MicroRNAs (miRNAs) act in concert with Argonaute (AGO) proteins to repress target messenger RNAs. After AGO loading, miRNAs generally exhibit slow turnover. An important exception occurs when miRNAs ...encounter highly complementary targets, which can trigger a process called target-directed miRNA degradation (TDMD). During TDMD, miRNAs undergo tailing and trimming, suggesting that this is an important step in the decay mechanism. We identified a cullin-RING ubiquitin ligase (CRL), containing the substrate adaptor ZSWIM8, that mediates TDMD. The ZSWIM8 CRL interacts with AGO proteins, promotes TDMD in a tailing and trimming-independent manner, and regulates miRNA expression in multiple cell types. These findings suggest a model in which the ZSWIM8 ubiquitin ligase mediates TDMD by directing proteasomal decay of miRNA-containing complexes engaged with highly complementary targets.
We describe laboratory experiments which reproduce characteristic signals observed on spacecraft, believed to be caused by dust impact. A simulated spacecraft, including an antenna system using a ...facsimile of the preamplifier electronics from the STEREO/WAVES instrument, was bombarded by 10 km/s submicron‐sized dust at the University of Colorado Institute for Modeling Plasma, Atmospheres, and Cosmic Dust accelerator facility. Signal variation was investigated as a function of the DC potentials of both the spacecraft and the antennas. We observed (1) signals corresponding to modification of the spacecraft body potential, an important process believed to be responsible for the so‐called “triple hit” antenna signals on STEREO, (2) a few‐eV energy distribution for the electrons and ions released in the impact leading to (3) signals corresponding to direct recollection of a substantial fraction of the impact charge by the spacecraft antennas, even at modest antenna bias potentials. We also observe (4) an unexpected class of fast antenna signals, which do not appear to be caused by charge recollection by either the spacecraft or the antennas and may be induced by charge separation in the expanding plasma cloud. Similar signals are also commonly observed by the STEREO/WAVES instrument but have not previously been analyzed.
Key Point
We observe fast electrostatically induced signals also seen in the STEREO data
The effective ion and electron temperatures of dust impact generated plasma clouds are measured experimentally as a function of impact speed in the range of 4–20 km/s. The measurements are performed ...in an experimental setup that resembles the detection of dust particles by electric field or plasma wave antennas on spacecraft. The spacecraft is modeled as a conductive plate and a cylindrical antenna connected to voltage follower electronics is used to measure the collected charge. The setup is bombarded with dust particles using the University of Colorado IMPACT dust accelerator facility. The effective ion and electron temperatures are determined from the variation of the impact signals with an applied bias voltage. The results show that the temperatures of the electrons remain at around or below 5 eV over the investigated impact speed range. The characteristic ion temperature is about 5 eV at 4 km/s; however, it increases with increasing impact speed to > 10 eV at 20 km/s. Given that the floating potentials of spacecraft and antennas are on the order of a few volts, the findings suggest that any model for the interpretation of dust impact signals should take into account the effects of a finite temperatures.
Key Points
The effective temperature of dust impact plasmas is measured experimentally
The electron temperature remains below 5 eV for impact velocities below 20 km/s
The ion temperature increases with impact velocity
The impact ionization charge yield is experimentally measured from four common materials used in space and specifically on the two STEREO spacecraft (germanium‐coated black Kapton, beryllium copper, ...multilayer insulation, and solar cells). Cosmic dust particle impacts on spacecraft have been detected by electric field and plasma and radio wave instruments. The accurate interpretation of these signals is complicated by many factors, including the details of the spacecraft antenna system, the local spacecraft plasma environment, and our understanding of the physics of the impact process. The most basic quantity, the amount of charge liberated upon impact, is generally considered poorly constrained and is suspected to depend on the target material. Here we show that for common materials used on spacecraft this variability is small for impacts around 10 km/s, and the impact charge yield can be approximated by 80 fC for a 1 pg projectile. At higher speeds (∼50 km/s), variation of up to a factor of 5 is observed. The measured yields in the 10–50 km/s range are compared to measurements and predictions from the literature and are found to be lower than predicted by at least a factor of 12 at 10 km/s and at least a factor of 1.7 at 50 km/s. Impact charge is also found to depend on angle of incidence; the data suggest a maximum at 45°.
