1,076 research outputs found
From stem cells to bone-forming cells
Bone formation starts near the end of the embryonic stage of development and continues throughout life during bone modeling and growth, remodeling, and when needed, regeneration. Bone-forming cells, traditionally termed osteoblasts, produce, assemble, and control the mineralization of the type I collagen-enriched bone matrix while participating in the regulation of other cell processes, such as osteoclastogenesis, and metabolic activities, such as phosphate homeostasis. Osteoblasts are generated by different cohorts of skeletal stem cells that arise from different embryonic specifications, which operate in the pre-natal and/or adult skeleton under the control of multiple regulators. In this review, we briefly define the cellular identity and function of osteoblasts and discuss the main populations of osteoprogenitor cells identified to date. We also provide examples of long-known and recently recognized regulatory pathways and mechanisms involved in the specification of the osteogenic lineage, as assessed by studies on mice models and human genetic skeletal diseases
Predicting the safety and efficacy of butter therapy to raise tumour pHe: an integrative modelling study
Background: Clinical positron emission tomography imaging has demonstrated the vast majority of human cancers exhibit significantly increased glucose metabolism when compared with adjacent normal tissue, resulting in an acidic tumour microenvironment. Recent studies demonstrated reducing this acidity through systemic buffers significantly inhibits development and growth of metastases in mouse xenografts.\ud
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Methods: We apply and extend a previously developed mathematical model of blood and tumour buffering to examine the impact of oral administration of bicarbonate buffer in mice, and the potential impact in humans. We recapitulate the experimentally observed tumour pHe effect of buffer therapy, testing a model prediction in vivo in mice. We parameterise the model to humans to determine the translational safety and efficacy, and predict patient subgroups who could have enhanced treatment response, and the most promising combination or alternative buffer therapies.\ud
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Results: The model predicts a previously unseen potentially dangerous elevation in blood pHe resulting from bicarbonate therapy in mice, which is confirmed by our in vivo experiments. Simulations predict limited efficacy of bicarbonate, especially in humans with more aggressive cancers. We predict buffer therapy would be most effectual: in elderly patients or individuals with renal impairments; in combination with proton production inhibitors (such as dichloroacetate), renal glomular filtration rate inhibitors (such as non-steroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors), or with an alternative buffer reagent possessing an optimal pK of 7.1–7.2.\ud
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Conclusion: Our mathematical model confirms bicarbonate acts as an effective agent to raise tumour pHe, but potentially induces metabolic alkalosis at the high doses necessary for tumour pHe normalisation. We predict use in elderly patients or in combination with proton production inhibitors or buffers with a pK of 7.1–7.2 is most promising
On Validating an Astrophysical Simulation Code
We present a case study of validating an astrophysical simulation code. Our
study focuses on validating FLASH, a parallel, adaptive-mesh hydrodynamics code
for studying the compressible, reactive flows found in many astrophysical
environments. We describe the astrophysics problems of interest and the
challenges associated with simulating these problems. We describe methodology
and discuss solutions to difficulties encountered in verification and
validation. We describe verification tests regularly administered to the code,
present the results of new verification tests, and outline a method for testing
general equations of state. We present the results of two validation tests in
which we compared simulations to experimental data. The first is of a
laser-driven shock propagating through a multi-layer target, a configuration
subject to both Rayleigh-Taylor and Richtmyer-Meshkov instabilities. The second
test is a classic Rayleigh-Taylor instability, where a heavy fluid is supported
against the force of gravity by a light fluid. Our simulations of the
multi-layer target experiments showed good agreement with the experimental
results, but our simulations of the Rayleigh-Taylor instability did not agree
well with the experimental results. We discuss our findings and present results
of additional simulations undertaken to further investigate the Rayleigh-Taylor
instability.Comment: 76 pages, 26 figures (3 color), Accepted for publication in the ApJ
Changes in gene expression in human skeletal stem cells transduced with constitutively active Gs\u3b1 correlates with hallmark histopathological changes seen in fibrous dysplastic bone
Fibrous dysplasia (FD) of bone is a complex disease of the skeleton caused by dominant activating mutations of the GNAS locus encoding for the \u3b1 subunit of the G protein-coupled receptor complex (Gs\u3b1). The mutation involves a substitution of arginine at position 201 by histidine or cysteine (Gs\u3b1R201H or R201C), which leads to overproduction of cAMP. Several signaling pathways are implicated downstream of excess cAMP in the manifestation of disease. However, the pathogenesis of FD remains largely unknown. The overall FD phenotype can be attributed to alterations of skeletal stem/progenitor cells which normally develop into osteogenic or adipogenic cells (in cis), and are also known to provide support to angiogenesis, hematopoiesis, and osteoclastogenesis (in trans). In order to dissect the molecular pathways rooted in skeletal stem/progenitor cells by FD mutations, we engineered human skeletal stem/progenitor cells with the Gs\u3b1R201C mutation and performed