Disturbed remodeling of the extracellular matrix (ECM) is frequently observed in several high-prevalence pathologies that include fibrotic diseases of organs such as the heart, lung, periodontium, ...liver, and the stiffening of the ECM surrounding invasive cancers. In many of these lesions, matrix remodeling mediated by fibroblasts is dysregulated, in part by alterations to the regulatory and effector systems that synthesize and degrade collagen, and by alterations to the functions of the integrin-based adhesions that normally mediate mechanical remodeling of collagen fibrils. Cell-matrix adhesions containing collagen-binding integrins are enriched with regulatory and effector systems that initiate localized remodeling of pericellular collagen fibrils to maintain ECM homeostasis. A large cadre of regulatory molecules is enriched in cell-matrix adhesions that affect ECM remodeling through synthesis, degradation, and contraction of collagen fibrils. One of these regulatory molecules is Transient Receptor Potential Vanilloid-type 4 (TRPV4), a mechanically sensitive, Ca
-permeable plasma membrane channel that regulates collagen remodeling. The gating of Ca
across the plasma membrane by TRPV4 and the consequent generation of intracellular Ca
signals affect several processes that determine the structural and mechanical properties of collagen-rich ECM. These processes include the synthesis of new collagen fibrils, tractional remodeling by contractile forces, and collagenolysis. While the specific mechanisms by which TRPV4 contributes to matrix remodeling are not well-defined, it is known that TRPV4 is activated by mechanical forces transmitted through collagen adhesion receptors. Here, we consider how TRPV4 expression and function contribute to physiological and pathological collagen remodeling and are associated with collagen adhesions. Over the long-term, an improved understanding of how TRPV4 regulates collagen remodeling could pave the way for new approaches to manage fibrotic lesions.
The expression ‘Fake News’ inside Internet memes engenders significant online virulence, possibly heralding an iconoclastic emergence of weaponized propaganda for assaulting agencies reared on public ...trust. Internet memes are multimodal artifacts featuring ideological singularities designed for ‘flash’ consumption, often composed by numerous voices echoing popular, online culture. This study proposes that ‘Fake News’ Internet memes are weaponized iconoclastic multimodal propaganda (WIMP) discourse and attempts to delineate them as such by asking: What power relations and ideologies do Internet memes featuring the expression ‘fake news’ harbor? How might those manifestations qualify as WIMP discourse? A multimodal critical discourse analysis of a small pool of ‘fake news’ Internet memes drawn from four popular social media websites revealed what agencies were often targeted and from what political canons they likely emerged. Findings indicate that many Internet memes featuring ‘fake news’ are specifically directed, revealing an underlying hazard that WIMP discourse could diminish democratic processes while influencing online trajectories of public discourse.
To assess if the in vivo mechanical displacement of the anterior laminar cribrosa surface (ALCS) as a response of an acute elevation in intraocular pressure (IOP) differs in individuals of European ...(ED) and African descent (AD).
Spectral-domain optical coherence tomography (SDOCT) scans were obtained from 24 eyes of 12 individuals of AD and 18 eyes of 9 individuals of ED at their normal baseline IOP and after 60 seconds IOP elevation using ophthalmodynamometry. Change in depth (displacement) of the LC and to the prelaminar tissue (PLT) were computed in association with the change (delta) in IOP (Δ IOP), race, age, corneal thickness, corneal rigidity (ocular response analyzer ORA), and axial.
In the ED group for small IOP elevations (Δ IOP < 12 mm Hg), the ALCS initially displaced posteriorly but for larger increase of IOP an anterior displacement of the lamina followed. Inversely, in the AD group the ALCS did not show a significant posterior displacement for small Δ IOP, while for larger IOP increases the ALCS significantly displaced posteriorly. Posterior displacement of the lamina cribrosa (LC) was also significantly correlated with longer axial length, higher corneal thickness, and ORA parameters. Prelaminar tissue posteriorly displaced for any magnitude of Δ IOP, in both groups.
