We present the outcome of a mission concept study that designed a small atmospheric entry probe and examined the feasibility and benefit of a future multi-probe mission to Uranus. We call our design ...the Small Next-generation Atmospheric Probe (SNAP). The primary scientific objective of a multi-probe mission is to reveal spatial variability of atmospheric conditions. This article first highlights that not all measurements must be repeated by multiple probes; some quantities, notably the noble gas abundances and elemental isotopic ratios, are not expected to be variable, and thus need to be performed only by a single large Primary Probe. Our study demonstrates that, by focusing its measurements on spatially variable quantities including atmospheric vapor concentrations, thermal stratification and wind speed, a viable atmospheric probe design is realized with an entry system with 50-cm heatshield diameter and 30-kg atmospheric entry mass.
As a case study, we present a detailed analysis of adding SNAP to a notional Uranus Orbiter with Probe mission, which launches in 2031 and arrives at Uranus in 2043, designed by the NASA-funded Science Definition Team study in 2017. We demonstrate that, with minimal changes to the notional carrier mission, a large Primary Probe and SNAP can be delivered to the winter and summer hemispheres to examine seasonal atmospheric variabilities, and transmit data to the Orbiter, which in turn relays the data to Earth. The additional maneuvers needed to deliver SNAP totals a Delta-V of 84 m/s, and consumes 43 kg of propellant. The addition of SNAP is expected to cost $79.5 million in FY2018 dollars; thus, our study demonstrates that a multi-probe mission can be implemented with a 4% cost increase relative to the $2.0 billion cost estimate of the notional mission designed by NASA’s Ice Giant Flagship Science Definition Team study reported in 2017.
The SNAP design incorporates several technologies that are currently under development at various Technology Readiness Levels (TRL) between TRL = 4 and TRL = 6. In particular, our study recommends targeted technology development in Thermal Protection System materials, advanced batteries, and miniaturized instruments to enable and enhance future small atmospheric probes like SNAP.
Obsessive-compulsive disorder (OCD) is a common, debilitating neuropsychiatric illness with complex genetic etiology. The International OCD Foundation Genetics Collaborative (IOCDF-GC) is a ...multi-national collaboration established to discover the genetic variation predisposing to OCD. A set of individuals affected with DSM-IV OCD, a subset of their parents, and unselected controls, were genotyped with several different Illumina SNP microarrays. After extensive data cleaning, 1465 cases, 5557 ancestry-matched controls and 400 complete trios remained, with a common set of 469,410 autosomal and 9657 X-chromosome single nucleotide polymorphisms (SNPs). Ancestry-stratified case-control association analyses were conducted for three genetically-defined subpopulations and combined in two meta-analyses, with and without the trio-based analysis. In the case-control analysis, the lowest two P-values were located within DLGAP1 (P=2.49 × 10(-6) and P=3.44 × 10(-6)), a member of the neuronal postsynaptic density complex. In the trio analysis, rs6131295, near BTBD3, exceeded the genome-wide significance threshold with a P-value=3.84 × 10(-8). However, when trios were meta-analyzed with the case-control samples, the P-value for this variant was 3.62 × 10(-5), losing genome-wide significance. Although no SNPs were identified to be associated with OCD at a genome-wide significant level in the combined trio-case-control sample, a significant enrichment of methylation QTLs (P<0.001) and frontal lobe expression quantitative trait loci (eQTLs) (P=0.001) was observed within the top-ranked SNPs (P<0.01) from the trio-case-control analysis, suggesting these top signals may have a broad role in gene expression in the brain, and possibly in the etiology of OCD.