transcriptomic analysis. Our data suggest that this FD mutation profoundly alters the properties of skeletal stem/progenitor cells by pushing them towards formation of disorganized bone with a concomitant alteration of adipogenic differentiation. In addition, the mutation creates an altered in trans environment that induces neovascularization, cytokine/chemokine changes and osteoclastogenesis. In silico comparison of our data with the signature of FD craniofacial samples highlighted common traits, such as the upregulation of ADAM (A Disintegrin and Metalloprotease) proteins and other matrix-related factors, and of PDE7B (Phosphodiesterase 7B), which can be considered as a buffering process, activated to compensate for excess cAMP. We also observed high levels of CEBPs (CCAAT-Enhancer Binding Proteins) in both data sets, factors related to browning of white fat. This is the first analysis of the reaction of human skeletal stem/progenitor cells to the introduction of the FD mutation and we believe it provides a useful background for further studies on the molecular basis of the disease and for the identification of novel potential therapeutic targets
Detection and Understanding of Natural CO2 Releases in KwaZulu-Natal, South Africa
Natural carbon dioxide (CO2) emanates from a number of sites along a N-S trend that coincides with a mapped fault near the village of Bongwana in KwaZulu-Natal, South Africa. In addition to the natural CO2 seeps a groundwater well drilled on a farm in Bongwana encountered CO2 and now leaks. Thus the Bongwana sites provide excellent analogues for failed CO2 storage under the two primary leakage scenarios; 1) abrupt leakage through injection well failure or leakage up an abandoned well, and 2) gradual leakage, through undetected faults, fractures or wells. Here we present results from preliminary fieldwork undertaken in September 2015
Orbital Physics in the Perovskite Ti Oxides
In the perovskite Ti oxide RTiO3 (R=rare-earth ions), the Ti t2g orbitals and
spins in the 3d^1 state couple each other through the strong electron
correlations, resulting in a rich variety of orbital-spin phases. The origin
and nature of orbital-spin states of these Mott insulators have been
intensively studied. In this article, we review the studies on orbital physics
in the perovskite titanates. We focus on the following three topics: (1) the
origin and nature of the ferromagnetism as well as the orbital ordering in the
compounds with relatively small R ions such as GdTiO3 and YTiO3, (2) the origin
of the G-type antiferromagnetism and the orbital state in LaTiO3, and (3) the
orbital-spin structures in other AFM(G) compounds with relatively large R ions
(R=Ce, Pr, Nd and Sm). On the basis of these discussions, we discuss the whole
phase diagram together with mechanisms of the magnetic phase transition. We
also show that the Ti t2g degeneracy is inherently lifted in the titanates,
which allows the single-band descriptions of the ground-state and low-energy
electronic structures as a good starting point. Our analyses indicate that
these compounds offer touchstone materials described by the single-band Hubbard
model on the cubic lattice. From this insight, we also reanalyze the hole-doped
titanates. Experimentally revealed filling-dependent and bandwidth-dependent
properties and the critical behavior of the metal-insulator transitions are
discussed in the light of theories based on the single-band Hubbard models.Comment: Review article, 26 pages, to appear in New Journal of Physic
Acidic microenvironment plays a key role in human melanoma progression through a sustained exosome mediated transfer of clinically relevant metastatic molecules
Background: Microenvironment cues involved in melanoma progression are largely unknown. Melanoma is highly influenced in its aggressive phenotype by the changes it determinates in its microenvironment, such as pH decrease, in turn influencing cancer cell invasiveness, progression and tissue remodelling through an abundant secretion of exosomes, dictating cancer strategy to the whole host. A role of exosomes in driving melanoma progression under microenvironmental acidity was never described. Methods: We studied four differently staged human melanoma lines, reflecting melanoma progression, under microenvironmental acidic pHs pressure ranging between pH 6.0-6.7. To estimate exosome secretion as a function of tumor stage and environmental pH, we applied a technique to generate native fluorescent exosomes characterized by vesicles integrity, size, density, markers expression, and quantifiable by direct FACS analysis. Functional roles of exosomes were tested in migration and invasion tests. Then we performed a comparative proteomic analysis of acid versus control exosomes to elucidate a specific signature involved in melanoma progression. Results: We found that metastatic melanoma secretes a higher exosome amount than primary melanoma, and that acidic pH increases exosome secretion when melanoma is in an intermediate stage, i.e. metastatic non-invasive. We were thus able to show that acidic pH influences the intercellular cross-talk mediated by exosomes. In fact when exposed to exosomes produced in an acidic medium, pH naïve melanoma cells acquire migratory and invasive capacities likely due to transfer of metastatic exosomal proteins, favoring cell motility and angiogenesis. A Prognoscan-based meta-analysis study of proteins enriched in acidic exosomes, identified 11 genes (HRAS, GANAB, CFL2, HSP90B1, HSP90AB1, GSN, HSPA1L, NRAS, HSPA5, TIMP3, HYOU1), significantly correlating with poor prognosis, whose high expression was in part confirmed in bioptic samples of lymph node metastases. Conclusions: A crucial step of melanoma progression does occur at melanoma intermediate -stage, when extracellular acidic pH induces an abundant release and intra-tumoral uptake of exosomes. Such exosomes are endowed with pro-invasive molecules of clinical relevance, which may provide a signature of melanoma advancement
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