The creation of genome-wide libraries for CRISPR knockout (CRISPRko), interference (CRISPRi), and activation (CRISPRa) has enabled the systematic interrogation of gene function. Here, we show that ...our recently-described CRISPRko library (Brunello) is more effective than previously published libraries at distinguishing essential and non-essential genes, providing approximately the same perturbation-level performance improvement over GeCKO libraries as GeCKO provided over RNAi. Additionally, we present genome-wide libraries for CRISPRi (Dolcetto) and CRISPRa (Calabrese), and show in negative selection screens that Dolcetto, with fewer sgRNAs per gene, outperforms existing CRISPRi libraries and achieves comparable performance to CRISPRko in detecting essential genes. We also perform positive selection CRISPRa screens and demonstrate that Calabrese outperforms the SAM approach at identifying vemurafenib resistance genes. We further compare CRISPRa to genome-scale libraries of open reading frames (ORFs). Together, these libraries represent a suite of genome-wide tools to efficiently interrogate gene function with multiple modalities.
To compare two-dimensional (2D) echocardiography, the current method of screening for treatment-related cardiomyopathy recommended by the Children's Oncology Group Guidelines, to cardiac magnetic ...resonance (CMR) imaging, the reference standard for left ventricular (LV) function.
Cross-sectional, contemporaneous evaluation of LV structure and function by 2D and three-dimensional (3D) echocardiography and CMR imaging in 114 adult survivors of childhood cancer currently median age 39 years (range, 22 to 53 years) exposed to anthracycline chemotherapy and/or chest-directed radiation therapy.
In this survivor population, 14% (n = 16) had an ejection fraction (EF) less than 50% by CMR. Survivors previously undiagnosed with cardiotoxicity (n = 108) had a high prevalence of EF (32%) and cardiac mass (48%) that were more than two standard deviations below the mean of normative CMR data. 2D echocardiography overestimated the mean EF of this population by 5%. Compared with CMR, 2D echocardiography (biplane method) had a sensitivity of 25% and a false-negative rate of 75% for detection of EF less than 50%, although 3D echocardiography had 53% and 47%, respectively. Twelve survivors (11%) had an EF less than 50% by CMR but were misclassified as ≥ 50% (range, 50% to 68%) by 2D echocardiography (biplane method). Detection of cardiomyopathy was improved (sensitivity, 75%) by using a higher 2D echocardiography cutoff (EF < 60%) to detect an EF less than 50% by the reference standard CMR.
CMR identified a high prevalence of cardiomyopathy among adult survivors previously undiagnosed with cardiac disease. 2D echocardiography demonstrated limited screening performance. In this high-risk population, survivors with an EF 50% to 59% by 2D echocardiography should be considered for comprehensive cardiac assessment, which may include CMR.
We present three STEVE (strong thermal emission velocity enhancement) events in conjunction with Time History of Events and Macroscale Interactions (THEMIS) in the magnetosphere and Defense ...Meteorological Satellite Program (DMSP) and Swarm in the ionosphere, for determining equatorial and interhemispheric signatures of the STEVE purple/mauve arc and picket fence. Both types of STEVE emissions are associated with subauroral ion drifts (SAID), electron heating, and plasma waves. The magnetosphere observations show structured electrons and flows and waves (likely kinetic Alfven, magnetosonic, or lower‐hybrid waves) just outside the plasmasphere. Interestingly, the event with the picket fence had a >~1 keV electron structure detached from the electron plasma sheet, upward field‐aligned currents (FACs), and ultraviolet emissions in the conjugate hemisphere, while the event with only the mauve arc did not have precipitation or ultraviolet emission. We suggest that the electron precipitation drives the picket fence, and heating drives the mauve as thermal emission.
