Therapeutic molecules for osteoarthritis treatment. role of phloretin, ipriflavone and raloxifene in lipopolysaccharide induced osteoarthritic chondrocytes

Purpose: The search of novel molecules for the treatment of osteoarthritis (OA) is complex as any new therapeutic approach should encompass these requirements: inhibition of cartilage degradation, protection of bone and inhibition of inflammation. In the last years, different drugs have been proposed though most of them did not succeed in fulfil these requirements. Moreover, few of them have been encapsulated in drug delivery systems to improve their therapeutic potential to achieve a sustained or controlled release compared to the administration of equivalent doses of the free compounds. Nanoscience has arisen in the last decades as a potential field of study in drug delivery because nanomaterials may overcome the main current limitations to achieve an efficient and localized drug delivery by improving the targeted delivery and providing a sustained or controlled delivery to prolong the therapeutic effect. On the other hand, different polyphenols and aromatic organic compounds are known to possess anti-inflammatory, antioxidant and bone density-building properties..

Therapeutic vulnerability to PARP1,2 inhibition in RB1-mutant osteosarcoma

Loss-of-function mutations in the RB1 tumour suppressor are key drivers in cancer, including osteosarcoma. RB1 loss-of-function compromises genome-maintenance and hence could yield vulnerability to therapeutics targeting such processes. Here we demonstrate selective hypersensitivity to clinically-approved inhibitors of Poly-ADP-Polymerase1,2 inhibitors (PARPi) in RB1-defective cancer cells, including an extended panel of osteosarcoma-derived lines. PARPi treatment results in extensive cell death in RB1-defective backgrounds and prolongs survival of mice carrying human RB1-defective osteosarcoma grafts. PARPi sensitivity is not associated with canonical homologous recombination defect (HRd) signatures that predict PARPi sensitivity in cancers with BRCA1,2 loss, but is accompanied by rapid activation of DNA replication checkpoint signalling, and active DNA replication is a prerequisite for sensitivity. Importantly, sensitivity in backgrounds with natural or engineered RB1 loss surpasses that seen in BRCA-mutated backgrounds where PARPi have established clinical benefit. Our work provides evidence that PARPi sensitivity extends beyond cancers identifiable by HRd and advocates PARP1,2 inhibition as a personalised strategy for RB1-mutated osteosarcoma and other cancers

Flower Development as an Interplay between Dynamical Physical Fields and Genetic Networks

In this paper we propose a model to describe the mechanisms by which undifferentiated cells attain gene configurations underlying cell fate determination during morphogenesis. Despite the complicated mechanisms that surely intervene in this process, it is clear that the fundamental fact is that cells obtain spatial and temporal information that bias their destiny. Our main hypothesis assumes that there is at least one macroscopic field that breaks the symmetry of space at a given time. This field provides the information required for the process of cell differentiation to occur by being dynamically coupled to a signal transduction mechanism that, in turn, acts directly upon the gene regulatory network (GRN) underlying cell-fate decisions within cells. We illustrate and test our proposal with a GRN model grounded on experimental data for cell fate specification during organ formation in early Arabidopsis thaliana flower development. We show that our model is able to recover the multigene configurations characteristic of sepal, petal, stamen and carpel primordial cells arranged in concentric rings, in a similar pattern to that observed during actual floral organ determination. Such pattern is robust to alterations of the model parameters and simulated failures predict altered spatio-temporal patterns that mimic those described for several mutants. Furthermore, simulated alterations in the physical fields predict a pattern equivalent to that found in Lacandonia schismatica, the only flowering species with central stamens surrounded by carpels

The Tordera Delta, a hotspot to storm impacts in the coast northwards ofBarcelona (NW Mediterranean)

The Catalan coast, as most of the developed Mediterranean coastal zone, can be characterized as a high-risk area to the impact of storms due to the large concentrationof values together with the dominance of eroding shorelines. In consequence, any long-term coastal management scheme must include a risk analysis to permitdecision makers to better allocate resources. This can be done in a nested approach in which hotspots are first identified along the coast at a regional scale andsecondly, they are further analysed to produce dedicated risk reduction strategies. In this work, we apply the methodology developed within the RISC-KIT project foridentifying and analysing coastal hotspots in the Catalan coast as a test for applying it to Mediterranean conditions. Obtained results show that this methodology isvery efficient in identifying hotspots of storm-induced flooding and erosion at a regional scale. The adoption of the response approach resulted in the direct assessmentof the hazards' probability distributions, which allowed for the selection of the severity of the hotspots to be identified. When a given coastal stretch behaves as ahotspot for both hazards, it is identified as a very highly-sensitive area to storm impacts. In the study area, the Tordera Delta possesses this condition of very high“hotspotness.” This has been demonstrated by the large and frequent damages suffered by the site during the past decades. The paper analyses different aspects related to the risk management of this area, including stakeholder actions

