Medication-related osteonecrosis of the jaw (MRONJ) is a potentially severe adverse event affecting patients with cancer and patients with osteoporosis who have been treated with powerful ...antiresorptives (pARs) or angiogenesis inhibitors (AgIs). pARs, including nitrogen-containing bisphosphonates (N-BPs; e.g., zoledronic acid, alendronate) and anti-RANKL antibodies (e.g., denosumab), are used to manage bone metastases in patients with cancer or to prevent fragility fractures in patients with osteoporosis.
Though significant advances have been made in understanding MRONJ, its pathophysiology is still not fully elucidated. Multiple species have been used in preclinical MRONJ research, including the rat, mouse, rice rat, rabbit, dog, sheep, and pig. Animal research has contributed immensely to advancing the MRONJ field, particularly, but not limited to, in developing models and investigating risk factors that were first observed in humans. MRONJ models have been developed using clinically relevant doses of systemic risk factors, like N-BPs, anti-RANKL antibodies, or AgIs. Specific local oral risk factors first noted in humans, including tooth extraction and inflammatory dental disease (e.g., periodontitis, periapical infection, etc.), were then added. Research in rodents, particularly the rat, and, to some extent, the mouse, across multiple laboratories, has contributed to establishing multiple relevant and complementary preclinical models. Models in larger species produced accurate clinical and histopathologic outcomes suggesting a potential role for confirming specific crucial findings from rodent research. We view the current state of animal models for MRONJ as good. The rodent models are now reliable enough to produce large numbers of MRONJ cases that could be applied in experiments testing treatment modalities. The course of MRONJ, including stage 0 MRONJ, is characterized well enough that basic studies of the molecular or enzyme-level findings in different MRONJ stages are possible.
This review provides a current overview of the existing models of MRONJ, their more significant features and findings, and important instances of their application in preclinical research.
A suite of climate change indices derived from daily temperature and precipitation data, with a primary focus on extreme events, were computed and analyzed. By setting an exact formula for each index ...and using specially designed software, analyses done in different countries have been combined seamlessly. This has enabled the presentation of the most up‐to‐date and comprehensive global picture of trends in extreme temperature and precipitation indices using results from a number of workshops held in data‐sparse regions and high‐quality station data supplied by numerous scientists world wide. Seasonal and annual indices for the period 1951–2003 were gridded. Trends in the gridded fields were computed and tested for statistical significance. Results showed widespread significant changes in temperature extremes associated with warming, especially for those indices derived from daily minimum temperature. Over 70% of the global land area sampled showed a significant decrease in the annual occurrence of cold nights and a significant increase in the annual occurrence of warm nights. Some regions experienced a more than doubling of these indices. This implies a positive shift in the distribution of daily minimum temperature throughout the globe. Daily maximum temperature indices showed similar changes but with smaller magnitudes. Precipitation changes showed a widespread and significant increase, but the changes are much less spatially coherent compared with temperature change. Probability distributions of indices derived from approximately 200 temperature and 600 precipitation stations, with near‐complete data for 1901–2003 and covering a very large region of the Northern Hemisphere midlatitudes (and parts of Australia for precipitation) were analyzed for the periods 1901–1950, 1951–1978 and 1979–2003. Results indicate a significant warming throughout the 20th century. Differences in temperature indices distributions are particularly pronounced between the most recent two periods and for those indices related to minimum temperature. An analysis of those indices for which seasonal time series are available shows that these changes occur for all seasons although they are generally least pronounced for September to November. Precipitation indices show a tendency toward wetter conditions throughout the 20th century.
Abstract
We present Atacama Large Millimeter Array C i(1 − 0) (rest frequency 492 GHz) observations for a sample of 13 strongly lensed dusty star-forming galaxies (DSFGs) originally discovered at ...1.4 mm in a blank-field survey by the South Pole Telescope (SPT). We compare these new data with available C i observations from the literature, allowing a study of the interstellar medium (ISM) properties of ∼30 extreme DSFGs spanning a redshift range 2 < z < 5. Using the C i line as a tracer of the molecular ISM, we find a mean molecular gas mass for SPT-DSFGs of 6.6 × 1010 M⊙. This is in tension with gas masses derived via low-J
12CO and dust masses; bringing the estimates into accordance requires either (a) an elevated CO-to-H2 conversion factor for our sample of αCO ∼ 2.5 and a gas-to-dust ratio ∼200, or (b) an high carbon abundance
$X_{\rm C\,\small {I}} \sim 7\times 10^{-5}$
. Using observations of a range of additional atomic and molecular lines (including C i, C iiand multiple transitions of CO), we use a modern photodissociation region code (3d-pdr) to assess the physical conditions (including the density, UV radiation field strength and gas temperature) within the ISM of the DSFGs in our sample. We find that the ISM within our DSFGs is characterized by dense gas permeated by strong UV fields. We note that previous efforts to characterize photodissociation region regions in DSFGs may have significantly under-estimated the density of the ISM. Combined, our analysis suggests that the ISM of extreme dusty starbursts at high redshift consists of dense, carbon-rich gas not directly comparable to the ISM of starbursts in the local Universe.