Despite recent advances, median survival for patients with resectable glioblastoma multiforme (GBM) is only 12 to 15 months. We previously observed minimal toxicity and a 9.0-month median survival ...after treatment with intralesional autologous lymphokine-activated killer (LAK) cells in 40 patients with recurrent GBM. In this study, GBM patients were treated with adjuvant intralesional LAK cells. Eligible patients had completed primary therapy for GBM without disease progression. LAK cells were produced by incubating autologous peripheral blood mononuclear cells with interleukin-2 for 3 to 7 days and then placed into the surgically exposed tumor cavity by a neurosurgeon. The 19 men and 14 women had a median age of 57 years. Prior therapy included surgical resection (97%), partial brain irradiation (97%), gamma knife radiosurgery (97%), and temozolomide chemotherapy (70%). Median time from diagnosis to LAK cell therapy was 5.3 months (range: 3.0 to 11.1 mo). LAK cell treatment was well tolerated; average length of hospitalization was 3 days. At the time of this analysis, 27 patients have died; the median survival from the date of original diagnosis is 20.5 months with a 1-year survival rate of 75%. In subset analyses, superior survival was observed for patients who received higher numbers of CD3+/CD16+/CD56+ (T-LAK) cells in the cell products, which was associated with not taking corticosteroids in the month before leukopheresis. Intralesional LAK cell therapy is safe and the survival sufficiently encouraging to warrant further evaluation in a randomized phase 2 trial of intralesional therapies with LAK or carmustine-impregnated wafers.
To study changes in food advertising on television after Chile's food marketing restriction was implemented in June 2016.
Food advertisements shown between 6 am and 12 am on the 4 primary broadcast ...and 4 cable channels with the largest Chilean youth audiences during 2 random weeks in April and May 2016 and 2017 were analyzed for product nutrition and child-directed marketing.
The percentage of ads for foods high in energy, saturated fats, sugars, or sodium (HEFSS) decreased from 41.9% before the regulation to 14.8% after the regulation (
< .001). This decrease occurred in programs intended for children (from 49.7% to 12.7%;
< .001) as well as general audiences (from 38.5% to 15.7%;
< .001). The largest declines were seen for sodas, desserts, breakfast cereals and industrialized fruit- and vegetable-flavored drinks. Fewer HEFSS ads featured child-directed content (a decrease from 44.0% to 12.0%;
< .001), and the remaining child-directed HEFSS ads primarily aired on internationally owned cable channels.
The significant postregulation decrease in the prevalence of HEFSS television ads suggests that children in Chile are now less exposed to unhealthy food advertising. However, television originating from national and international outlets should still be monitored for compliance. (
. Published online ahead of print May 21, 2020: e1-e6. doi:10.2105/AJPH.2020.305658).
Entomopathogenic nematodes (EPNs) are unique parasites due to their symbiosis with entomopathogenic bacteria and their ability to kill insect hosts quickly after infection. It is widely believed that ...EPNs rely on their bacterial partners for killing hosts. Here we disproved this theory by demonstrating that the in vitro activated infective juveniles (IJs) of Steinernema carpocapsae (a well-studied EPN species) release venom proteins that are lethal to several insects including Drosophila melanogaster. We confirmed that the in vitro activation is a good approximation of the in vivo process by comparing the transcriptomes of individual in vitro and in vivo activated IJs. We further analyzed the transcriptomes of non-activated and activated IJs and revealed a dramatic shift in gene expression during IJ activation. We also analyzed the venom proteome using mass spectrometry. Among the 472 venom proteins, proteases and protease inhibitors are especially abundant, and toxin-related proteins such as Shk domain-containing proteins and fatty acid- and retinol-binding proteins are also detected, which are potential candidates for suppressing the host immune system. Many of the venom proteins have conserved orthologs in vertebrate-parasitic nematodes and are differentially expressed during IJ activation, suggesting conserved functions in nematode parasitism. In summary, our findings strongly support a new model that S. carpocapsae and likely other Steinernema EPNs have a more active role in contributing to the pathogenicity of the nematode-bacterium complex than simply relying on their symbiotic bacteria. Furthermore, we propose that EPNs are a good model system for investigating vertebrate- and human-parasitic nematodes, especially regarding the function of excretory/secretory products.
