The Indirect Search for Dark Matter from the centre of the Galaxy with the Fermi LAT

Dark matter (DM) constitutes around a 25% of the Universe, while baryons only a 4%. DM can be reasonably assumed to be made of particles, and many theories (Super-symmetry, Universal Extra Dimensions, etc.) predict Weakly Interacting Massive Particles (WIMPs) as natural DM candidates at the weak scale. Self-annihilation (or decay) of WIMPs might produce secondary gamma-rays, via hadronization or as final state radiation. Since its launch in the 2008, the Large Area Telescope on-board of the Fermi gamma-ray Space Telescope has detected the largest amount of gamma-rays to date, in the 20MeV 300GeV energy range, allowing to perform a very sensitive indirect experimental search for DM (by means of high-energy gamma-rays). DM forms large gravitationally bounded structures, the halos, which can host entire galaxies, such as the Milky Way. The DM distribution in the central part of the halos is not experimentally know, despite a very large density enhancement might be present. As secondary gamma rays production is very sensitive to WIMP density, a very effective search can be performed from the regions where the largest density is expected. Therefore the information provided by the DM halo N-body simulations are crucial. The largest gamma-ray signal from DM annihilation is expected from the centre of the Galaxy. In the same region a large gamma-ray background is produced by bright discrete sources and the cosmic-rays interacting with the interstellar gas and the photons fields. Here we report an update of the indirect search for DM from the Galactic Center (GC).Comment: 6 pages, 2 figures. Invited talk presented at the Workshop "SciNeGHE 2010", September 8-10, 2010, Trieste, Italy. To appear in Il Nuovo Cimento C - Colloquia on physic

Cartilage and bone regeneration: how close are we to bedside?

The treatment/regeneration of bone and cartilage diseases or defects, whether induced by rheumatism, joint dysplasia, trauma, or surgery presents great challenges that have not been fully solved by the current therapies. In the last few years, tissue engineering and regenerative medicine have been proposing advanced tools and technologies for bone and cartilage tissue regeneration, and some of which have successfully reached the market. Beyond the source of cells, the creation of superior structures for replacing defective bone and cartilage requires strong research in biomechanical signaling and synthesis of advanced biomaterials to mimic human tissues at the most varied levels. Natural and synthetic polymers, bioresorbable inorganic materials, and composites have been investigated for its potential as scaffolding materials with enhanced mechanical and biological properties. Porous scaffolds, hydrogels, and fibers are the most commonly biomimetic structures used for bone and cartilage tissue engineering. Herein, the concepts and current treatment strategies for bone and cartilage repair, as well as biomimetic strategies for bone and cartilage tissue engineering are overviewed. A global review of the ongoing clinical trials and of the scaffolds commercially available for the repair of osteochondral tissue is also presented.(undefined

Novel bilayered Gellan gum/Gellan gum hydroxyapatite scaffolds for osteochondral tissue engineering applications

Osteoarthritis is a major cause of disability during aging. By the age of 60, close to 100% of the population will have histologic changes of degeneration in their knee cartilage (Loeser, 2000). Because of its avascular nature, cartilage has little capacity to self-regenerate. Despite the progress already achieved in osteochondral regeneration, some limitations have to be overcome. The formation of fibrocartilage has to be avoided and the innervation has to be improved. Further, one main feature to be promoted is the induction of vascularization in the bony part but not in the cartilage part and to avoid de-differentiation processes. A promising strategy could pass through the development and optimization of novel culture systems. The ideal approach could integrate scaffolds presenting regions with different physical characteristics, combined with different growth factors to support different stem cells fates, regarding the complex tissue physiology to be regenerate. This work aims to develop novel bilayered gellan gum (GG)/gellan gumhydroxyapatite (HAp) hydrogels based structures for osteochondral tissue engineering applications. Bilayered GG/GG-HAp hydrogels were produced by joining both solutions of GG 2% (w/v) with and without HAp (20% wt.) for bony and cartilage parts, respectively. The solutions were introduced into a silicone mould with 20:10 mm (height and diameter, respectively). Gelation of GG was promoted by immersion in PBS solution for 24 h. The architecture of the bilayered scaffolds was investigated by micro-computed tomography. Results have shown that the freeze-dried bilayered scaffolds composed by low acyl GG(2%(w/ v)/low acyl GG(2%(w/v)-HAp20%(w/w) possess a porosity of 83.4 ± 0.8%, pore size of 279.3 ± 38.6 lm and interconnectivity of 62.2 ± 5.4%. Degradability assays are being performed with the intent to use this system to culture human adipose derived stem cells inducing cell co-differentiation into chondrocytes and osteoblasts. Ultimately, the developed bilayered scaffolds will provide new therapeutic possibilities for the regeneration of osteochondral defects

