and NGC 5206). The NSC kinematics show they are rotating, especially in M32 and NGC 5102 ($V/{\sigma }_{\star }\sim 0.7$)

The Black Hole in the Most Massive Ultracompact Dwarf Galaxy M59-UCD3

We examine the internal properties of the most massive ultracompact dwarf galaxy (UCD), M59-UCD3, by combining adaptive optics assisted near-IR integral field spectroscopy from Gemini/NIFS, and Hubble Space Telescope (HST) imaging. We use the multi-band HST imaging to create a mass model that suggests and accounts for the presence of multiple stellar populations and structural components. We combine these mass models with kinematics measurements from Gemini/NIFS to find a best-fit stellar mass-to-light ratio ($M/L$) and black hole (BH) mass using Jeans Anisotropic Models (JAM), axisymmetric Schwarzschild models, and triaxial Schwarzschild models. The best fit parameters in the JAM and axisymmetric Schwarzschild models have black holes between 2.5 and 5.9 million solar masses. The triaxial Schwarzschild models point toward a similar BH mass, but show a minimum $\chi^2$ at a BH mass of $\sim 0$. Models with a BH in all three techniques provide better fits to the central $V_{rms}$ profiles, and thus we estimate the BH mass to be $4.2^{+2.1}_{-1.7} \times 10^{6}$ M$_\odot$ (estimated 1$\sigma$ uncertainties). We also present deep radio imaging of M59-UCD3 and two other UCDs in Virgo with dynamical BH mass measurements, and compare these to X-ray measurements to check for consistency with the fundamental plane of BH accretion. We detect faint radio emission in M59cO, but find only upper limits for M60-UCD1 and M59-UCD3 despite X-ray detections in both these sources. The BH mass and nuclear light profile of M59-UCD3 suggests it is the tidally stripped remnant of a $\sim$10$^{9-10}$ M$_\odot$ galaxy.Comment: 17 pages, 14 figures, 5 table