How are skeletal tissues derived from skeletal stem cells? Here, we map bone, cartilage, and stromal development from a population of highly pure, postnatal skeletal stem cells (mouse skeletal stem ...cells, mSSCs) to their downstream progenitors of bone, cartilage, and stromal tissue. We then investigated the transcriptome of the stem/progenitor cells for unique gene-expression patterns that would indicate potential regulators of mSSC lineage commitment. We demonstrate that mSSC niche factors can be potent inducers of osteogenesis, and several specific combinations of recombinant mSSC niche factors can activate mSSC genetic programs in situ, even in nonskeletal tissues, resulting in de novo formation of cartilage or bone and bone marrow stroma. Inducing mSSC formation with soluble factors and subsequently regulating the mSSC niche to specify its differentiation toward bone, cartilage, or stromal cells could represent a paradigm shift in the therapeutic regeneration of skeletal tissues.
Display omitted
•Bone, cartilage, and stroma are derived from clonal, lineage-restricted progenitors•We defined a postnatal skeletal stem cell (mSSC) and seven downstream progenitors•Skeletal progenitor fate can be directed from bone to cartilage and vice versa•Manipulation of mSSC niche signaling can induce de novo bone or cartilage formation
Bone, cartilage, and stroma development in mice is mapped from a population of postnatal skeletal stem cells to their downstream progenitors of bone, cartilage, and stromal tissue.
Coronary artery calcium (CAC) is an established predictor of future major adverse atherosclerotic cardiovascular events in asymptomatic individuals. However, limited data exist as to how CAC compares ...with functional testing (FT) in estimating prognosis in symptomatic patients.
In the PROMISE trial (Prospective Multicenter Imaging Study for Evaluation of Chest Pain), patients with stable chest pain (or dyspnea) and intermediate pretest probability for obstructive coronary artery disease were randomized to FT (exercise electrocardiography, nuclear stress, or stress echocardiography) or anatomic testing. We evaluated those who underwent CAC testing as part of the anatomic evaluation (n=4209) and compared that with results of FT (n=4602). We stratified CAC and FT results as normal or mildly, moderately, or severely abnormal (for CAC: 0, 1-99 Agatston score AS, 100-400 AS, and >400 AS, respectively; for FT: normal, mild=late positive treadmill, moderate=early positive treadmill or single-vessel ischemia, and severe=large ischemic region abnormality). The primary end point was all-cause death, myocardial infarction, or unstable angina hospitalization over a median follow-up of 26.1 months. Cox regression models were used to calculate hazard ratios (HRs) and C statistics to determine predictive and discriminatory values.
Overall, the distribution of normal or mildly, moderately, or severely abnormal test results was significantly different between FT and CAC (FT: normal, n=3588 78.0%; mild, n=432 9.4%; moderate, n=217 4.7%; severe, n=365 7.9%; CAC: normal, n=1457 34.6%; mild, n=1340 31.8%; moderate, n=772 18.3%; severe, n=640 15.2%;
<0.0001). Moderate and severe abnormalities in both arms robustly predicted events (moderate: CAC: HR, 3.14; 95% confidence interval, 1.81-5.44; and FT: HR, 2.65; 95% confidence interval, 1.46-4.83; severe: CAC: HR, 3.56; 95% confidence interval, 1.99-6.36; and FT: HR, 3.88; 95% confidence interval, 2.58-5.85). In the CAC arm, the majority of events (n=112 of 133, 84%) occurred in patients with any positive CAC test (score >0), whereas fewer than half of events occurred in patients with mildly, moderately, or severely abnormal FT (n=57 of 132, 43%;
<0.001). In contrast, any abnormality on FT was significantly more specific for predicting events (78.6% for FT versus 35.2% for CAC;
<0.001). Overall discriminatory ability in predicting the primary end point of mortality, nonfatal myocardial infarction, and unstable angina hospitalization was similar and fair for both CAC and FT (C statistic, 0.67 versus 0.64). Coronary computed tomographic angiography provided significantly better prognostic information compared with FT and CAC testing (C index, 0.72).
Among stable outpatients presenting with suspected coronary artery disease, most patients experiencing clinical events have measurable CAC at baseline, and fewer than half have any abnormalities on FT. However, an abnormal FT was more specific for cardiovascular events, leading to overall similarly modest discriminatory abilities of both tests.
URL: https://www.clinicaltrials.gov. Unique identifier: NCT01174550.
Millions of individuals have used illicit anabolic-androgenic steroids (AAS), but the long-term cardiovascular associations of these drugs remain incompletely understood.
