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A variety of covalent modifications of RNA have been identified and demonstrated to affect RNA processing, stability, and translation. Methylation of adenosine at the N6 position (m6A) in messenger RNA (mRNA) is currently the most well-studied RNA modification and is catalyzed by the RNA methyltransferase complex METTL3/METTL14. Once generated, m6A can modulate mRNA splicing, export, localization, degradation, and translation. Although potent and selective inhibitors exist for several members of the Type I S-adenosylmethionine (SAM)-dependent methyltransferase family, no inhibitors have been reported for METTL3/METTL14 to date. To facilitate drug discovery efforts, a sensitive and robust mass spectrometry–based assay for METTL3/METTL14 using self-assembled monolayer desorption/ionization (SAMDI) technology has been developed. The assay uses an 11-nucleotide single-stranded RNA compared to a previously reported 27-nucleotide substrate. IC50values of mechanism-based inhibitors S-adenosylhomocysteine (SAH) and sinefungin (SFG) are comparable between the SAMDI and radiometric assays that use the same substrate. This work demonstrates that SAMDI technology is amenable to RNA substrates and can be used for high-throughput screening and compound characterization for RNA-modifying enzymes.

In this article author talks about looking forward to emerging from the COVID-19 pandemic as America remains in the grip of an epidemic of deaths from drug overdose, suicide, and alcohol poisoning. Topics include examines that the FDA approved OxyContin, an ostensibly safe, "time-released" opioid, as a pain treatment and case and Deaton describe it as "legalized heroin."

During the solar minimum, when the Sun is at its least active, the solar wind1,2is observed at high latitudes as a predominantly fast (more than 500 kilometres per second), highly Alfvénic rarefied stream of plasma originating from deep within coronal holes. Closer to the ecliptic plane, the solar wind is interspersed with a more variable slow wind3of less than 500 kilometres per second. The precise origins of the slow wind streams are less certain4; theories and observations suggest that they may originate at the tips of helmet streamers5,6, from interchange reconnection near coronal hole boundaries7,8, or within coronal holes with highly diverging magnetic fields9,10. The heating mechanism required to drive the solar wind is also unresolved, although candidate mechanisms include Alfvén-wave turbulence11,12, heating by reconnection in nanoflares13, ion cyclotron wave heating14and acceleration by thermal gradients1. At a distance of one astronomical unit, the wind is mixed and evolved, and therefore much of the diagnostic structure of these sources and processes has been lost. Here we present observations from the Parker Solar Probe15at 36 to 54 solar radii that show evidence of slow Alfvénic solar wind emerging from a small equatorial coronal hole. The measured magnetic field exhibits patches of large, intermittent reversals that are associated with jets of plasma and enhanced Poynting flux and that are interspersed in a smoother and less turbulent flow with a near-radial magnetic field. Furthermore, plasma-wave measurements suggest the existence of electron and ion velocity-space micro-instabilities10,16that are associated with plasma heating and thermalization processes. Our measurements suggest that there is an impulsive mechanism associated with solar-wind energization and that micro-instabilities play a part in heating, and we provide evidence that low-latitude coronal holes are a key source of the slow solar wind.

The prediction of a supersonic solar wind1was first confirmed by spacecraft near Earth2,3and later by spacecraft at heliocentric distances as small as 62 solar radii4. These missions showed that plasma accelerates as it emerges from the corona, aided by unidentified processes that transport energy outwards from the Sun before depositing it in the wind. Alfvénic fluctuations are a promising candidate for such a process because they are seen in the corona and solar wind and contain considerable energy5–7. Magnetic tension forces the corona to co-rotate with the Sun, but any residual rotation far from the Sun reported until now has been much smaller than the amplitude of waves and deflections from interacting wind streams8. Here we report observations of solar-wind plasma at heliocentric distances of about 35 solar radii9–11, well within the distance at which stream interactions become important. We find that Alfvén waves organize into structured velocity spikes with duration of up to minutes, which are associated with propagating S-like bends in the magnetic-field lines. We detect an increasing rotational component to the flow velocity of the solar wind around the Sun, peaking at 35 to 50 kilometres per second—considerably above the amplitude of the waves. These flows exceed classical velocity predictions of a few kilometres per second, challenging models of circulation in the corona and calling into question our understanding of how stars lose angular momentum and spin down as they age12–14.

