329 research outputs found
Wnt/β-Catenin Signaling in Mesenchymal Progenitors Controls Osteoblast and Chondrocyte Differentiation during Vertebrate Skeletogenesis
SummaryChondrocytes and osteoblasts are two primary cell types in the skeletal system that are differentiated from common mesenchymal progenitors. It is believed that osteoblast differentiation is controlled by distinct mechanisms in intramembranous and endochondral ossification. We have found that ectopic canonical Wnt signaling leads to enhanced ossification and suppression of chondrocyte formation. Conversely, genetic inactivation of β-catenin, an essential component transducing the canonical Wnt signaling, causes ectopic formation of chondrocytes at the expense of osteoblast differentiation during both intramembranous and endochondral ossification. Moreover, inactivation of β-catenin in mesenchymal progenitor cells in vitro causes chondrocyte differentiation under conditions allowing only osteoblasts to form. Our results demonstrate that β-catenin is essential in determining whether mesenchymal progenitors will become osteoblasts or chondrocytes regardless of regional locations or ossification mechanisms. Controlling Wnt/β-catenin signaling is a common molecular mechanism underlying chondrocyte and osteoblast differentiation and specification of intramembranous and endochondral ossification
Reaction Landscape of a Pentadentate N5-Ligated MnII Complex with O2•− and H2O2 Includes Conversion of a Peroxomanganese(III) Adduct to a Bis(μ-oxo)dimanganese(III,IV) Species
Herein we describe the chemical reactivity of the mononuclear [MnII(N4py)(OTf)](OTf) (1) complex with hydrogen peroxide and superoxide. Treatment of 1 with one equivalent superoxide at −40 °C in MeCN formed the peroxomanganese(III) adduct, [MnIII(O2)(N4py)]+ (2) in ~30% yield. Complex 2 decayed over time and the formation of the bis(μ-oxo)dimanganese(III,IV) complex, [MnIIIMnIV(μ-O)2(N4py)2]3+ (3) was observed. When 2 was formed in higher yields (~60%) using excess superoxide, the [MnIII(O2)(N4py)]+ species thermally decayed to MnII species and 3 was formed in no greater than 10% yield. Treatment of [MnIII(O2)(N4py)]+ with 1 resulted in the formation of 3 in ~90% yield, relative to the concentration of [MnIII(O2)(N4py)]+. This reaction mimics the observed chemistry of Mn-ribonucleotide reductase, as it features the conversion of two MnII species to an oxo-bridged MnIIIMnIV compound using O2− as oxidant. Complex 3 was independently prepared through treatment of 1 with H2O2 and base at −40 °C. The geometric and electronic structures of 3 were probed using electronic absorption, electron paramagnetic resonance (EPR), magnetic circular dichroism (MCD), variable-temperature, variable-field MCD (VTVH-MCD), and X-ray absorption (XAS) spectroscopies. Complex 3 was structurally characterized by X-ray diffraction (XRD), which revealed the N4py ligand bound in an unusual tetradentate fashion
College Students’ Sense Of Cycling Capability Deters Helmet Use: Implications For Safety Helmet Ordinances
Proponents frequently cite increased injury protection as a reason for supporting bicycle helmet ordinances; yet, many cyclists oppose such policies. In this study, six focus groups of college students discussed cycling behaviors and attitudes toward using bicycle safety helmets, and perceptions of the local helmet ordinance. The usual concerns were voiced such as “inconvenience” and “helmet hair”. Participants reported very high confidence in their cycling ability and their ability to avoid a crash which might require a helmet. They failed to take into account external factors or the actions of others which may increase risk for injury. They also did not understand how health insurance spreads the financial risk for traumatic events. These findings have implications for designing education campaigns to promote college student health, as well as initiatives for helmet ordinance advocacy.