Using a cross-sectional ...cohort design, we recruited 140 experienced male weightlifters 34 to 54 years of age, comprising 86 men reporting ≥2 years of cumulative lifetime AAS use and 54 nonusing men. Using transthoracic echocardiography and coronary computed tomography angiography, we assessed 3 primary outcome measures: left ventricular (LV) systolic function (left ventricular ejection fraction), LV diastolic function (early relaxation velocity), and coronary atherosclerosis (coronary artery plaque volume).
Compared with nonusers, AAS users demonstrated relatively reduced LV systolic function (mean±SD left ventricular ejection fraction = 52±11% versus 63±8%;
<0.001) and diastolic function (early relaxation velocity = 9.3±2.4 cm/second versus 11.1±2.0 cm/second;
<0.001). Users currently taking AAS at the time of evaluation (N=58) showed significantly reduced LV systolic (left ventricular ejection fraction = 49±10% versus 58±10%;
<0.001) and diastolic function (early relaxation velocity = 8.9±2.4 cm/second versus 10.1±2.4 cm/second;
=0.035) compared with users currently off-drug (N=28). In addition, AAS users demonstrated higher coronary artery plaque volume than nonusers (median interquartile range 3 0, 174 mL
versus 0 0, 69 mL
;
=0.012). Lifetime AAS dose was strongly associated with coronary atherosclerotic burden (increase 95% confidence interval in rank of plaque volume for each 10-year increase in cumulative duration of AAS use: 0.60 SD units 0.16-1.03 SD units;
=0.008).
Long-term AAS use appears to be associated with myocardial dysfunction and accelerated coronary atherosclerosis. These forms of AAS-associated adverse cardiovascular phenotypes may represent a previously underrecognized public-health problem.
Stem cell regulation and hierarchical organization of human skeletal progenitors remain largely unexplored. Here, we report the isolation of a self-renewing and multipotent human skeletal stem cell ...(hSSC) that generates progenitors of bone, cartilage, and stroma, but not fat. Self-renewing and multipotent hSSCs are present in fetal and adult bones and can also be derived from BMP2-treated human adipose stroma (B-HAS) and induced pluripotent stem cells (iPSCs). Gene expression analysis of individual hSSCs reveals overall similarity between hSSCs obtained from different sources and partially explains skewed differentiation toward cartilage in fetal and iPSC-derived hSSCs. hSSCs undergo local expansion in response to acute skeletal injury. In addition, hSSC-derived stroma can maintain human hematopoietic stem cells (hHSCs) in serum-free culture conditions. Finally, we combine gene expression and epigenetic data of mouse skeletal stem cells (mSSCs) and hSSCs to identify evolutionarily conserved and divergent pathways driving SSC-mediated skeletogenesis.
Display omitted
Display omitted
•PDPN+CD146−CD73+CD164+ marks a self-renewing, multipotent human skeletal stem cell•hSSCs can be isolated from fetal, adult, BMP2-treated human adipose stroma, and iPSCs•hSSCs undergo local expansion in response to acute skeletal injury•Comparison of mouse and human SSCs reveals evolutionary differences in skeletogenesis
Identification of a human skeletal stem cell reveals conserved and species-specific pathways in skeletal development, and response to injury and will guide future regenerative approaches.
Rising oceanic and atmospheric oxygen levels through time have been crucial to enhanced habitability of surface Earth environments. Few redox proxies can track secular variations in dissolved oxygen ...concentrations around threshold levels for metazoan survival in the upper ocean. We present an extensive compilation of iodine-to-calcium ratios (I/Ca) in marine carbonates. Our record supports a major rise in the partial pressure of oxygen in the atmosphere at ~400 million years (Ma) ago and reveals a step change in the oxygenation of the upper ocean to relatively sustainable near-modern conditions at ~200 Ma ago. An Earth system model demonstrates that a shift in organic matter remineralization to greater depths, which may have been due to increasing size and biomineralization of eukaryotic plankton, likely drove the I/Ca signals at ~200 Ma ago.