In line with calls for action from international health organizations, Chile implemented in June 2016 a set of regulations to tackle the obesity epidemic. The new regulation includes the mandatory ...use of front-of-package warning labels on packaged foods/beverages high in energy, sugars, saturated fats and sodium. Additionally, such foods cannot be sold nor offered in daycares/schools and cannot be promoted to children under 14yo. The law is targeted to children; thus, this study examined mothers' understanding, perceptions, and behaviors associated with the regulation one year after its implementation, using a qualitative approach.
Nine focus groups of mothers (7-10 people each) of children (2-14yo) were conducted in July 2017 in Santiago-Chile. They were stratified by socioeconomic status (SES) and children's age. Macrocodes were developed by three researchers, combining an iterative process of deductive and inductive thematic analyses. Quotations representing each category were selected.
Mothers understood the new regulation as a policy to fight child obesity and were aware that products with more labels were less healthy than products with fewer labels. Attention and use of labels in the buying decision-making process ranged from participants who did not pay attention to others who relied on them as a quick shortcut (mostly from middle and upper-SES); many mothers indicated changing their purchase habits only when buying new products. Mothers declared that young children accepted school environment changes while teens/preteens resisted them more. Many mothers agreed that schools have become key promoters of food behavioral change. Mothers were less aware about the food marketing regulations. Mothers declared that they perceived that the regulation was changing the perceptions, attitudes and behaviors toward healthier eating patterns.
After the first year of implementation, the regulation was well known by mothers of diverse SES and different children ages. The degree of use of warning labels was heterogeneous among participants, but most of them agreed that their children, particularly the youngest have positive attitudes toward the regulation and have become promoters of change in their families. Many mothers also expressed that they perceived an important shift toward healthier eating, which may lead to a change in eating social norms. This information contributes to better understand how regulatory actions may influence people's consumer behaviors.
Transgenic (Tg) mice overexpressing rat heat shock protein 70 (hsp70) demonstrated less infarction than did wild-type (WT) littermates after permanent focal cerebral ischemia. The purpose of this ...study was to determine whether neuronal injury and apoptosis were reduced in hsp70 Tg mice after transient focal ischemia. The effects of hsp70 overexpression were also evaluated after transient global ischemia or kainic acid (KA)-induced seizures, to verify the results in other excitotoxic stress models.
Transient focal ischemia was produced with middle cerebral artery occlusion via intraluminal suture cannulation. Infarction volumes were assessed 24 hours after 30 minutes of middle cerebral artery occlusion. Transient global ischemia was produced with 25 minutes of bilateral common carotid artery occlusion. KA (30 mg/kg) was administered subcutaneously, and seizure activity was evaluated. The number of eosinophilic neurons was assessed in the CA1 region 72 hours after bilateral common carotid artery occlusion and in the CA3 region 24 hours after KA administration.
The infarction volume after transient middle cerebral artery occlusion was significantly smaller in hsp70 Tg mice than in WT mice (9.1 +/- 5.7 mm(3) versus 22.4 +/- 16.8 mm(3), P < 0.05). The number of eosinophilic neurons in the CA1 area after bilateral common carotid artery occlusion and in CA3 after KA injection was significantly lower in hsp70 Tg mice than in WT mice (949.1 +/- 1095.5 versus 2406.9 +/- 1380.3, P < 0.05, and 33.8 +/- 45.3 versus 119.4 +/- 112.1, P < 0.05, respectively). Fewer terminal deoxynucleotidyl transferase-mediated biotinylated deoxyuridine triphosphate nick end-labeling-positive cells were observed in hsp70 Tg mice than in WT mice in each model.
The results demonstrate that overexpression of hsp70 reduces neuronal injury after ischemia and seizures. The reduction in the number of terminal deoxynucleotidyl transferase-mediated biotinylated deoxyuridine triphosphate nick end-labeling-positive cells in hsp70 Tg mice suggests that hsp70 overexpression might reduce apoptotic cell death.