The African descent group demonstrated a greater acute posterior bowing of the LC after adjustment for age, axial length, Bruch's membrane opening (BMO) area, and ORA parameters. Greater PLT posterior displacement was also seen in the AD group with increasing IOP, which was tightly correlated with the displacement of the LC.
Mxra8 is a receptor for multiple arthritogenic alphaviruses that cause debilitating acute and chronic musculoskeletal disease in humans. Herein, we present a 2.2 Å resolution X-ray crystal structure ...of Mxra8 and 4 to 5 Å resolution cryo-electron microscopy reconstructions of Mxra8 bound to chikungunya (CHIKV) virus-like particles and infectious virus. The Mxra8 ectodomain contains two strand-swapped Ig-like domains oriented in a unique disulfide-linked head-to-head arrangement. Mxra8 binds by wedging into a cleft created by two adjacent CHIKV E2-E1 heterodimers in one trimeric spike and engaging a neighboring spike. Two binding modes are observed with the fully mature VLP, with one Mxra8 binding with unique contacts. Only the high-affinity binding mode was observed in the complex with infectious CHIKV, as viral maturation and E3 occupancy appear to influence receptor binding-site usage. Our studies provide insight into how Mxra8 binds CHIKV and creates a path for developing alphavirus entry inhibitors.
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•A 2.2 Å resolution X-ray structure of Mxra8 shows an unusual Ig-like fold topology•Mxra8 has a complex quaternary binding site that spans CHIKV E2 and E1 proteins•Mutational and epitope analyses support cryo-EM structures of Mxra8 with CHIKV•The presence of CHIKV E3 protein on the virion affects the mode of Mxra8 binding
Basore et al. describe an X-ray crystal structure of Mxra8, an entry receptor for arthritogenic alphaviruses, and cryo-EM structures of Mxra8 bound to CHIKV. Mxra8 has an unusual Ig-like domain architecture with a head-to-head arrangement, with domain 1 emanating from a loop of domain 2. Mxra8 binds into a complex quaternary cleft formed between two E2-E1 heterodimers within a trimeric spike, while also contacting E1 from a neighboring spike. Mxra8 occupancy is lower when E3 protein is retained on the virion.
Hospitalized patients are designated alternate level of care (ALC) when they no longer require hospitalization but discharge is delayed while they await alternate disposition or living arrangements. ...We assessed hospital costs and complications for general internal medicine (GIM) inpatients who had delayed discharge. In addition, we developed a clinical prediction rule to identify patients at risk for delayed discharge.
We conducted a retrospective cohort study of consecutive GIM patients admitted between 1 January 2015 and 1 January 2016 at a large tertiary care hospital in Canada. We compared hospital costs and complications between ALC and non-ALC patients. We derived a clinical prediction rule for ALC designation using a logistic regression model and validated its diagnostic properties.
Of 4311 GIM admissions, 255 (6%) patients were designated ALC. Compared to non-ALC patients, ALC patients had longer median length of stay (30.85 vs. 3.95 days p < 0.0001), higher median hospital costs ($22,459 vs. $5003 p < 0.0001) and more complications in hospital (25.5% vs. 5.3% p < 0.0001) especially nosocomial infections (14.1% vs. 1.9% p < 0.0001). Sensitivity analyses using propensity score and pair matching yielded similar results. In a derivation cohort, seven significant risk factors for ALC were identified including age > =80 years, female sex, dementia, diabetes with complications as well as referrals to physiotherapy, occupational therapy and speech language pathology. A clinical prediction rule that assigned each of these predictors 1 point had likelihood ratios for ALC designation of 0.07, 0.25, 0.66, 1.48, 6.07, 17.13 and 21.85 for patients with 0, 1, 2, 3, 4, 5, and 6 points respectively in the validation cohort.