Much of the current volume of Earth's continental crust had formed by the end of the Archaean eon
(2.5 billion years ago), through melting of hydrated basaltic rocks at depths of approximately 25-50 ...kilometres, forming sodic granites of the tonalite-trondhjemite-granodiorite (TTG) suite
. However, the geodynamic setting and processes involved are debated, with fundamental questions arising, such as how and from where the required water was added to deep-crustal TTG source regions
. In addition, there have been no reports of voluminous, homogeneous, basaltic sequences in preserved Archaean crust that are enriched enough in incompatible trace elements to be viable TTG sources
. Here we use variations in the oxygen isotope composition of zircon, coupled with whole-rock geochemistry, to identify two distinct groups of TTG. Strongly sodic TTGs represent the most-primitive magmas and contain zircon with oxygen isotope compositions that reflect source rocks that had been hydrated by primordial mantle-derived water. These primitive TTGs do not require a source highly enriched in incompatible trace elements, as 'average' TTG does. By contrast, less sodic 'evolved' TTGs require a source that is enriched in both water derived from the hydrosphere and also incompatible trace elements, which are linked to the introduction of hydrated magmas (sanukitoids) formed by melting of metasomatized mantle lithosphere. By concentrating on data from the Palaeoarchaean crust of the Pilbara Craton, we can discount a subduction setting
, and instead propose that hydrated and enriched near-surface basaltic rocks were introduced into the mantle through density-driven convective overturn of the crust. These results remove many of the paradoxical impediments to understanding early continental crust formation. Our work suggests that sufficient primordial water was already present in Earth's early mafic crust to produce the primitive nuclei of the continents, with additional hydrated sources created through dynamic processes that are unique to the early Earth.
•A resource recovery microbial fuel cell is proposed for urine-containing wastewater treatment.•Urea hydrolysis rate is increased by microbial and electrical processes.•Ammonium migration through the ...ion exchange membrane replaces ammonia stripping.•N, P, and S nutrients are efficiently recovered.•No external energy consumption is needed.
Resources in urine-containing wastewater are useful if recovered as nutrients. In this study, a three-chamber resource recovery microbial fuel cell (RRMFC) is proposed to treat synthetic urine-containing wastewater with various organic pollutants and recover N, P, and S nutrients. In the treatment, urea hydrolysis was increased by microbial and electrical processes. Ions migration driven by the self-generated electric field was used to recover nutrients from the wastewater. Over one cycle (∼3 days), 99% of urea, 97% of COD, 99% of histidine, 91% of creatinine, 99% of sodium acetate, 98% of SO42−, and 99% of PO43− were removed from the wastewater, and at the same time, 42% of total nitrogen, 37% of PO43−, 59% of SO42−, and 33% of total salts were recovered in the middle chamber. This technology is very attractive for sustainable resource recovery from urine-containing wastewater.
Small molecules can affect many cellular processes. The disambiguation of these effects to identify the causative mechanisms of cell death is extremely challenging. This challenge impacts both ...clinical development and the interpretation of chemical genetic experiments. CX-5461 was developed as a selective RNA polymerase I inhibitor, but recent evidence suggests that it may cause DNA damage and induce G-quadraplex formation. Here we use three complimentary data mining modalities alongside biochemical and cell biological assays to show that CX-5461 exerts its primary cytotoxic activity through topoisomerase II poisoning. We then show that acquired resistance to CX-5461 in previously sensitive lymphoma cells confers collateral resistance to the topoisomerase II poison doxorubicin. Doxorubicin is already a frontline chemotherapy in a variety of hematopoietic malignancies, and CX-5461 is being tested in relapse/refractory hematopoietic tumors. Our data suggest that themechanism of cell death induced by CX-5461 is critical for rational clinical development in these patients. Moreover, CX-5461 usage as a specific chemical genetic probe of RNA polymerase I function is challenging to interpret. Our multimodal data-driven approach is a useful way to detangle the intended and unintended mechanisms of drug action across diverse essential cellular processes.
Checkpoint blockade immunotherapy relies on energized cytotoxic T cells attacking tumour tissue systemically. However, for many cancers, the reliance on T cell infiltration leads to low response ...rates. Conversely, radiotherapy has served as a powerful therapy for local tumours over the past 100 years, yet is rarely sufficient to cause systemic tumour rejection. Here, we describe a treatment strategy that combines nanoscale metal-organic framework (nMOF)-enabled radiotherapy-radiodynamic therapy with checkpoint blockade immunotherapy for both local and systemic tumour elimination. In mouse models of breast and colorectal cancer, intratumorally injected nMOFs treated with low doses of X-ray irradiation led to the eradication of local tumours and, when loaded with an inhibitor of the immune checkpoint molecule indoleamine 2,3-dioxygenase, the irradiated nMOFs led to consistent abscopal responses that rejected distal tumours. By combining the advantages of local radiotherapy and systemic tumour rejection via synergistic X-ray-induced in situ vaccination and indoleamine 2,3-dioxygenase inhibition, nMOFs may overcome some of the limitations of checkpoint blockade in cancer treatment.
PDF