NASA’s Parker Solar Probe mission1recently plunged through the inner heliosphere of the Sun to its perihelia, about 24 million kilometres from the Sun. Previous studies farther from the Sun (performed mostly at a distance of 1 astronomical unit) indicate that solar energetic particles are accelerated from a few kiloelectronvolts up to near-relativistic energies via at least two processes: ‘impulsive’ events, which are usually associated with magnetic reconnection in solar flares and are typically enriched in electrons, helium-3 and heavier ions2, and ‘gradual’ events3,4, which are typically associated with large coronal-mass-ejection-driven shocks and compressions moving through the corona and inner solar wind and are the dominant source of protons with energies between 1 and 10 megaelectronvolts. However, some events show aspects of both processes and the electron–proton ratio is not bimodally distributed, as would be expected if there were only two possible processes5. These processes have been very difficult to resolve from prior observations, owing to the various transport effects that affect the energetic particle population en route to more distant spacecraft6. Here we report observations of the near-Sun energetic particle radiation environment over the first two orbits of the probe. We find a variety of energetic particle events accelerated both locally and remotely including by corotating interaction regions, impulsive events driven by acceleration near the Sun, and an event related to a coronal mass ejection. We provide direct observations of the energetic particle radiation environment in the region just above the corona of the Sun and directly explore the physics of particle acceleration and transport.

THIS ELECTION season, residents of Washington state are seeing some unusual ads. In one, a young girl is sobbing outside an intensive-care unit, plaintively crying, 'My father never thought he'd [...]

•Improvement in N95 respirator fitted efficiency occurred with escalating instructions.•Previous use of an N95 may not convey performance benefits without instruction reminders.•Performance increases were noted after video demonstration and staff fit advice.•Written manufacturer instructions may not yield as good protection in general-use cases.•N95 respirator video demonstration training has the potential to benefit public health.

We report observations of reconnection exhausts in the Heliospheric Current Sheet (HCS) during Parker Solar Probe Encounters 08 and 07, at 16 Rsand 20 Rs, respectively. Heliospheric current sheet (HCS) reconnection accelerated protons to almost twice the solar wind speed and increased the proton core energy by a factor of ∼3, due to the Alfvén speed being comparable to the solar wind flow speed at these near‐Sun distances. Furthermore, protons were energized to super‐thermal energies. During E08, energized protons were found to have leaked out of the exhaust along separatrix field lines, appearing as field‐aligned energetic proton beams in a broad region outside the HCS. Concurrent dropouts of strahl electrons, indicating disconnection from the Sun, provide further evidence for the HCS being the source of the beams. Around the HCS in E07, there were also proton beams but without electron strahl dropouts, indicating that their origin was not the local HCS reconnection exhaust. Magnetic reconnection in current sheets is a universal plasma process that converts magnetic energy into particle energy. The process is important in many laboratory, solar, and astrophysical plasmas. The heliospheric current sheet (HCS), which originates from the Sun and extends throughout the heliosphere, is the largest current sheet in the solar system. One of the surprises of the Parker Solar Probe mission is the finding that magnetic reconnection is almost always active in the near‐Sun HCS, despite its enormous scales. In this paper, we report direct evidence showing that reconnection in the HCS close to the Sun can be a source of energetic protons observed in the solar wind. The reason protons can be accelerated to high energies (to tens of kilo‐electronvolts) is because the available magnetic energy per particle is high close to the Sun. This finding is important because the source of energetic protons in the heliosphere is unknown. Large available magnetic energy per particle led to significant proton acceleration by reconnection in the near‐Sun heliospheric current sheet (HCS) at 16 and 20 RsProton beams and strahl electron dropouts in separatrices are evidence for HCS being a source of energetic protons seen outside the HCSEnergetic protons beams outside the HCS also exist without strahl electron dropouts. Their origin is unlikely to be the local HCS exhaust Large available magnetic energy per particle led to significant proton acceleration by reconnection in the near‐Sun heliospheric current sheet (HCS) at 16 and 20 Rs Proton beams and strahl electron dropouts in separatrices are evidence for HCS being a source of energetic protons seen outside the HCS Energetic protons beams outside the HCS also exist without strahl electron dropouts. Their origin is unlikely to be the local HCS exhaust