Medication-related osteonecrosis of the jaw (MRONJ) is a potentially severe, debilitating condition affecting patients with cancer and patients with osteoporosis who have been treated with powerful ...antiresorptives (pARs) or angiogenesis inhibitors (AgIs). Oral risk factors associated with the development of MRONJ include tooth extraction and inflammatory dental disease (e.g., periodontitis, periapical infection). In bone tissues, osteocytes play a bidirectional role in which they not only act as the “receiver” of systemic signals from blood vessels, such as hormones and drugs, or local signals from the mineralized matrix as it is deformed, but they also play a critical role as “transmitter” of signals to the cells that execute bone modeling and remodeling (osteoclasts, osteoblasts and lining cells). When the survival capacity of osteocytes is overwhelmed, they can die. Osteocyte death has been associated with several pathological conditions. Whereas the causes and mechanisms of osteocyte death have been studied in conditions like osteonecrosis of the femoral head (ONFH), few studies of the causes and mechanisms of osteocyte death have been done in MRONJ. The three forms of cell death that affect most of the different cells in the body (apoptosis, autophagy, and necrosis) have been recognized in osteocytes. Notably, necroptosis, a form of regulated cell death with “a necrotic cell death phenotype,” has also been identified as a form of cell death in osteocytes under certain pathologic conditions. Improving the understanding of osteocyte death in MRONJ may be critical for preventing disease and developing treatment approaches. In this review, we intend to provide insight into the biology of osteocytes, cell death, in general, and osteocyte death, in particular, and discuss hypothetical mechanisms involved in osteocyte death associated with MRONJ.
•Osteocytes can die by apoptosis, autophagy, or necrosis.•Necroptosis is a form of regulated cell death with identical cytologic features as necrosis.•Osteocytes can die by necroptosis.•TNFα/TNFR1 signaling is involved in apoptosis, necroptosis, and inflammation.•A hypothetical model for MRONJ is proposed.
The force balance of rotating Rayleigh–Bénard convection regimes is investigated using direct numerical simulation on a laterally periodic domain, vertically bounded by no-slip walls. We provide a ...comprehensive view of the interplay between governing forces both in the bulk and near the walls. We observe, as in other prior studies, regimes of cells, convective Taylor columns, plumes, large-scale vortices (LSVs) and rotation-affected convection. Regimes of rapidly rotating convection are dominated by geostrophy, the balance between Coriolis and pressure-gradient forces. The higher-order interplay between inertial, viscous and buoyancy forces defines a subdominant balance that distinguishes the geostrophic states. It consists of viscous and buoyancy forces for cells and columns, inertial, viscous and buoyancy forces for plumes, and inertial forces for LSVs. In rotation-affected convection, inertial and pressure-gradient forces constitute the dominant balance; Coriolis, viscous and buoyancy forces form the subdominant balance. Near the walls, in geostrophic regimes, force magnitudes are larger than in the bulk; buoyancy contributes little to the subdominant balance of cells, columns and plumes. Increased force magnitudes denote increased ageostrophy near the walls. Nonetheless, the flow is geostrophic as the bulk. Inertia becomes increasingly more important compared with the bulk, and enters the subdominant balance of columns. As the bulk, the near-wall flow loses rotational constraint in rotation-affected convection. Consequently, kinetic boundary layers deviate from the expected behaviour from linear Ekman boundary layer theory. Our findings elucidate the dynamical balances of rotating thermal convection under realistic top/bottom boundary conditions, relevant to laboratory settings and large-scale natural flows.
Mass bleaching associated with unusually high sea temperatures represents one of the greatest threats to corals and coral reef ecosystems. Deeper reef areas are hypothesized as potential refugia, but ...the susceptibility of Scleractinian species over depth has not been quantified. During the most severe bleaching event on record, we found up to 83% of coral cover severely affected on Maldivian reefs at a depth of 3–5 m, but significantly reduced effects at 24–30 m. Analysis of 153 species' responses showed depth, shading and species identity had strong, significant effects on susceptibility. Overall, 73.3% of the shallow-reef assemblage had individuals at a depth of 24–30 m with reduced effects, potentially mitigating local extinction and providing a source of recruits for population recovery. Although susceptibility was phylogenetically constrained, species-level effects caused most lineages to contain some partially resistant species. Many genera showed wide variation between species, including Acropora, previously considered highly susceptible. Extinction risk estimates showed species and lineages of concern and those likely to dominate following repeated events. Our results show that deeper reef areas provide refuge for a large proportion of Scleractinian species during severe bleaching events and that the deepest occurring individuals of each population have the greatest potential to survive and drive reef recovery.
