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Circadian rhythms are endogenous oscillations in nearly all organisms, from prokaryotes to humans, allowing them to adapt to cyclical environments for close to 24 h. Circadian rhythms are regulated by a central clock, based on a transcription-translation feedback loop. One important protein in the central loop in metazoan clocks is PERIOD, which is regulated in part by Casein kinase 1ε/δ (CK1ε/δ) phosphorylation. In the nematode Caenorhabditis elegans, period and casein kinase 1ε/δ are conserved as lin-42 and kin-20, respectively. Here, we studied the involvement of lin-42 and kin-20 in the circadian rhythms of the adult nematode using a bioluminescence-based circadian transcriptional reporter. We show that mutations of lin-42 and kin-20 generate a significantly longer endogenous period, suggesting a role for both genes in the nematode circadian clock, as in other organisms. These phenotypes can be partially rescued by overexpression of either gene under their native promoter. Both proteins are expressed in neurons and epidermal seam cells, as well as in other cells. Depletion of LIN-42 and KIN-20, specifically in neuronal cells after development, was sufficient to lengthen the period of oscillating sur-5 expression. Therefore, we conclude that LIN-42 and KIN-20 are critical regulators of the adult nematode circadian clock through neuronal cells.

INTRODUCTION: Clinical guidelines offer little guidance for treatment selection following inadequate response to conventional synthetic disease-modifying antirheumatic drug (csDMARD) in rheumatoid arthritis (RA). A molecular signature response classifier (MSRC) was validated to predict tumor necrosis factor inhibitor (TNFi) inadequate response. The decision impact of MSRC results on biologic and targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) selection was evaluated. METHODS: This is an analysis of AIMS, a longitudinal, prospective database of patients with RA tested using the MSRC. This study assessed selection of b/tsDMARDs class after MSRC testing by surveying physicians, the rate of b/tsDMARD prescriptions aligning with MSRC results, and the percentage of physicians utilizing MSRC results for decision-making. RESULTS: Of 1018 participants, 70.7% (720/1018) had treatment selected after receiving MSRC results. In this MSRC-informed cohort, 75.6% (544/720) of patients received a b/tsDMARD aligned with MSRC results, and 84.6% (609/720) of providers reported using MSRC results to guide treatment selection. The most prevalent reason reported (8.2%, 59/720) for not aligning treatment selection with MSRC results from the total cohort was health insurance coverage issues. CONCLUSION: This study showed that rheumatologists reported using the MSRC test to guide b/tsDMARD selection for patients with RA. In most cases, MSRC test results appeared to influence clinical decision-making according to physician self-report. Wider adoption of precision medicine tools like the MSRC could support rheumatologists and patients in working together to achieve optimal outcomes for RA.

Circadian rhythms are endogenous oscillations present in nearly all organisms from prokaryotes to humans, allowing them to adapt to cyclical environments close to 24 hours. Circadian rhythms are regulated by a central clock, which is based on a transcription-translation feedback loop. One important protein in the central loop in metazoan clocks is PERIOD, which is regulated in part by Casein kinase 1 ε/δ (CK1 ε/δ ) phosphorylation. In the nematode Caenorhabditis elegans , period and casein kinase 1ε/δ are conserved as lin-42 and kin-20 , respectively. Here we studied the involvement of lin-42 and kin-20 in circadian rhythms of the adult nematode using a bioluminescence-based circadian transcriptional reporter. We show that mutations of lin-42 and kin-20 generate a significantly longer endogenous period, suggesting a role for both genes in the nematode circadian clock, as in other organisms. These phenotypes can be partially rescued by overexpression of either gene under their native promoter. Both proteins are expressed in neurons and seam cells, a population of epidermal stem cells in C. elegans that undergo multiple divisions during development. Depletion of LIN-42 and KIN-20 specifically in neuronal cells after development was sufficient to lengthen the period of oscillating sur-5 expression. Therefore, we conclude that LIN-42 and KIN-20 are critical regulators of the adult nematode circadian clock through neuronal cells.

