The Tyrosine Kinase Inhibitor Dasatinib Induces a Marked Adipogenic Differentiation of Human Multipotent Mesenchymal Stromal Cells

BACKGROUND: The introduction of specific BCR-ABL inhibitors in chronic myelogenous leukemia therapy has entirely mutated the prognosis of this hematologic cancer from being a fatal disorder to becoming a chronic disease. Due to the probable long lasting treatment with tyrosine-kinase inhibitors (TKIs), the knowledge of their effects on normal cells is of pivotal importance. DESIGN AND METHODS: We investigated the effects of dasatinib treatment on human bone marrow-derived mesenchymal stromal cells (MSCs). RESULTS: Our findings demonstrate, for the first time, that dasatinib induces MSCs adipocytic differentiation. Particularly, when the TKI is added to the medium inducing osteogenic differentiation, a high MSCs percentage acquires adipocytic morphology and overexpresses adipocytic specific genes, including PPARγ, CEBPα, LPL and SREBP1c. Dasatinib also inhibits the activity of alkaline phosphatase, an osteogenic marker, and remarkably reduces matrix mineralization. The increase of PPARγ is also confirmed at protein level. The component of osteogenic medium required for dasatinib-induced adipogenesis is dexamethasone. Intriguingly, the increase of adipocytic markers is also observed in MSCs treated with dasatinib alone. The TKI effect is phenotype-specific, since fibroblasts do not undergo adipocytic differentiation or PPARγ increase. CONCLUSIONS: Our data demonstrate that dasatinib treatment affects bone marrow MSCs commitment and suggest that TKIs therapy might modify normal phenotypes with potential significant negative consequences

The QUaD Galactic Plane Survey. I. Maps and Analysis of Diffuse Emission

We present a survey of ~800 deg$^{2}$ of the galactic plane observed with the QUaD telescope. The primary products of the survey are maps of Stokes I, Q, and U parameters at 100 and 150 GHz, with spatial resolution of 5' and 3'.5, respectively. Two regions are covered, spanning approximately 245°-295° and 315°-5° in the galactic longitude l and –4° < b < +4° in the galactic latitude b. At 0°.02 square pixel size, the median sensitivity is 74 and 107 kJy sr$^{–1}$ at 100 GHz and 150 GHz respectively in I, and 98 and 120 kJy sr$^{–1}$ for Q and U. In total intensity, we find an average spectral index of α = 2.35 ± 0.01(stat) ± 0.02(sys) for |b| ≤ 1°, indicative of emission components other than thermal dust. A comparison to published dust, synchrotron, and free-free models implies an excess of emission in the 100 GHz QUaD band, while better agreement is found at 150 GHz. A smaller excess is observed when comparing QUaD 100 GHz data to the WMAP five-year W band; in this case, the excess is likely due to the wider bandwidth of QUaD. Combining the QUaD and WMAP data, a two-component spectral fit to the inner galactic plane (|b| ≤ 1°) yields mean spectral indices of α s = –0.32 ± 0.03 and α$_{d}$ = 2.84 ± 0.03; the former is interpreted as a combination of the spectral indices of synchrotron, free-free, and dust, while the second is largely attributed to the thermal dust continuum. In the same galactic latitude range, the polarization data show a high degree of alignment perpendicular to the expected galactic magnetic field direction, and exhibit mean polarization fraction 1.38 ± 0.08(stat) ± 0.1(sys)% at 100 GHz and 1.70 ± 0.06(stat) ± 0.1(sys)% at 150 GHz. We find agreement in polarization fraction between QUaD 100 GHz and the WMAP W band, the latter giving 1.1% ± 0.4%.Astronom

Parameter Estimation From Improved Measurements of the Cosmic Microwave Background From QUaD

We evaluate the contribution of cosmic microwave background (CMB) polarization spectra to cosmological parameter constraints. We produce cosmological parameters using high-quality CMB polarization data from the ground-based QUaD experiment and demonstrate for the majority of parameters that there is significant improvement on the constraints obtained from satellite CMB polarization data. We split a multi-experiment CMB data set into temperature and polarization subsets and show that the best-fit confidence regions for the ΛCDM six-parameter cosmological model are consistent with each other, and that polarization data reduces the confidence regions on all parameters. We provide the best limits on parameters from QUaD EE/BB polarization data and we find best-fit parameters from the multi-experiment CMB data set using the optimal pivot scale of k$_{p}$ = 0.013 Mpc$^{–1}$ to be {h$^{2}$Ω$_{c}$, h$^{2}$Ω$_{b}$, H$_{0}$, A$_{s}$, n$_{s}$, τ} = {0.113, 0.0224, 70.6, 2.29 × 10$^{-9}$, 0.960, 0.086}.Astronom

Periodontal status of rheumatoid arthritis patients in khartoum state

<p>Abstract</p> <p>Background</p> <p>Few studies have investigated the periodontal condition among Rheumatoid arthritis in Sudan. The present study described the periodontal condition among Sudanese patients suffering from rheumatoid arthritis and to compare them with those of non-rheumatic subjects.</p> <p>Methods</p> <p>A group of eighty rheumatoid arthritis patients was selected from Patient's Rheumatoid Clinics in Khartoum State during the period of January to May 2010. A control group of eighty patients with the same age and gender was selected for the study. Both Rheumatoid arthritis patients and the control group were examined for their plaque index, gingival index, and clinical attachment loss.</p> <p>Results</p> <p>The results revealed that there were no significant differences in plaque and gingival index among study and control groups, with mean plaque index of (1.25 ± 0.4) for patients and (1.17 ± 0.28) for the control group (p-value is 0.3597). The mean gingival index was (1.2 ± 0.24) for the patients and (1.2 ± 0.33) for the control (p = is 0.3049). The results showed statistically significant differences in clinical attachment loss between study and control groups, with mean clinical attachment loss of (1.03 ± 0.95) for the study group and (0.56 ± 0.63) for the control group (p = 0.0002). The study revealed that no association exists between the type of drug used to treat rheumatoid arthritis (NSAIDs & DMARDs) and the periodontal parameters (plaque index, gingival index, and clinical attachment loss).</p> <p>Conclusion</p> <p>A significant relationship between periodontal disease and Rheumatoid Arthritis does exist, but no difference between plaque and gingival index has been detected among study and control groups.</p