Proton exchange membranes (PEMs) in fuel cell stacks develop biaxial hygrothermal fatigue stresses in response to changing operation conditions. Determination of these stresses is complicated as both constitutive properties of PEM and the hygrothermal strain in PEM are highly dependent on time, temperature and water absorption. In this study, by tracking the spherical bending curvature of a bimaterial strip composed of a 25-um thick PEM (Nafion) and a 250-um thick PEEK (polyether ether ketone) substrate using a Digital Image Correlation (DIC) system, the biaxial tensile and compressive stresses in the plane of the PEM during humidity cycles are recorded. Due to the relatively high bending stiffness ratio between PEEK and PEM, the hygral stresses in the PEM are determined from the bimaterial curvature without requiring knowledge of the constitutive properties of the PEM. As the strain in the PEM released due to bending of the bimaterial strip is limited, the stresses measured using the bimaterial strip are very close to that in a fully constrained membrane, mimicking those in a fuel cell. The hygral strain in a freestanding membrane placed next to the bimaterial structure is recorded at the same time using the DIC system. The full stress and strain histories during incremental relative humidity (RH) test between 10%RH and liquid wet as well as during larger RH cycles are presented. The hygral expansion of Nafion during the increasing and decreasing RH step changes exhibits an asymmetry that resembles the behavior of glassy polymers during the classic Kovacs temperature jump test. The stress history also reveals the RH-dependent viscoelasticity of Nafion.

Anxiety disorders are the most common mental illnesses in the United States. Despite having a number of medication options readily available, benzodiazepines (BZs) and antidepressants have achieved remission rates of only 35% after 8 weeks of acute treatment. In the development of new anxiolytics, particularly those that affect the γ-aminobutyric acid system, it is essential to assess the new compound's potential to cause discontinuation symptoms after stopping the medication as part of both short- and long-term treatment. This report describes the development of the 20-item Penn Physician Withdrawal Checklist (PWC), a smaller version of the original 35-item PWC, and examines its validity, internal consistency, test-retest and interrater reliability, and factor structure. The PWC scores, assessed at the peak of withdrawal severity, were selected from 143 of our patients for an orthogonal factor analysis. Our results suggest that the Penn Physician Withdrawal Checklist is a simple and accurate method to assess anxiolytic discontinuation symptoms.

Efficient quality control is essential to ensure high sensitivity of Papanicolaou (Pap) smears. For this purpose, rescreening of 10% random negative smears is increasingly felt to be ineffective. Rapid rescreening (RR) of all negative Pap smears is more practical and has received widespread acceptance, especially in Europe, although its sensitivity is difficult to monitor and its retrospective nature may influence the vigilance of the screeners. The method of rapid prescreening (RPS) overcomes these drawbacks because rapid review of Pap smears precedes full screening.All routine conventional Pap smears (n = 8364) over 2 months underwent RPS by 12 cytotechnologists, followed by full screening. Data were analyzed to determine correlation between the RPS sensitivity of individual cytotechnologists and both their sensitivity in full screening and their years of experience as cytotechnologists.There was a striking variability in sensitivity (15.4%–72.7%) among the 12 screeners with an atypical squamous cells of undetermined significance (ASCUS) threshold. There was no correlation between RPS sensitivity of individual cytotechnologists with either their sensitivity in full screening or their years of experience as cytotechnologists.The skills required of a cytotechnologist for achieving a high sensitivity in RPS are apparently different from those of full screening and are independent of the sensitivity of the screeners at full screening or of the years of experience as cytotechnologists. Cancer (Cancer Cytopathol) 2006; © 2006 American Cancer Society.