Abstract Circadian rhythms are endogenous oscillations in nearly all organisms, from prokaryotes to humans, allowing them to adapt to cyclical environments for close to 24 h. Circadian rhythms are regulated by a central clock, based on a transcription-translation feedback loop. One important protein in the central loop in metazoan clocks is PERIOD, which is regulated in part by Casein kinase 1ε/δ (CK1ε/δ) phosphorylation. In the nematode Caenorhabditis elegans, period and casein kinase 1ε/δ are conserved as lin-42 and kin-20, respectively. Here, we studied the involvement of lin-42 and kin-20 in the circadian rhythms of the adult nematode using a bioluminescence-based circadian transcriptional reporter. We show that mutations of lin-42 and kin-20 generate a significantly longer endogenous period, suggesting a role for both genes in the nematode circadian clock, as in other organisms. These phenotypes can be partially rescued by overexpression of either gene under their native promoter. Both proteins are expressed in neurons and epidermal seam cells, as well as in other cells. Depletion of LIN-42 and KIN-20, specifically in neuronal cells after development, was sufficient to lengthen the period of oscillating sur-5 expression. Therefore, we conclude that LIN-42 and KIN-20 are critical regulators of the adult nematode circadian clock through neuronal cells.

The most distant marsquake recorded so far by the InSight seismometer occurred at an epicentral distance of 146.3 ± 6.9o, close to the western end of Valles Marineris. On the seismogram of this event, we have identified seismic wave precursors, i.e., underside reflections off a subsurface discontinuity halfway between the marsquake and the instrument, which directly constrain the crustal structure away (about 4100-4500 km) from the InSight landing site. Here we show that the Martian crust at the bounce point between the lander and the marsquake is characterized by a discontinuity at about 20 km depth, similar to the second (deeper) intra-crustal interface seen beneath the InSight landing site. We propose that this 20-km interface, first discovered beneath the lander, is not a local geological structure but likely a regional or global feature, and is consistent with a transition from porous to non-porous Martian crustal materials.

We detected surface waves from two meteorite impacts on Mars. By measuring group velocity dispersion along the impact-lander path, we obtained a direct constraint on crustal structure away from the InSight lander. The crust north of the equatorial dichotomy had a shear wave velocity of approximately 3.2 kilometers per second in the 5- to 30-kilometer depth range, with little depth variation. This implies a higher crustal density than inferred beneath the lander, suggesting either compositional differences or reduced porosity in the volcanic areas traversed by the surface waves. The lower velocities and the crustal layering observed beneath the landing site down to a 10-kilometer depth are not a global feature. Structural variations revealed by surface waves hold implications for models of the formation and thickness of the martian crust.

Analyses of seismic data from the InSight mission have provided the first in situ constraints on the thickness of the crust of Mars. These crustal thickness constraints are currently limited to beneath the lander that is located in the northern lowlands, and we use gravity and topography data to construct global crustal thickness models that satisfy the seismic data. These models consider a range of possible mantle and core density profiles, a range of crustal densities, a low-density surface layer, and the possibility that the crustal density of the northern lowlands is greater than that of the southern highlands. Using the preferred InSight three-layer seismic model of the crust, the average crustal thickness of the planet is found to lie between 30 and 72 km. Depending on the choice of the upper mantle density, the maximum permissible density of the northern lowlands and southern highlands crust is constrained to be between 2,850 and 3,100 kg m−3. These crustal densities are lower than typical Martian basaltic materials and are consistent with a crust that is on average more felsic than the materials found at the surface. We argue that a substantial portion of the crust of Mars is a primary crust that formed during the initial differentiation of the planet. Various hypotheses for the origin of the observed intracrustal seisimic layers are assessed, with our preferred interpretation including thick volcanic deposits, ejecta from the Utopia basin, porosity closure, and differentiation products of a Borealis impact melt sheet.

Abstract Introduction Clinical guidelines offer little guidance for treatment selection following inadequate response to conventional synthetic disease-modifying antirheumatic drug (csDMARD) in rheumatoid arthritis (RA). A molecular signature response classifier (MSRC) was validated to predict tumor necrosis factor inhibitor (TNFi) inadequate response. The decision impact of MSRC results on biologic and targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) selection was evaluated. Methods This is an analysis of AIMS, a longitudinal, prospective database of patients with RA tested using the MSRC. This study assessed selection of b/tsDMARDs class after MSRC testing by surveying physicians, the rate of b/tsDMARD prescriptions aligning with MSRC results, and the percentage of physicians utilizing MSRC results for decision-making. Results Of 1018 participants, 70.7% (720/1018) had treatment selected after receiving MSRC results. In this MSRC-informed cohort, 75.6% (544/720) of patients received a b/tsDMARD aligned with MSRC results, and 84.6% (609/720) of providers reported using MSRC results to guide treatment selection. The most prevalent reason reported (8.2%, 59/720) for not aligning treatment selection with MSRC results from the total cohort was health insurance coverage issues. Conclusion This study showed that rheumatologists reported using the MSRC test to guide b/tsDMARD selection for patients with RA. In most cases, MSRC test results appeared to influence clinical decision-making according to physician self-report. Wider adoption of precision medicine tools like the MSRC could support rheumatologists and patients in working together to achieve optimal outcomes for RA.