Posterior talar process as a suitable cell source for treatment of cartilage and osteochondral defects of the talus

Osteochondral defects of the ankle are common lesions affecting the talar cartilage and subchondral bone. Current treatments include cell-based therapies but are frequently associated with donor-site morbidity. Our objective is to characterize the posterior process of the talus (SP) and the os trigonum (OT) tissues and investigate its potential as a new source of viable cells for application in tissue engineering and regenerative medicine.SP and OT tissues obtained from six patients were characterized by micro-computed tomography, and histological, histomorphometric and immunohistochemical analyses. Isolated cells proliferation and viability were evaluated by MTS assay, DNA quantification and Live/Dead staining. The TUNEL assay was performed to evaluate cell death by apoptosis. Moreover, the production of extracellular matrix was evaluated by toluidine blue staining, whereas cells phenotype was investigated by flow cytometry. Ankle explants characterization showed the presence of a cartilage tissue layer in both SP and OT tissues, which represent, at least 20% in average of the explant. The presence of type II collagen was detected in the extracellular matrix. Isolated cells presented a round morphology typical of chondrocytes. In in vitro studies, cells were viable and proliferating up to 21 days of culturing. No signs of apoptosis were detected. Flow cytometry analysis revealed that isolated cells maintained the expression of several chondrocytic markers during culturing. The results indicate that the SP and OT tissues are a reliable source of viable chondrocytes, which can find promising applications in ACI/MACI strategies with minimal concerns regarding donor zone complications.Portuguese Foundation for Science and Technology (FCT) through the project OsteoCart (Grant No. PTDC/CTM-BPC/115977/2009), Fundación MAPFRE (Ayudas a la Investigación Ignacio H. de Larramendi, Prevención, Salud y Medio Ambiente, Spain) under the project 'Preventing the progression of the knee osteoarthritis: advanced therapies combining injectable hydrogels, autologous stem cells and PRP' (Grant No. BIL/13/SA/235). This study was also carried out with the support of Fundo Europeu de Desenvolvimento Regional (FEDER) through Programa Operacional do Norte through the project Articulate (Grant No. 23189

Gellan gum-based hydrogel bilayered scaffolds for osteochondral tissue engineering

It has been shown that hydrogel bilayered scaffolds combining cartilage- and bone-like layers are most advantageous for treating osteochondral defects. In this study, it is proposed the use of low acyl gellan gum (LAGG) for developing bilayered hydrogel scaffolds for osteochondral tissue engineering. The cartilage-like layer of the GG-based bilayered hydrogel scaffolds is composed of LAGG (2 wt%). By adding a 2 wt% LAGG aqueous solution to different amounts of HAp (5-20 wt%) it was possible to produce the bone-like layer. In vitro bioactivity tests were performed by means of soaking the LAGG/LAGG-HAp hydrogel scaffolds in a simulated body fluid solution up to 14 days. Scanning electron microscopy, Fourier transform infra-red spectroscopy and X-ray diffraction analyses demonstrated that apatite formation is limited to the bone-like layer of the LAGG/LAGG-HAp bilayered hydrogel scaffolds

Validation of a small-animal PET simulation using GAMOS: a Geant4-based framework