Information flow during gene activation by signaling molecules: ethylene transduction in Arabidopsis cells as a study system

<p>Abstract</p> <p>Background</p> <p>We study root cells from the model plant <it>Arabidopsis thaliana </it>and the communication channel conformed by the ethylene signal transduction pathway. A basic equation taken from our previous work relates the probability of expression of the gene <it>ERF</it>1 to the concentration of ethylene.</p> <p>Results</p> <p>The above equation is used to compute the Shannon entropy (<it>H</it>) or degree of uncertainty that the genetic machinery has during the decoding of the message encoded by the ethylene specific receptors embedded in the endoplasmic reticulum membrane and transmitted into the nucleus by the ethylene signaling pathway. We show that the amount of information associated with the expression of the master gene <it>ERF</it>1 (Ethylene Response Factor 1) can be computed. Then we examine the system response to sinusoidal input signals with varying frequencies to determine if the cell can distinguish between different regimes of information flow from the environment. Our results demonstrate that the amount of information managed by the root cell can be correlated with the frequency of the input signal.</p> <p>Conclusion</p> <p>The ethylene signaling pathway cuts off very low and very high frequencies, allowing a window of frequency response in which the nucleus reads the incoming message as a sinusoidal input. Out of this window the nucleus reads the input message as an approximately non-varying one. From this frequency response analysis we estimate: a) the gain of the system during the synthesis of the protein ERF1 (~-5.6 dB); b) the rate of information transfer (0.003 bits) during the transport of each new ERF1 molecule into the nucleus and c) the time of synthesis of each new ERF1 molecule (~21.3 s). Finally, we demonstrate that in the case of the system of a single master gene (<it>ERF</it>1) and a single slave gene (<it>HLS</it>1), the total Shannon entropy is completely determined by the uncertainty associated with the expression of the master gene. A second proposition shows that the Shannon entropy associated with the expression of the <it>HLS</it>1 gene determines the information content of the system that is related to the interaction of the antagonistic genes <it>ARF</it>1, 2 and <it>HLS</it>1.</p

Towards the high-accuracy determination of the 238U fission cross section at the threshold region at CERN - N-TOF

The 238U fission cross section is an international standard beyond 2 MeV where the fission plateau starts. However, due to its importance in fission reactors, this cross-section should be very accurately known also in the threshold region below 2 MeV. The 238U fission cross section has been measured relative to the 235U fission cross section at CERN - n-TOF with different detection systems. These datasets have been collected and suitably combined to increase the counting statistics in the threshold region from about 300 keV up to 3 MeV. The results are compared with other experimental data, evaluated libraries, and the IAEA standards

The Sensitivity of HAWC to High-Mass Dark Matter Annihilations

The High Altitude Water Cherenkov (HAWC) observatory is a wide field-of-view detector sensitive to gamma rays of 100 GeV to a few hundred TeV. Located in central Mexico at 19 degrees North latitude and 4100 m above sea level, HAWC will observe gamma rays and cosmic rays with an array of water Cherenkov detectors. The full HAWC array is scheduled to be operational in Spring 2015. In this paper, we study the HAWC sensitivity to the gamma-ray signatures of high-mass (multi- TeV) dark matter annihilation. The HAWC observatory will be sensitive to diverse searches for dark matter annihilation, including annihilation from extended dark matter sources, the diffuse gamma-ray emission from dark matter annihilation, and gamma-ray emission from non-luminous dark matter subhalos. Here we consider the HAWC sensitivity to a subset of these sources, including dwarf galaxies, the M31 galaxy, the Virgo cluster, and the Galactic center. We simulate the HAWC response to gamma rays from these sources in several well-motivated dark matter annihilation channels. If no gamma-ray excess is observed, we show the limits HAWC can place on the dark matter cross-section from these sources. In particular, in the case of dark matter annihilation into gauge bosons, HAWC will be able to detect a narrow range of dark matter masses to cross-sections below thermal. HAWC should also be sensitive to non-thermal cross-sections for masses up to nearly 1000 TeV. The constraints placed by HAWC on the dark matter cross-section from known sources should be competitive with current limits in the mass range where HAWC has similar sensitivity. HAWC can additionally explore higher dark matter masses than are currently constrained.Comment: 15 pages, 4 figures, version to be published in PR