Detection of a glitch in the pulsar J1709-4429
We report the detection of a glitch event in the pulsar J17094429 (also
known as B170644) during regular monitoring observations with the Molonglo
Observatory Synthesis Telescope (UTMOST). The glitch was found during timing
operations, in which we regularly observe over 400 pulsars with up to daily
cadence, while commensally searching for Rotating Radio Transients, pulsars,
and FRBs. With a fractional size of ,
the glitch reported here is by far the smallest known for this pulsar,
attesting to the efficacy of glitch searches with high cadence using UTMOST.Comment: 3 pages, 1 figur
Phase separation of an actin nucleator by junctional microtubules regulates epithelial function
Liquid-liquid phase separation (LLPS) is involved in various dynamic biological phenomena. In epithelial cells, dynamic regulation of junctional actin filaments tethered to the apical junctional complex (AJC) is critical for maintaining internal homeostasis against external perturbations; however, the role of LLPS in this process remains unknown. Here, after identifying a multifunctional actin nucleator, cordon bleu (Cobl), as an AJC-enriched microtubule-associated protein, we conducted comprehensive in vitro and in vivo analyses. We found that apical microtubules promoted LLPS of Cobl at the AJC, and Cobl actin assembly activity increased upon LLPS. Thus, microtubules spatiotemporally regulated junctional actin assembly for epithelial morphogenesis and paracellular barriers. Collectively, these findings established that LLPS of the actin nucleator Cobl mediated dynamic microtubule-actin cross-talk in junctions, which fine-tuned the epithelial barrier
Effects of Mergers and Core Structure on the Bulk Properties of Nearby Galaxy Clusters
We use morphological measurements and the scatter of clusters about observed
and simulated scaling relations to examine the impact of merging and
core-related phenomena on the structure of galaxy clusters. All relations
constructed from emission-weighted mean temperature and intracluster medium
mass, X-ray luminosity, isophotal size, or near-IR luminosity show a separation
between cool core (CC) and non-cool core (NCC) clusters. We attribute this
partially to a temperature bias in CC clusters, and partially to other cool
core-related structural changes. We attempt to minimize CC/NCC separation in
scaling relations by applying a uniform scale factor to CC cluster temperatures
and determining the scale factor for each relation that minimizes the
separation between CC and NCC populations, and by introducing central surface
brightness as a third parameter in relations. The latter approach reduces
scatter in relations more than temperature scaling. We compare the scatter
within subsamples split by CC/NCC and morphological merger indicators. CC
clusters and clusters with less substructure generally exhibit higher scatter
about relations. The larger structural variations in CC clusters exit well
outside the core, suggesting that a process more global than core radiative
instability is at work. Simulations without cooling mechanisms also show no
correlation between substructure and larger scatter about relations, indicating
that any merger-related scatter increases are subtle. The results indicate that
cool core related phenomena, not merging processes, are the primary contributor
to scatter in scaling relations. Our analysis does not appear to support the
scenario in which clusters evolve cool cores over time unless they experience
major mergers. (Abridged)Comment: 18 pages, 17 figures; minor changes to text to match accepted
version. To appear in Ap
Prospective evaluation of methylated SEPT9 in plasma for detection of asymptomatic colorectal cancer
As screening methods for colorectal cancer (CRC) are limited by uptake and adherence, further options are sought. A blood test might increase both, but none has yet been tested in a screening setting
Proteomic and phosphoproteomic landscapes of acute myeloid leukemia
We have developed a deep-scale proteome and phosphoproteome database from 44 representative acute myeloid leukemia (AML) patients from the LAML TCGA dataset and 6 healthy bone marrow-derived controls. After confirming data quality, we orthogonally validated several previously undescribed features of AML revealed by the proteomic data. We identified examples of posttranscriptionally regulated proteins both globally (ie, in all AML samples) and also in patients with recurrent AML driver mutations. For example, samples with IDH1/2 mutations displayed elevated levels of the 2-oxoglutarate-dependent histone demethylases KDM4A/B/C, despite no changes in messenger RNA levels for these genes; we confirmed this finding in vitro. In samples with NPMc mutations, we identified several nuclear importins with posttranscriptionally increased protein abundance and showed that they interact with NPMc but not wild-type NPM1. We identified 2 cell surface proteins (CD180 and MRC1/CD206) expressed on AML blasts of many patients (but not healthy CD34+ stem/progenitor cells) that could represent novel targets for immunologic therapies and confirmed these targets via flow cytometry. Finally, we detected nearly 30 000 phosphosites in these samples; globally, AML samples were associated with the abnormal phosphorylation of specific residues in PTPN11, STAT3, AKT1, and PRKCD. FLT3-TKD samples were associated with increased phosphorylation of activating tyrosines on the cytoplasmic Src-family tyrosine kinases FGR and HCK and related signaling proteins. PML-RARA-initiated AML samples displayed a unique phosphorylation signature, and TP53-mutant samples showed abundant phosphorylation of serine-183 on TP53 itself. This publicly available database will serve as a foundation for further investigations of protein dysregulation in AML pathogenesis
Genomic landscape of TP53-mutated myeloid malignancies
TP53-mutated myeloid malignancies are associated with complex cytogenetics and extensive structural variants, which complicates detailed genomic analysis by conventional clinical techniques. We performed whole-genome sequencing (WGS) of 42 acute myeloid leukemia (AML)/myelodysplastic syndromes (MDS) cases with paired normal tissue to better characterize the genomic landscape of TP53-mutated AML/MDS. WGS accurately determines TP53 allele status, a key prognostic factor, resulting in the reclassification of 12% of cases from monoallelic to multihit. Although aneuploidy and chromothripsis are shared with most TP53-mutated cancers, the specific chromosome abnormalities are distinct to each cancer type, suggesting a dependence on the tissue of origin. ETV6 expression is reduced in nearly all cases of TP53-mutated AML/MDS, either through gene deletion or presumed epigenetic silencing. Within the AML cohort, mutations of NF1 are highly enriched, with deletions of 1 copy of NF1 present in 45% of cases and biallelic mutations in 17%. Telomere content is increased in TP53-mutated AMLs compared with other AML subtypes, and abnormal telomeric sequences were detected in the interstitial regions of chromosomes. These data highlight the unique features of TP53-mutated myeloid malignancies, including the high frequency of chromothripsis and structural variation, the frequent involvement of unique genes (including NF1 and ETV6) as cooperating events, and evidence for altered telomere maintenance
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