Plain Language Summary
STEVE (strong thermal emission velocity enhancement) has become increasingly popular among citizen scientists due to its distinct colors and structures of emission in the night sky and its occurrence over more populated areas than for typical aurora in the auroral oval. This study addresses two major questions of STEVE: What is the energy source of the STEVE purple or mauve colored arc and green picket fence up in space? and Does STEVE occur in the Northern and Southern Hemispheres at the same time? Using a set of imaging and satellite observations, this study found that STEVE is connected to fast plasma flows, sharp plasma boundaries, and intense waves 25,000 km (15,000 miles) up in space. Photographs taken by citizen scientists have played a key role in finding STEVE and its morphology. Plasma heating due to the fast flows and waves is suggested to drive the mauve colored arc. But this mechanism does not explain the picket fence. We found that energetic particle precipitation drives the picket fence. The picket fence is found to occur in both hemispheres at the same time, supporting that the energy source far up in space feeds energy to both hemispheres.
Key Points
Magnetosphere observations show that STEVE corresponds to SAID, plasmapause, structured plasma boundaries, and waves in the magnetosphere
The picket fence is driven by electron precipitation; the red arc is driven by heat flux or frictional heating
Simultaneous conjugate observations show that part of STEVE has interhemispheric conjugacy
The study of monozygotic twins discordant for attention deficit hyperactivity disorder can elucidate mechanisms that contribute to the disorder, which affects ~7% of children. First, using in vivo ...neuroanatomic imaging on 14 pairs of monozygotic twins (mean age 9.7, s.d. 1.9 years), we found that discordance for the disorder is mirrored by differing dimensions of deep brain structures (the striatum and cerebellum), but not the cerebral cortex. Next, using whole-blood DNA from the same twins, we found a significant enrichment of epigenetic differences in genes expressed in these 'discordant' brain structures. Specifically, there is differential methylation of probes lying in the shore and shelf and enhancer regions of striatal and cerebellar genes. Notably, gene sets pertaining to the cerebral cortex (which did not differ in volume between affected and unaffected twins) were not enriched by differentially methylated probes. Genotypic differences between the twin pairs-such as copy number and rare, single-nucleotide variants-did not contribute to phenotypic discordance. Pathway analyses of the genes implicated by the most differentially methylated probes implicated γ-aminobutyric acid (GABA), dopamine and serotonin neurotransmitter systems. The study illustrates how neuroimaging can help guide the search for epigenomic mechanisms in neurodevelopmental disorders.
Auroral substorms are often associated with optical ray or bead structures during initial brightening (substorm auroral onset waves). Occurrence probabilities and properties of substorm onset waves ...have been characterized using 112 substorm events identified in Time History of Events and Macroscale Interactions during Substorms (THEMIS) all‐sky imager data and compared to Rice Convection Model–Equilibrium (RCM‐E) and kinetic instability properties. All substorm onsets were found to be associated with optical waves, and thus, optical waves are a common feature of substorm onset. Eastward propagating wave events are more frequent than westward propagating wave events and tend to occur during lower‐latitude substorms (stronger solar wind driving). The wave propagation directions are organized by orientation of initial brightening arcs. We also identified notable differences in wave propagation speed, wavelength (wave number), period, and duration between westward and eastward propagating waves. In contrast, the wave growth rate does not depend on the propagation direction or substorm strength but is inversely proportional to the wave duration. This suggests that the waves evolve to poleward expansion at a certain intensity threshold and that the wave properties do not directly relate to substorm strengths. However, waves are still important for mediating the transition between the substorm growth phase and poleward expansion. The relation to arc orientation can be explained by magnetotail structures in the RCM‐E, indicating that substorm onset location relative to the pressure peak determines the wave propagation direction. The measured wave properties agree well with kinetic ballooning interchange instability, while cross‐field current instability and electromagnetic ion cyclotron instability give much larger propagation speed and smaller wave period.
Key Points
Occurrence probability and property of different types of auroral onset waves are determined
Wave property does not relate to substorm strength but to plasma sheet configuration
Wave properties are most consistent with kinetic ballooning interchange instability
Ice particles play an important role in precipitation formation and
radiation balance. Therefore, an accurate description of ice initiation in
the atmosphere is of great importance for weather ...prediction models and
climate simulations. Despite the abundance of ice crystals in the
atmosphere, the mechanisms for their formation remain not well understood.