Key PointsImpact ionization was measured for spacecraft‐relevant materialsYields are smaller than predicted by certain published lawsYields do not differ strongly between materials tested at 10 km/s
HES3 is a basic helix-loop-helix transcription factor that regulates neural stem cell renewal during development. HES3 overexpression is predictive of reduced overall survival in patients with ...fusion-positive rhabdomyosarcoma, a pediatric cancer that resembles immature and undifferentiated skeletal muscle. However, the mechanisms of HES3 cooperation in fusion-positive rhabdomyosarcoma are unclear and are likely related to her3/HES3's role in neurogenesis. To investigate HES3's function during development, we generated a zebrafish CRISPR/Cas9 null mutation of her3, the zebrafish ortholog of HES3. Loss of her3 is not embryonic lethal and adults exhibit expected Mendelian ratios. Embryonic her3 zebrafish mutants exhibit dysregulated neurog1 expression, a her3 target gene, and the mutant her3 fails to bind the neurog1 promoter sequence. Further, her3 mutants are significantly smaller than wildtype and a subset present with lens defects as adults. Transcriptomic analysis of her3 mutant embryos indicates that genes involved in organ development, such as pctp and grinab, are significantly downregulated. Further, differentially expressed genes in her3 null mutant embryos are enriched for Hox and Sox10 motifs. Several cancer-related gene pathways are impacted, including the inhibition of matrix metalloproteinases. Altogether, this new model is a powerful system to study her3/HES3-mediated neural development and its misappropriation in cancer contexts.
Display omitted
•Generated zebrafish her3 CRISPR/Cas9 knockouts with loss-of-function mutations.•her3 mutant is unable to bind known target, neurog1, causing dysregulated expression.•her3 loss causes abnormal expression of core subset of developmental regulatory genes.•Sox10 DNA binding motifs are enriched in her3 knockout differentially expressed genes.•Tumor microenvironment and matrix metalloprotease pathways are enriched in her3 knockout.
Kratom (
) exhibits μ-receptor agonism and is used as an opioid substitute. While opioids are known to inhibit sexual behavior, less is known regarding kratom. We conducted a pilot study to assess ...the subjective impact of kratom upon male sexual health including erectile and ejaculatory function.
Twitter and Reddit (r/Kratom) were accessed to disseminate our survey featuring validated instruments (the International Index of Erectile Function, IIEF, and the premature ejaculation diagnostic tool, PEDT). Sexual health prior to and after 4 weeks of kratom use was assessed.
Most males surveyed (n = 165) were 18-40 years old (84.9%), with 95.8% of respondents using it at least weekly and 82.4% using kratom for ≥1 year. Reasons for use included treating pain (39.4%), and mental health conditions (63.6%). Kratom was associated with a positive (37.7%) and negative (20.5%) impact on sexual health. Kratom subjectively increased time to ejaculation in 104 (66.6%) patients, perceived as positive by 62 (59.6%). Seventy-eight patients answered questions about premature ejaculation. The median (with interquartile range, IQR, following;) pre-kratom and kratom use scores were 13.0; 8.0 and 6.5; 5.0, respectively (p < 0.001). Ejaculation before 5 minutes improved after kratom (51.3% vs 12.8%) (p < 0.0001). Following kratom use, patients reported lack of frustration with ejaculation prior to desire (21.8% vs 61.5%) (p < 0.001). The erectile function domain of the IIEF was statistically significantly different however - clinically similar pre-kratom use (29.0; 5.75) versus 27.0; 6.75 during kratom use (p = 0.037).
Clinicians treating male sexual health should be aware of kratom and its potential effect on ejaculatory and erectile function.