Parasitic helminths release molecular effectors into their hosts and these effectors can directly damage host tissue and modulate host immunity. Excreted/secreted proteins (ESPs) are one category of ...parasite molecular effectors that are critical to their success within the host. However, most studies of nematode ESPs rely on in vitro stimulation or culture conditions to collect the ESPs, operating under the assumption that in vitro conditions mimic actual in vivo infection. This assumption is rarely if ever validated. Entomopathogenic nematodes (EPNs) are lethal parasites of insects that produce and release toxins into their insect hosts and are a powerful model parasite system. We compared transcriptional profiles of individual Steinernema feltiae nematodes at different time points of activation under in vitro and in vivo conditions and found that some but not all time points during in vitro parasite activation have similar transcriptional profiles with nematodes from in vivo infections. These findings highlight the importance of experimental validation of ESP collection conditions. Additionally, we found that a suite of genes in the neuropeptide pathway were downregulated as nematodes activated and infection progressed in vivo, suggesting that these genes are involved in host-seeking behavior and are less important during active infection. We then characterized the ESPs of activated S. feltiae infective juveniles (IJs) using mass spectrometry and identified 266 proteins that are released by these nematodes. In comparing these ESPs with those previously identified in activated S. carpocapsae IJs, we identified a core set of 52 proteins that are conserved and present in the ESPs of activated IJs of both species. These core venom proteins include both tissue-damaging and immune-modulating proteins, suggesting that the ESPs of these parasites include both a core set of effectors as well as a specialized set, more adapted to the particular hosts they infect.
Theba pisana
is an invasive snail pest which has established itself in San Diego County and some areas of Los Angeles County, California. The snail has grown to large populations in some areas and ...mitigation is becoming necessary to stop the spread of the species. In a previous study, three US strains of
Phasmarhabditis
species (
P
.
californica
,
P
.
papillosa
, and
P
.
hermaphrodita
) effectively killed juvenile (0.25 gram each, 4–6 mm wide)
T
.
pisana
in laboratory conditions at 5 times (150 IJs/cm
2
) the recommended dose. Based on laboratory assays, we demonstrated that the same three US strains of
Phasmarhabditis
can effectively kill larger adult
T
.
pisana
(0.4–1.2 gram, 11.5-15mm wide) in two weeks at the same dose. The strains were more efficient at killing
T
.
pisana
than the compared molluscicide Sluggo Plus®. Results further showed that the most virulent
P
.
californica
did not effectively kill
T
.
pisana
at lower doses of 30 IJs/cm
2
and 90 IJs/cm
2
. Additional research is needed to develop the most efficient means of application of
Phasmarhabditis
to mitigate
T
.
pisana
in the field.
Generation of the “epitranscriptome” through post-transcriptional ribonucleoside modification embeds a layer of regulatory complexity into RNA structure and function. Here, we describe ...N4-acetylcytidine (ac4C) as an mRNA modification that is catalyzed by the acetyltransferase NAT10. Transcriptome-wide mapping of ac4C revealed discretely acetylated regions that were enriched within coding sequences. Ablation of NAT10 reduced ac4C detection at the mapped mRNA sites and was globally associated with target mRNA downregulation. Analysis of mRNA half-lives revealed a NAT10-dependent increase in stability in the cohort of acetylated mRNAs. mRNA acetylation was further demonstrated to enhance substrate translation in vitro and in vivo. Codon content analysis within ac4C peaks uncovered a biased representation of cytidine within wobble sites that was empirically determined to influence mRNA decoding efficiency. These findings expand the repertoire of mRNA modifications to include an acetylated residue and establish a role for ac4C in the regulation of mRNA translation.
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•NAT10 catalyzes N4-acetylcytidine (ac4C) modification of a broad range of mRNAs•mRNA acetylation within coding sequences promotes translation and mRNA stability•ac4C in wobble sites stimulates translation efficiency
Post-transcriptional acetylation of cytidines in mammalian mRNAs enhances RNA stability and translation.
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