We report flow measurements in rotating Rayleigh–Bénard convection in the rotationally constrained geostrophic regime. We apply stereoscopic particle image velocimetry to measure the three components ...of velocity in a horizontal cross-section of a water-filled cylindrical convection vessel. At a constant, small Ekman number $Ek=5\times 10^{-8}$, we vary the Rayleigh number $Ra$ between $10^{11}$ and $4\times 10^{12}$ to cover various subregimes observed in geostrophic convection. We also include one non-rotating experiment. The scaling of the velocity fluctuations (expressed as the Reynolds number $Re$) is compared to theoretical relations expressing balances of viscous–Archimedean–Coriolis (VAC) and Coriolis–inertial–Archimedean (CIA) forces. Based on our results we cannot decide which balance is most applicable here; both scaling relations match equally well. A comparison of the current data with several other literature datasets indicates a convergence towards diffusion-free scaling of velocity as $Ek$ decreases. However, at lower $Ra$, the use of confined domains leads to prominent convection in the wall mode near the sidewall. Kinetic energy spectra point at an overall flow organisation into a quadrupolar vortex filling the cross-section. This quadrupolar vortex is a quasi-two-dimensional feature; it manifests only in energy spectra based on the horizontal velocity components. At larger $Ra$, the spectra reveal the development of a scaling range with exponent close to $-5/3$, the classical exponent for inertial range scaling in three-dimensional turbulence. The steeper $Re(Ra)$ scaling at low $Ek$ and development of a scaling range in the energy spectra are distinct indicators that a fully developed, diffusion-free turbulent bulk flow state is approached, sketching clear perspectives for further investigation.
The enteric nervous system (ENS) coordinates diverse functions in the intestine but has eluded comprehensive molecular characterization because of the rarity and diversity of cells. Here we develop ...two methods to profile the ENS of adult mice and humans at single-cell resolution: RAISIN RNA-seq for profiling intact nuclei with ribosome-bound mRNA and MIRACL-seq for label-free enrichment of rare cell types by droplet-based profiling. The 1,187,535 nuclei in our mouse atlas include 5,068 neurons from the ileum and colon, revealing extraordinary neuron diversity. We highlight circadian expression changes in enteric neurons, show that disease-related genes are dysregulated with aging, and identify differences between the ileum and proximal/distal colon. In humans, we profile 436,202 nuclei, recovering 1,445 neurons, and identify conserved and species-specific transcriptional programs and putative neuro-epithelial, neuro-stromal, and neuro-immune interactions. The human ENS expresses risk genes for neuropathic, inflammatory, and extra-intestinal diseases, suggesting neuronal contributions to disease.
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•RAISIN RNA-seq of 1.6 million cells and 6,513 enteric neurons from adult mice and humans•Dozens of neuron subsets that vary by location, circadian phase, age, and species•Putative interactions between neurons and epithelial, stromal, and immune cells•Enteric neurons express risk genes for extraintestinal diseases with gut dysmotility
Comprehensive mapping and comparison of the adult mouse and human enteric nervous system is achieved with development of methods to isolate intact nuclei with ribosome-bound mRNA and label-free profiling of rare cell types. The atlases reveal the neuronal diversity of the ENS; its potential to link the gut, immune system, and brain; and contributions to disease.
Limited scope for latitudinal extension of reef corals Muir, Paul R.; Wallace, Carden C.; Done, Terence ...
Science (American Association for the Advancement of Science),
06/2015, Letnik:
348, Številka:
6239
Journal Article
Recenzirano
An analysis of present-day global depth distributions of reef-building corals and underlying environmental drivers contradicts a commonly held belief that ocean warming will promote tropical coral ...expansion into temperate latitudes. Using a global data set of a major group of reef corals, we found that corals were confined to shallower depths at higher latitudes (up to 0.6 meters of predicted shallowing per additional degree of latitude). Latitudinal attenuation of the most important driver of this phenomenon—the dose of photosynthetically available radiation over winter—would severely constrain latitudinal coral range extension in response to ocean warming. Latitudinal gradients in species richness for the group also suggest that higher winter irradiance at depth in low latitudes allowed a deep-water fauna that was not viable at higher latitudes.
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