Abstract Background The main objective of this study was to describe the relationship between working conditions, sleep and psycho-affective variables and medical errors. Methods This was an observational, analytical and cross-sectional study in which 661 medical residents answered questionnaires about working conditions, sleep and psycho-affective variables. Actigraphic sleep parameters and peripheral temperature circadian rhythm were measured in a subgroup of 38 subjects. Bivariate and multivariate predictors of medical errors were assessed. Results Medical residents reported working 66.2 ± 21.9 weekly hours. The longest continuous shift was of 28.4 ± 10.9 h. They reported sleeping 6.1 ± 1.6 h per day, with a sleep debt of 94 ± 129 min in workdays. A high percentage of them reported symptoms related to psycho-affective disorders. The longest continuous shift duration (OR = 1.03 [95% CI, 1.00–1.05], p = 0.01), working more than six monthly on-call shifts (OR = 1.87 [95% CI, 1.16–3.02], p = 0.01) and sleeping less than six hours per working day (OR = 1.66 [95% CI, 1.10–2.51], p = 0.02) were independently associated with self-reported medical errors. The report of medical errors was associated with an increase in the percentage of diurnal sleep (2.2% [95% CI, 0.1–4.3] vs 14.5% [95% CI, 5.9–23.0]; p = 0.01) in the actigraphic recording. Conclusions Medical residents have a high working hour load that affect their sleep opportunities, circadian rhythms and psycho-affective health, which are also related to the report of medical errors. These results highlight the importance of implementing multidimensional strategies to improve medical trainees’ sleep and wellbeing, increasing in turn their own and patients’ safety.

Seismic anisotropy is now commonly studied on Earth and has been detected at various depths, from the crust to the top of the lower mantle, in the lowermost mantle, and in the inner core. In the mantle, observations of seismic anisotropy are often taken as an indication of past or present deformation resulting in the preferential orientation of anisotropic minerals. In the crust, it can come from stress-induced oriented cracks, compositional layering, or crystallographic preferred orientation of minerals. While many questions remain regarding the presence and interpretation of seismic anisotropy on Earth, scientists are now faced with new, exciting challenges in trying to constrain the structure of other planetary bodies. One of the goals of NASA’s InSight mission, which landed on Mars in November 2018 and includes a very broadband seismometer, is to constrain Mars interior structure. Compared to seismic studies of Earth, which benefit from the availability of a wealth of high quality data recorded on many seismic stations, difficulties with InSight stem from having only one seismic instrument and only a few high quality events. In this study, we analyzed the horizontally polarized (SH)-wave reflections generated from the shallowest crustal layer (layer 1) detected at 8 ± 2 km beneath the InSight lander site by a previous receiver function (RF) study. From Sol 105, when the first low-frequency marsquake was recorded, to Sol 1094, a total of 83 broadband and low-frequency events were detected, but only nine are rated as quality-A with constraints on both their epicentral distance and back azimuth. Of those nine events, we selected four that did not show any interference with mantle triplications generated by the olivine to the wadsleyite phase transition and that had a clear signal after the direct SH phase. A model space search approach enabled us to obtain a range of acceptable SH-wave velocities and layer thicknesses, which we then compared with the RF models of Knapmeyer-Endrun et al. (2021). We found that the acceptable SH-wave speeds are systematically lower than those from the RF study. Since this RF analysis is sensitive to vertically polarized (SV)-waves, we interpret this difference as the signature of radial anisotropy with an anisotropy coefficient ?=(???/???)2 between 0.7 and 0.9. Modeling of preferred alignment of inclusions shows that dry or fluid-filled cracks/fractures, and igneous inclusions can reproduce the observed radial anisotropy amplitude with VSV>VSH.