onte Carlo-based modelling is a powerful tool to help in the design and optimization of positron emission tomography (PET) systems. The performance of these systems depends on several parameters, such as detector physical characteristics, shielding or electronics, whose effects can be studied on the basis of realistic simulated data. The aim of this paper is to validate a comprehensive study of the Raytest ClearPET small-animal PET scanner using a new Monte Carlo simulation platform which has been developed at CIEMAT (Madrid, Spain), called GAMOS (GEANT4-based Architecture for Medicine-Oriented Simulations). This toolkit, based on the GEANT4 code, was originally designed to cover multiple applications in the field of medical physics from radiotherapy to nuclear medicine, but has since been applied by some of its users in other fields of physics, such as neutron shielding, space physics, high energy physics, etc. Our simulation model includes the relevant characteristics of the ClearPET system, namely, the double layer of scintillator crystals in phoswich configuration, the rotating gantry, the presence of intrinsic radioactivity in the crystals or the storage of single events for an off-line coincidence sorting. Simulated results are contrasted with experimental acquisitions including studies of spatial resolution, sensitivity, scatter fraction and count rates in accordance with the National Electrical Manufacturers Association (NEMA) NU 4-2008 protocol. Spatial resolution results showed a discrepancy between simulated and measured values equal to 8.4% (with a maximum FWHM difference over all measurement directions of 0.5 mm). Sensitivity results differ less than 1% for a 250–750 keV energy window. Simulated and measured count rates agree well within a wide range of activities, including under electronic saturation of the system (the measured peak of total coincidences, for the mouse-sized phantom, was 250.8 kcps reached at 0.95 MBq mL−1 and the simulated peak was 247.1 kcps at 0.87 MBq mL−1). Agreement better than 3% was obtained in the scatter fraction comparison study. We also measured and simulated a mini-Derenzo phantom obtaining images with similar quality using iterative reconstruction methods. We concluded that the overall performance of the simulation showed good agreement with the measured results and validates the GAMOS package for PET applications. Furthermore, its ease of use and flexibility recommends it as an excellent tool to optimize design features or image reconstruction techniques

Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses.

Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance1-4. This phenomenon has been implicated in chemorefractory small cell lung cancer and resistance to targeted therapies5-8, but remains incompletely defined. Here, we identify a subclass of endogenous retroviruses (ERVs) that engages innate immune signaling in these cells. Stimulated 3 prime antisense retroviral coding sequences (SPARCS) are oriented inversely in 3' untranslated regions of specific genes enriched for regulation by STAT1 and EZH2. Derepression of these loci results in double-stranded RNA generation following IFN-γ exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5' long terminal repeat of the antisense ERV. Engagement of MAVS and STING activates downstream TBK1, IRF3, and STAT1 signaling, sustaining a positive feedback loop. SPARCS induction in human tumors is tightly associated with major histocompatibility complex class 1 expression, mesenchymal markers, and downregulation of chromatin modifying enzymes, including EZH2. Analysis of cell lines with high inducible SPARCS expression reveals strong association with an AXL/MET-positive mesenchymal cell state. While SPARCS-high tumors are immune infiltrated, they also exhibit multiple features of an immune-suppressed microenviroment. Together, these data unveil a subclass of ERVs whose derepression triggers pathologic innate immune signaling in cancer, with important implications for cancer immunotherapy

An in vitro approach to study effects of prebiotics and probiotics on the faecal microbiota and selected immune parameters relevant to the elderly

The aging process leads to alterations of gut microbiota and modifications to the immune response, such changes may be associated with increased disease risk. Prebiotics and probiotics can modulate microbiome changes induced by aging; however, their effects have not been directly compared. The aim of this study was to use anaerobic batch culture fermenters to assess the impact of various fermentable carbohydrates and microorganisms on the gut microbiota and selected immune markers. Elderly volunteers were used as donors for these experiments to enable relevance to an aging population. The impact of fermentation supernatants on immune markers relevant to the elderly were assessed in vitro. Levels of IL-1β, IL-6, IL-8, IL-10 and TNF-α in peripheral blood mononuclear cell culture supernatants were measured using flow cytometry. Trans-galactooligosaccharides (B-GOS) and inulin both stimulated bifidobacteria compared to other treatments (p<0.05). Fermentation supernatants taken from faecal batch cultures supplemented with B-GOS, inulin, B. bifidum, L. acidophilus and Ba. coagulans inhibited LPS induced TNF-α (p<0.05). IL-10 production, induced by LPS, was enhanced by fermentation supernatants from faecal batch cultures supplemented with B-GOS, inulin, B. bifidum, L. acidophilus, Ba. coagulans and Bac. thetaiotaomicron (p<0.05). To conclude, prebiotics and probiotics could lead to potentially beneficial effects to host health by targeting specific bacterial groups, increasing saccharolytic fermentation and decreasing inflammation associated with aging. Compared to probiotics, prebiotics led to greater microbiota modulation at the genus level within the fermenters