Mobile learning has the potential to supplement information communication technology (ICT), online learning and the traditional teaching and learning methods to educate practitioners in the clinical ...practice area. Following the development of several Post Graduate modules of learning for the theory and clinical skills required to undertake the Newborn Infant Physical Examination (NIPE), a small research study was undertaken to combine mobile learning and NIPE. The research study explored the hypothesis that mobile devices could be used in pedagogically effective ways to support and enhance the learning and acquisition of clinical skills in the clinical arena. Participants in the study each received a handheld mobile device (iPod) that had been loaded with several Reusable Learning Objects (RLO) outlining each aspect of the physical examination to be performed. At the end of the module (12 weeks in duration), each participant completed an evaluation questionnaire. Participants confirmed that mobile learning afforded flexibility in time and place of learning and captured their interest in the learning material. This study reports that the use of mobile technology for skill acquisition is creative and innovative, placing learning firmly in the hands of the learner.
Alveolar rhabdomyosarcoma is a pediatric soft-tissue sarcoma caused by
fusion oncogenes and is characterized by impaired skeletal muscle development. We developed human
-driven zebrafish models of ...tumorigenesis and found that
exhibits discrete cell lineage susceptibility and transformation. Tumors developed by 1.6-19 months and were primitive neuroectodermal tumors or rhabdomyosarcoma. We applied this
transgenic zebrafish model to study how
leverages early developmental pathways for oncogenesis and found that
is a unique target. Ectopic expression of the
human ortholog,
, inhibits myogenesis in zebrafish and mammalian cells, recapitulating the arrested muscle development characteristic of rhabdomyosarcoma. In patients,
is overexpressed in fusion-positive versus fusion-negative tumors. Finally,
overexpression is associated with reduced survival in patients in the context of the fusion. Our novel zebrafish rhabdomyosarcoma model identifies a new
target,
/
, that contributes to impaired myogenic differentiation and has prognostic significance in human disease.
Clinical sequencing efforts are rapidly identifying sarcoma gene fusions that lack functional validation. An example is the fusion of transcriptional coactivators, VGLL2-NCOA2, found in infantile ...rhabdomyosarcoma. To delineate VGLL2-NCOA2 tumorigenic mechanisms and identify therapeutic vulnerabilities, we implement a cross-species comparative oncology approach with zebrafish, mouse allograft, and patient samples. We find that VGLL2-NCOA2 is sufficient to generate mesenchymal tumors that display features of immature skeletal muscle and recapitulate the human disease. A subset of VGLL2-NCOA2 zebrafish tumors transcriptionally cluster with embryonic somitogenesis and identify VGLL2-NCOA2 developmental programs, including a RAS family GTPase, ARF6. In VGLL2-NCOA2 zebrafish, mouse, and patient tumors, ARF6 is highly expressed. ARF6 knockout suppresses VGLL2-NCOA2 oncogenic activity in cell culture, and, more broadly, ARF6 is overexpressed in adult and pediatric sarcomas. Our data indicate that VGLL2-NCOA2 is an oncogene that leverages developmental programs for tumorigenesis and that reactivation or persistence of ARF6 could represent a therapeutic opportunity.
Display omitted
•VGLL2-NCOA2 is transforming in transgenic zebrafish and mouse allograft models•Tumors resemble immature skeletal muscle and express developmental genes•Zebrafish, mouse, and human tumors overexpress a small GTPase, ARF6•ARF6 and VGLL2-NCOA2 genetically cooperate for pro-tumorigenic activity
Watson et al. use a cross-species comparative approach to develop zebrafish and mouse models of a rare fusion-driven pediatric sarcoma. These models recapitulate the human disease, and the integration of these systems identifies a conserved developmental target, ARF6. ARF6 cooperates with the primary oncogenic driver, representing a potential therapeutic opportunity.
Dust is common close to the martian surface, but no known process can lift appreciable concentrations of particles to altitudes above ~150 kilometers. We present observations of dust at altitudes ...ranging from 150 to above 1000 kilometers by the Langmuir Probe and Wave instrument on the Mars Atmosphere and Volatile Evolution spacecraft. Based on its distribution, we interpret this dust to be interplanetary in origin. A comparison with laboratory measurements indicates that the dust grain size ranges from 1 to 12 micrometers, assuming a typical grain velocity of ~18 kilometers per second. These direct observations of dust entering the martian atmosphere improve our understanding of the sources, sinks, and transport of interplanetary dust throughout the inner solar system and the associated impacts on Mars's atmosphere.
PDF