The tensile stress–strain behavior of Nafion 117 and sulfonated poly(arylene ether sulfone) copolymer (BPSH35) membranes were explored with respect to the effects of the strain rate, counterion type, molecular weight, and presence of inorganic fillers. The yielding properties of the two films were most affected by the change in the strain rate. The stress–strain curves of Nafion films in acid and salt forms exhibited larger deviations at strains above the yield strain. As the molecular weight of the BPSH35 samples increased, the elongation at break improved significantly. Enhanced mechanical properties were observed for the composite membrane of BPSH35 and zirconium phenylphosphonate (2% w/w) in comparison with its matrix BPSH35 film. The stress‐relaxation behavior of Nafion and BPSH35 membranes was measured at different strain levels and different strain rates. Master curves were constructed in terms of plots of the stress‐relaxation modulus and time on a double‐logarithm scale. A three‐dimensional bundle‐cluster model was proposed to interpret these observations, combining the concepts of elongated polymer aggregates, proton‐conduction channels, and states of water. The rationale focused on the polymer bundle rotation/interphase chain readjustment before yielding and polymer aggregate disentanglements and reorientation after yielding. © 2006 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 44: 1453–1465, 2006

There are a lack of data on the quantity and location of eosinophils in the gastrointestinal tract of healthy individuals. Accordingly, we examined gastrointestinal biopsies obtained during endoscopic evaluation of pediatric patients. Biopsies were previously interpreted as having no diagnostic abnormality. The presence of extracellular eosinophil constituents and the quantity of eosinophils in atopic versus nonatopic individuals was determined. In the esophagus, eosinophils were present in only 2.7% of high-power fields (hpf), with a mean value of 0.03 ± 0.10 eosinophils/hpf (mean ± standard deviation) and a maximum of 1 eosinophil/hpf. Examination of the antrum and fundus revealed similar numbers of eosinophils in the lamina propria (1.9 ± 1.3 and 2.1 ± 2.4 eosinophils/hpf, respectively), with no eosinophils observed in the surface epithelium. In the small intestine, there were 9.6 ± 5.3 (maximum, 26 eosinophils/hpf) and 12.4 ± 5.4 eosinophils/hpf (maximum, 28 eosinophils/hpf) in the intercryptal lamina propria of the duodenum and ileum, respectively. The number of eosinophils in the surface epithelium and crypt epithelium was minimal. In the large intestine, the highest concentration of eosinophils was observed in the cecum (20.3 ±8.2 eosinophils/hpf; maximum, 50 eosinophils/hpf), and there were lower concentrations in the transverse and sigmoid colon (16.3 ± 5.6 and 8.3 ± 5.9 eosinophils/hpf, respectively). The percentage of fields demonstrating extracellular eosinophil granules in all gastrointestinal segments was 70% to 93%, and extracellular granules were most numerous at the edge of the biopsy (P< 0.05). Atopic and nonatopic patients had comparable numbers of eosinophils. These data establish baseline gastrointestinal eosinophil values in pediatric patients without apparent pathological disease.

The widely used yttria-stabilized zirconia (YSZ) electrolyte is subjected to thermal and external stresses under operation, so that the enhancement of the mechanical properties is an important issue in planar solid oxide fuel cells. Fracture strengths of 8mol% YSZ electrolytes as 100×100mm squire plates, 23mm disks, and 17mm disks were evaluated using plate tensile, ball-on-ring, and pressure-on-ring testing methodologies, respectively. Finite element analysis (FEA) was validated and used to calculate the stress distribution and peak stress for the biaxial strength tests. A Weibull analysis was carried out on the test∕FEA-predicted peak stresses, and Weibull strength, modulus, and material scale parameters were found for each test methodology. The methodologies were compared and evaluated based on the results of the Weibull analysis; the pressure-on-ring test is preferred for brittle thin-film fracture strength testing.

The work of psychologists can be stressful and demanding, which calls for an understanding of how psychologists cope with the stress of their work and how they prevent distress by establishing habits of well-functioning. Previous studies on psychologists' well-functioning and coping behaviors have not considered the role of spiritual practices in the life of the professional. 400 psychologists (69% response rate) returned questionnaires rating their levels of distress, coping behaviors, methods of well-functioning, and religious coping. No overall differences were observed in levels of distress between more religious and less religious psychologists. Spiritual practices, especially attending religious services and prayer/meditation, were among the most frequently endorsed for a religious subset of the sample. Spiritual practices also appear to play an important role in the prevention of distress for religious psychologists, in that spiritual practices appear to be the first line of defense against distress and are considered to play a very important role in functioning well as a professional.