There are two major sets of mechanisms of ice initiation in the atmosphere:
primary nucleation and secondary ice production. Secondary ice production
occurs in the presence of preexisting ice, which results in an enhancement
of the concentration of ice particles. Until recently, secondary ice
production was mainly attributed to the rime-splintering mechanism, known as
the Hallett–Mossop process, which is active in a relatively narrow
temperature range from −3 to −8 ∘C. The existence of
the Hallett–Mossop process was well supported by in situ observations. The
present study provides an explicit in situ observation of secondary ice
production at temperatures as low as −27 ∘C, which is well outside
the range of the Hallett–Mossop process. This observation expands our
knowledge of the temperature range of initiation of secondary ice in clouds.
The obtained results are intended to stimulate laboratory and theoretical
studies to develop physically based parameterizations for weather prediction
and climate models.
In this multicenter, randomized trial, neonates with moderate or severe hypoxic–ischemic encephalopathy randomly assigned to whole-body hypothermia had a significantly reduced risk of death or ...moderate or severe disability at 18 to 22 months of age. This study suggests that whole-body hypothermia may improve substantially the outcomes for infants with hypoxic–ischemic encephalopathy.
Neonates with moderate or severe hypoxic–ischemic encephalopathy randomly assigned to whole-body hypothermia had a significantly reduced risk of death or moderate or severe disability at 18 to 22 months of age.
Among term infants, hypoxic–ischemic encephalopathy due to acute perinatal asphyxia remains an important cause of neurodevelopmental deficits in childhood. Infants with moderate encephalopathy have a 10 percent risk of death, and those who survive have a 30 percent risk of disabilities. Sixty percent of infants with severe encephalopathy die, and many, if not all, survivors are handicapped.
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Treatment is currently limited to supportive intensive care.
Reductions in brain temperature by 2°C to 5°C provide neuroprotection in newborn and adult animal models of brain ischemia.
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Brain cooling has a favorable effect on multiple pathways contributing to brain injury, including . . .
Necrotizing enterocolitis (NEC) is a significant complication for the premature infant. However, subsequent neurodevelopmental and growth outcomes of extremely low birth weight (ELBW) infants with ...NEC have not been well described. We hypothesized that ELBW infants with surgically managed (SurgNEC) are at greater risk for poor neurodevelopmental and growth outcomes than infants with medically managed NEC (MedNEC) compared with infants without a history of NEC (NoNEC). The objective of this study was to compare growth, neurologic, and cognitive outcomes among ELBW survivors of SurgNEC and MedNEC with NoNEC at 18 to 22 months' corrected age.
Multicenter, retrospective analysis was conducted of infants who were born between January 1, 1995, and December 31, 1998, and had a birth weight <1000 g in the National Institute of Child Health and Human Development Neonatal Research Network Registry. Neurodevelopment and growth were assessed at 18 to 22 months' postmenstrual age. chi2, t test, and logistic regression analyses were used.
A total of 2948 infants were evaluated at 18 to 22 months, 124 of whom were SurgNEC and 121 of whom were MedNEC. Compared with NoNEC, both SurgNEC and MedNEC infants were of lower birth weight and had a greater incidence of late sepsis; SurgNEC but not MedNEC infants were more likely to have received a diagnosis of cystic periventricular leukomalacia and bronchopulmonary dysplasia and been treated with postnatal steroids. Weight, length, and head circumference <10 percentile at 18 to 22 months were significantly more likely among SurgNEC but not MedNEC compared with NoNEC infants. After correction for anthropometric measures at birth and adjusted age at follow-up, all growth parameters at 18 to 22 months for SurgNEC but not MedNEC infants were significantly less than for NoNEC infants. SurgNEC but not MedNEC was a significant independent risk factor for Mental Developmental Index <70 (odds ratio OR: 1.61; 95% confidence interval CI: 1.05-2.50), Psychomotor Developmental Index <70 (OR: 1.95; 95% CI: 1.25-3.04), and neurodevelopmental impairment (OR: 1.78; 95% CI: 1.17-2.73) compared with NoNEC.
Among ELBW infants, SurgNEC is associated with significant growth delay and adverse neurodevelopmental outcomes at 18 to 22 months' corrected age compared with NoNEC. MedNEC does not seem to confer additional risk. SurgNEC is likely to be associated with greater severity of disease.
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