The mechanisms of humic substances self-assembly with biological molecules: The case study of the prion protein

Humic substances (HS) are the largest constituent of soil organic matter and are considered as a key component of the terrestrial ecosystem. HS may facilitate the transport of organic and inorganic molecules, as well as the sorption interactions with environmentally relevant proteins such as prions. Prions enter the environment through shedding from live hosts, facilitating a sustained incidence of animal prion diseases such as Chronic Wasting Disease and scrapie in cervid and ovine populations, respectively. Changes in prion structure upon environmental exposure may be significant as they can affect prion infectivity and disease pathology. Despite its relevance, the mechanisms of prion interaction with HS are still not completely understood. The goal of this work is to advance a structural-level picture of the encapsulation of recombinant, non-infectious, prion protein (PrP) into different natural HS. We observed that PrP precipitation upon addition of HS is mainly driven by a mechanism of “salting-out” whereby PrP molecules are rapidly removed from the solution and aggregate in insoluble adducts with humic molecules. Importantly, this process does not alter the protein folding since insoluble PrP retains its α-helical content when in complex with HS. The observed ability of HS to promote PrP insolubilization without altering its secondary structure may have potential relevance in the context of “prion ecology”. These results suggest that soil organic matter interacts with prions possibly without altering the protein structures. This may facilitate prions preservation from biotic and abiotic degradation leading to their accumulation in the environment

Addressing the climate challenge

In 2021, colleagues from across the University of Birmingham community were invited to write articles about topics relevant to the COP26 climate change summit. In this series of articles, experts from across many different disciplines provide new insight and evidence on how we might all understand and tackle climate change

Fusion Learning Colloquium 2022 - Proceedings

This is the proceedings of the 2022 Fusion Learning Colloquium held at Bournemouth University in the UK

Early phase of plasticity-related gene regulation and SRF dependent transcription in the hippocampus

Hippocampal organotypic cultures are a highly reliable in vitro model for studying neuroplasticity: in this paper, we analyze the early phase of the transcriptional response induced by a 20 \ub5M gabazine treatment (GabT), a GABA-Ar antagonist, by using Affymetrix oligonucleotide microarray, RT-PCR based time-course and chromatin-immuno-precipitation. The transcriptome profiling revealed that the pool of genes up-regulated by GabT, besides being strongly related to the regulation of growth and synaptic transmission, is also endowed with neuro-protective and pro-survival properties. By using RT-PCR, we quantified a time-course of the transient expression for 33 of the highest up-regulated genes, with an average sampling rate of 10 minutes and covering the time interval [10 3690] minutes. The cluster analysis of the time-course disclosed the existence of three different dynamical patterns, one of which proved, in a statistical analysis based on results from previous works, to be significantly related with SRF-dependent regulation (p-value<0.05). The chromatin immunoprecipitation (chip) assay confirmed the rich presence of working CArG boxes in the genes belonging to the latter dynamical pattern and therefore validated the statistical analysis. Furthermore, an in silico analysis of the promoters revealed the presence of additional conserved CArG boxes upstream of the genes Nr4a1 and Rgs2. The chip assay confirmed a significant SRF signal in the Nr4a1 CArG box but not in the Rgs2 CArG box

Search for electron antineutrino appearance in a long-baseline muon antineutrino beam

Electron antineutrino appearance is measured by the T2K experiment in an accelerator-produced antineutrino beam, using additional neutrino beam operation to constrain parameters of the Pontecorvo-Maki-Nakagawa-Sakata (PMNS) mixing matrix. T2K observes 15 candidate electron antineutrino events with a background expectation of 9.3 events. Including information from the kinematic distribution of observed events, the hypothesis of no electron antineutrino appearance is disfavored with a significance of 2.40σ and no discrepancy between data and PMNS predictions is found. A complementary analysis that introduces an additional free parameter which allows non-PMNS values of electron neutrino and antineutrino appearance also finds no discrepancy between data and PMNS predictions

Human malarial disease: a consequence of inflammatory cytokine release

Malaria causes an acute systemic human disease that bears many similarities, both clinically and mechanistically, to those caused by bacteria, rickettsia, and viruses. Over the past few decades, a literature has emerged that argues for most of the pathology seen in all of these infectious diseases being explained by activation of the inflammatory system, with the balance between the pro and anti-inflammatory cytokines being tipped towards the onset of systemic inflammation. Although not often expressed in energy terms, there is, when reduced to biochemical essentials, wide agreement that infection with falciparum malaria is often fatal because mitochondria are unable to generate enough ATP to maintain normal cellular function. Most, however, would contend that this largely occurs because sequestered parasitized red cells prevent sufficient oxygen getting to where it is needed. This review considers the evidence that an equally or more important way ATP deficency arises in malaria, as well as these other infectious diseases, is an inability of mitochondria, through the effects of inflammatory cytokines on their function, to utilise available oxygen. This activity of these cytokines, plus their capacity to control the pathways through which oxygen supply to mitochondria are restricted (particularly through directing sequestration and driving anaemia), combine to make falciparum malaria primarily an inflammatory cytokine-driven disease