Examines the exposures and disease variables in 111 chrysotile miners and millers of Quebec, Canada. Background information on the study; Methodology used; Findings and analysis of results; Conclusions.

In this paper, an analysis is developed to predict the stress redistribution in the presence of single and multiple fractured fibers in a unidirectional composite material. This analysis includes the effects of constituent properties, fiber volume fraction, and crack size on the strain concentrations experienced by the adjacent fibers. These effects are not included in other predictions such as shear lag or those of Hedgepeth and Van Dyke. In addition, the predictions are compared with direct experimental measurements obtained from model composite tests.

In this manuscript we use a concentric cylinder model to determine the stresses in a composite material subjected to transverse loading. After selecting a failure criterion, it is possible for us to determine a fiber coating which optimizes the strain to failure of the composite material. Experimental results are presented for a model composite system and the results are compared to the analytical predictions. The model is shown to give reasonable agreement with the experimental data.

In this paper, the problem of a penny-shaped crack in the center of multiple concentric cylinders is considered. By making appropriate choices for the stress functions in each of the constituents and making the standard assumptions of linear elasticity, it is possible to reduce the problem to the solution of a Fredholm integral equation of the second kind which may be solved numerically. This solution is used in conjunction with a geometry approximation to model the stress concentrations due to a broken fiber in a unidirectional composite material. The results suggest that models of such a shear lag may be missing important features of the stress state including surrounding broken fibers in composite materials.

The proportion of sulphur found in vegetation increases as an industrial sulphur dioxide emission source is approached, but this trend is modified by topographic extremes. Stable sulphur isotope analysis revealed that increased sulphur concentrations in arborcal and terricolous lichens, andPicea glauca needles were due to incorporation of sulphur emitted as sulphur dioxide by the Kaybob sour gas plant near Fox Creek, Alberta, Canada. It is confirmed thatPicea glauca gets its sulphur from both the soil and the air; arboreal lichens get their sulphur primarily from the atmosphere; and terricolous lichens get theirs from the air and particulate fallout. It is suggested that arboreal lichens selectively excrete isotopically light sulphur when thallus concentrations exceed 1,400 ppm. Accumulation of sulphur in vegetation is dependent, on fumigation episode duration, frequency, and concentration, as well as the plant's ability to avoid injury, but is not closely correlated with average sulphation rates. The implications of terrestrial moss-lichen carpet destruction is discussed.

The morphology of the plasma membrane of ciliated and nonciliated bronchiolar epithelial cells of the hamster lung was studied using freeze fracture electron microscopy and transmission electron microscopy of thin sections. Tight junction structure of bronchiolar epithelial cells was evaluated with respect to the total number of junctional strands, and the organization of tight junctional fibrils. Tight junctional complexes seen on the surfaces of nonciliated cells had from 4 to 9 junctional strands (mean: 6.0±0.1). Ciliated cells displayed 4 to 10 tight junctional strands (mean: 6.9±0.1). Nonciliated bronchiolar epithelial cell (NC) membranes showed aggregates of 6 nm particles organized into rectilinear arrays of 2 to 30 particles. These particle clusters were seen predominantly at the basal pole of cells in close association with areas of intercellular interdigitation. NC cells also displayed membrane areas of particle clearing and aggregation consistent with intermediate phases of membrane fusion and exocytosis.

& Reflective teachers are never satisfied that they have all the answers. By continually seeking new information, they constantly challenge their own practices and assumptions. In the process, new dilemmas surface and teachers initiate a new cycle of planning, acting, observing, and reflecting. (Ross et al., 1993, p. 337)

Calculus reform has not taken sufficient cognizance of the importance of altering the teaching method. An experiment carried out by the author in which two sections of calculus were taught by contrasting methods - one by traditional lecture, the other with Socratic discovery - indicated clear advantages to be gained by employing the discovery method.

Features tricks and tips about the AutoCAD computer software. menus; Calculation of centroid, volume and weight from a two-dimensional profile; Recording of drawings; Listings.