Delayed discharge is associated with higher hospital costs and complication rates especially nosocomial infections. A clinical prediction rule can identify patients at risk for delayed discharge.
The Next Generation Transit Survey (NGTS) Wheatley, Peter J; West, Richard G; Goad, Michael R ...
Monthly notices of the Royal Astronomical Society,
04/2018, Letnik:
475, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Abstract
We describe the Next Generation Transit Survey (NGTS), which is a ground-based project searching for transiting exoplanets orbiting bright stars. NGTS builds on the legacy of previous ...surveys, most notably WASP, and is designed to achieve higher photometric precision and hence find smaller planets than have previously been detected from the ground. It also operates in red light, maximizing sensitivity to late K and early M dwarf stars. The survey specifications call for photometric precision of 0.1 per cent in red light over an instantaneous field of view of 100 deg2, enabling the detection of Neptune-sized exoplanets around Sun-like stars and super-Earths around M dwarfs. The survey is carried out with a purpose-built facility at Cerro Paranal, Chile, which is the premier site of the European Southern Observatory (ESO). An array of twelve 20 cm f/2.8 telescopes fitted with back-illuminated deep-depletion CCD cameras is used to survey fields intensively at intermediate Galactic latitudes. The instrument is also ideally suited to ground-based photometric follow-up of exoplanet candidates from space telescopes such as TESS, Gaia and PLATO. We present observations that combine precise autoguiding and the superb observing conditions at Paranal to provide routine photometric precision of 0.1 per cent in 1 h for stars with I-band magnitudes brighter than 13. We describe the instrument and data analysis methods as well as the status of the survey, which achieved first light in 2015 and began full-survey operations in 2016. NGTS data will be made publicly available through the ESO archive.
ABSTRACT
We determine rotation periods for 127 stars in the ∼115-Myr-old Blanco 1 open cluster using ∼200 d of photometric monitoring with the Next Generation Transit Survey. These stars span F5–M3 ...spectral types (1.2 M⊙ ≳ M ≳ 0.3 M⊙) and increase the number of known rotation periods in Blanco 1 by a factor of four. We determine rotation periods using three methods: Gaussian process (GP) regression, generalized autocorrelation function (G-ACF), and Lomb–Scargle (LS) periodogram, and find that the GP and G-ACF methods are more applicable to evolving spot modulation patterns. Between mid-F and mid-K spectral types, single stars follow a well-defined rotation sequence from ∼2 to 10 d, whereas stars in photometric multiple systems typically rotate faster. This may suggest that the presence of a moderate-to-high mass ratio companion inhibits angular momentum loss mechanisms during the early pre-main sequence, and this signature has not been erased at ∼100 Myr. The majority of mid-F to mid-K stars display evolving modulation patterns, whereas most M stars show stable modulation signals. This morphological change coincides with the shift from a well-defined rotation sequence (mid-F to mid-K stars) to a broad rotation period distribution (late-K and M stars). Finally, we compare our rotation results for Blanco 1 to the similarly aged Pleiades: the single-star populations in both clusters possess consistent rotation period distributions, which suggests that the angular momentum evolution of stars follows a well-defined pathway that is, at least for mid-F to mid-K stars, strongly imprinted by ∼100 Myr.