Loss of elastin due to aging, disease, or injury can lead to impaired tissue function. In this study, de novo tropoelastin (TE) synthesis is investigated in vitro and in vivo using different TE-encoding synthetic mRNA variants after codon optimization and nucleotide modification. Codon optimization shows a strong effect on protein synthesis without affecting cell viability in vitro, whereas nucleotide modifications strongly modulate translation and reduce cell toxicity. Selected TE mRNA variants (3, 10, and 30 μg) are then analyzed in vivo in porcine skin after intradermal application. Administration of 30 μg of native TE mRNA with a me1 Ψ modification or 10 and 30 μg of unmodified codon-optimized TE mRNA is required to increase TE protein expression in vivo. In contrast, just 3 μg of a codon-optimized TE mRNA variant with the me1 Ψ modification is able to increase protein expression. Furthermore, skin toxicity is investigated in vitro by injecting 30 μg of mRNA of selected TE mRNA variants into a human full-thickness skin model, and no toxic effects are observed. Thereby, for the first time, an increased dermal TE synthesis by exogenous administration of synthetic mRNA is demonstrated in vivo. Codon optimization of a synthetic mRNA can significantly increase protein expression and therapeutic outcome.

Abstract Background For phylogenetic reconstructions, conflict in signal is a potential problem for tree reconstruction. For instance, molecular data from different cellular components, such as the mitochondrion and nucleus, may be inconsistent with each other. Mammalian studies provide one such case of conflict where mitochondrial data, which display compositional biases, support the Marsupionta hypothesis, but nuclear data confirm the Theria hypothesis. Most observations of compositional biases in tree reconstruction have focused on lineages with different composition than the majority of the lineages under analysis. However in some situations, the position of taxa that lack compositional bias may be influenced rather than the position of taxa that possess compositional bias. This situation is due to apparent symplesiomorphic characters and known as "the symplesiomorphy trap". Results Herein, we report an example of the sympleisomorphy trap and how to detect it. Worms within Terebelliformia (sensu Rouse & Pleijel 2001) are mainly tube-dwelling annelids comprising five 'families': Alvinellidae, Ampharetidae, Terebellidae, Trichobranchidae and Pectinariidae. Using mitochondrial genomic data, as well as data from the nuclear 18S, 28S rDNA and elongation factor-1α genes, we revealed incongruence between mitochondrial and nuclear data regarding the placement of Trichobranchidae. Mitochondrial data favored a sister relationship between Terebellidae and Trichobranchidae, but nuclear data placed Trichobranchidae as sister to an Ampharetidae/Alvinellidae clade. Both positions have been proposed based on morphological data. Conclusions Our investigation revealed that mitochondrial data of Ampharetidae and Alvinellidae exhibited strong compositional biases. However, these biases resulted in a misplacement of Trichobranchidae, rather than Alvinellidae and Ampharetidae. Herein, we document that Trichobranchidae was apparently caught in the symplesiomorphy trap suggesting that in certain situations even homologies can be misleading.

According to IEA (2018), there is a huge gap between the first-best social optimal utilization of Carbon Capture and Storage (CCS) technologies to lower global C[O.sub.2] emissions and the current, negligible diffusion of this technology. This calls for a financial support mechanism for CCS. We study to what extent promotion of CCS in Europe should be through subsidizing development and production of CCS technologies--an upstream subsidy--or by subsidising the purchasers of CCS technologies--a downstream subsidy. This question is examined theoretically in a stylized model and numerically by using a new approach that integrates strategic trade policy with an economic model of the European energy markets. The theory model suggests that upstream subsidies should clearly be preferred, and this is confirmed by the numerical simulations. For the European power market, the numerical simulations suggest that subsidies to CCS coal power should exceed subsidies to CCS gas power. Keywords: Carbon capture and storage (CCS), Electricity, Strategic trade policy, Upstream subsidy, Downstream subsidy, Profit shifting, Cournot, 1. INTRODUCTION According to IEA (2018), there is a huge gap between the first-best social optimal utilization of Carbon Capture and Storage (CCS) technologies to lower global C[O.sub.2] emissions and [...]

We offer a more nuanced characterization of teachers' narrative inquiry as professional development (Johnson & Golombek, 2002) by grounding our definition of and empirical research on teachers' narrative inquiry from a Vygotskian sociocultural theoretical perspective. Our goal is to reaffirm our belief in the educational value of teachers' narrative inquiry as "systematic exploration that is conducted "by" teachers and "for" teachers through their own stories and language" (p. 6), while empirically documenting the crucial role of teacher educators in creating mediational spaces, dialogic interactions, and pedagogical tools for teachers' narrative inquiry to flourish as professional development. It is also our goal to re-conceptualize teachers' narrative inquiry as unbounded by time and place, and as a more fluid and emerging process.