Two mechanisms safeguard the bipolar attachment of chromosomes in mitosis. A correction mechanism destabilizes erroneous attachments that do not generate tension across sister kinetochores 1. In ...response to unattached kinetochores, the mitotic checkpoint delays anaphase onset by inhibiting the anaphase-promoting complex/cyclosome (APC/CCdc20) 2. Upon satisfaction of both pathways, the APC/CCdc20 elicits the degradation of securin and cyclin B 3. This liberates separase triggering sister chromatid disjunction and inactivates cyclin-dependent kinase 1 (Cdk1) causing mitotic exit. How eukaryotic cells avoid the engagement of attachment monitoring mechanisms when sister chromatids split and tension is lost at anaphase is poorly understood 4. Here we show that Cdk1 inactivation disables mitotic checkpoint surveillance at anaphase onset in human cells. Preventing cyclin B1 proteolysis at the time of sister chromatid disjunction destabilizes kinetochore-microtubule attachments and triggers the engagement of the mitotic checkpoint. As a consequence, mitotic checkpoint proteins accumulate at anaphase kinetochores, the APC/CCdc20 is inhibited, and securin reaccumulates. Conversely, acute pharmacological inhibition of Cdk1 abrogates the engagement and maintenance of the mitotic checkpoint upon microtubule depolymerization. We propose that the simultaneous destruction of securin and cyclin B elicited by the APC/CCdc20 couples chromosome segregation to the dissolution of attachment monitoring mechanisms during mitotic exit.
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•Cyclin B degradation stabilizes kinetochore attachments in anaphase•Cdk1 inactivation prevents mitotic checkpoint engagement after anaphase onset•Chromatid disjunction by separase causes APC/C inhibition if Cdk1 remains active•APC/C links separase activation to dissolution of attachment monitoring mechanisms
Vázquez-Novelle et al. propose that Cdk1-cyclin B activity sets the temporal window for microtubule-kinetochore attachment surveillance. Failure to degrade cyclin B at anaphase onset destabilizes attachments and engages the mitotic checkpoint. APC/C-induced proteolysis could couple sister chromatid disjunction to checkpoint dissolution when sister chromatids split.
Developmentally, the articular joints are derived from lateral plate (LP) mesoderm. However, no study has produced both LP derived prechondrocytes and preosteoblasts from human pluripotent stem cells ...(hPSC) through a common progenitor in a chemically defined manner. Differentiation of hPSCs through the authentic route, via an LP-osteochondral progenitor (OCP), may aid understanding of human cartilage development and the generation of effective cell therapies for osteoarthritis. We refined our existing chondrogenic protocol, incorporating knowledge from development and other studies to produce a LP-OCP from which prechondrocyte- and preosteoblast-like cells can be generated. Results show the formation of an OCP, which can be further driven to prechondrocytes and preosteoblasts. Prechondrocytes cultured in pellets produced cartilage like matrix with lacunae and superficial flattened cells expressing lubricin. Additionally, preosteoblasts were able to generate a mineralised structure. This protocol can therefore be used to investigate further cartilage development and in the development of joint cartilage for potential treatments.
Ecological factors contributing to depth-related diversification of marine Thaumarchaeota populations remain largely unresolved. To investigate the role of potential microbial associations in shaping ...thaumarchaeal ecotype diversification, we examined co-occurrence relationships in a community composition dataset (16S rRNA V4-V5 region) collected as part of a 2-year time series in coastal Monterey Bay. Ecotype groups previously defined based on functional gene diversity-water column A (WCA), water column B (WCB) and Nitrosopumilus-like clusters-were recovered in the thaumarchaeal 16S rRNA gene phylogeny. Networks systematically reflected depth-related patterns in the abundances of ecotype populations, suggesting thaumarchaeal ecotypes as keystone members of the microbial community below the euphotic zone. Differential environmental controls on the ecotype populations were further evident in subnetwork modules showing preferential co-occurrence of OTUs belonging to the same ecotype cluster. Correlated abundances of Thaumarchaeota and heterotrophic bacteria (e.g., Bacteroidetes, Marinimicrobia and Gammaproteobacteria) indicated potential reciprocal interactions via dissolved organic matter transformations. Notably, the networks recovered ecotype-specific associations between thaumarchaeal and Nitrospina OTUs. Even at depths where WCB-like Thaumarchaeota dominated, Nitrospina OTUs were found to preferentially co-occur with WCA-like and Nitrosopumilus-like thaumarchaeal OTUs, highlighting the need to investigate the ecological implications of the composition of nitrifier assemblages in marine waters.
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