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OBJECTIVES/GOALS: To characterize the oncogenic potential of HNSCC cell lines harboring 17 non-canonical PIK3CA mutations. METHODS/STUDY POPULATION: Non-canonical PIK3CA mutant constructs generated via site-directed mutagenesis are subcloned into doxycycline-inducible vector pLVX-Puro. Serum-dependent HNSCC cell line (PCI-52-SD1) is then stably transfected with vectors and undergo doxycycline-induction. Cell survival is determined by depriving cells of fetal bovine serum for 72 hours and quantifying remaining cells with 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Cell proliferation and migration is evaluated with colony formation assays and transwell assays respectively. RESULTS/ANTICIPATED RESULTS: To date, the survival behavior of eight non-canonical mutants was assessed. Three mutants – Q75E, V71I, and E970K – exhibited 18.7-26.7% greater survival rate relative to cells transfected with wild-type. Five mutants – R519G, Y606C, W328S, C905S, and M1040I – demonstrated survival rates that differed only by −4.3% to +6.6% relative to wild-type. We hypothesize the three activating mutants that exhibited increased survival will also demonstrate increased cell proliferation and migratory behavior whereas the three neutral mutants will not differ from control. DISCUSSION/SIGNIFICANCE OF IMPACT: Ongoing HNSCC PI3K inhibitor trials could be more effective if all PIK3CA hyperactivation mutations are known. Identifying non-canonical mutation effects could result in greater efficacy if drugs are restricted only to those with activating mutations. CONFLICT OF INTEREST DESCRIPTION: JRG and DEJ are co-inventors of cyclic STAT3 decoy and have financial interests in STAT3 Therapeutics, Inc. STAT3 Therapeutics, Inc. holds an interest in a cyclic STAT3 decoy oligonucleotide. The remaining authors declare no conflicts.
This paper studies the propagation of free, long waves on a potential vorticity front in the presence of a vertical coast, using a
-layer, quasi-geostrophic model with piecewise-constant potential vorticity. The coastal boundary induces flow through image vorticity and a Kelvin wave, either of which can reinforce or oppose the Rossby wave dynamics at the front. The behaviour of the front depends strongly on the relative strengths of these three mechanisms, which are explicit in our model. The richest behaviour, which includes kink solitons (under-compressive shocks) and compound-wave structures, occurs in the regime where vortical effects are dominant. The evolution of the front is described by a fully nonlinear finite-amplitude equation including first-order dispersive effects, which is related to the modified Korteweg–de Vries equation. The different behaviours are classified using the canonical example of the Riemann problem, which we analyse using El’s technique of ‘dispersive shock-fitting’. Contour-dynamic simulations show that the dispersive long-wave theory captures the behaviour of the full quasi-geostrophic system to a high degree of accuracy.
The spread of the Zika virus (ZIKV) in the Americas led to large outbreaks across the region and most of the Southern hemisphere. Of greatest concern were complications following acute infection during pregnancy. At the beginning of the outbreak, the risk to unborn babies and their clinical presentation was unclear. This report describes the methods and results of the UK surveillance response to assess the risk of ZIKV to children born to returning travellers. Established surveillance systems operating within the UK – the paediatric and obstetric surveillance units for rare diseases, and national laboratory monitoring – enabled rapid assessment of this emerging public health threat. A combined total of 11 women experiencing adverse pregnancy outcomes after possible ZIKV exposure were reported by the three surveillance systems; five miscarriages, two intrauterine deaths and four children with clinical presentations potentially associated with ZIKV infection. Sixteen women were diagnosed with ZIKV during pregnancy in the UK. Amongst the offspring of these women, there was unequivocal laboratory evidence of infection in only one child. In the UK, the number and risk of congenital ZIKV infection for travellers returning from ZIKV-affected countries is very small.
The rocky shores of the north-east Atlantic have been long studied. Our focus is from Gibraltar to Norway plus the Azores and Iceland. Phylogeographic processes shape biogeographic patterns of biodiversity. Long-term and broadscale studies have shown the responses of biota to past climate fluctuations and more recent anthropogenic climate change. Inter- and intra-specific species interactions along sharp local environmental gradients shape distributions and community structure and hence ecosystem functioning. Shifts in domination by fucoids in shelter to barnacles/mussels in exposure are mediated by grazing by patellid limpets. Further south fucoids become increasingly rare, with species disappearing or restricted to estuarine refuges, caused by greater desiccation and grazing pressure. Mesoscale processes influence bottom-up nutrient forcing and larval supply, hence affecting species abundance and distribution, and can be proximate factors setting range edges (e.g., the English Channel, the Iberian Peninsula). Impacts of invasive non-native species are reviewed. Knowledge gaps such as the work on rockpools and host–parasite dynamics are also outlined.
Inadequate protein quality may be a risk factor for poor growth. To examine the effect of a macronutrient–micronutrient supplement KOKO Plus (KP), provided to infants from 6 to 18 months of age, on linear growth, a single-blind cluster-randomised study was implemented in Ghana. A total of thirty-eight communities were randomly allocated to receive KP (fourteen communities, n 322), a micronutrient powder (MN, thirteen communities, n 329) and nutrition education (NE, eleven communities, n 319). A comparison group was followed cross-sectionally (n 303). Supplement delivery and morbidity were measured weekly and anthropometry monthly. NE education was provided monthly. Baseline, midline and endline measurements at 6, 12 and 18 months included venous blood draws, diet, anthropometry, morbidity, food security and socio-economics. Length-for-age Z-score (LAZ) was the primary outcome. Analyses were intent-to-treat using mixed-effects regressions adjusted for clustering, sex, age and baseline. No differences existed in mean LAZ scores at endline (−1·219 (sd 0·06) KP, −1·211 (sd 0·03) MN, −1·266 (sd 0·03) NE). Acute infection prevalence was lower in the KP than NE group (P = 0·043). Mean serum Hb was higher in KP infants free from acute infection (114·02 (sd 1·87) g/l) than MN (107·8 (sd 2·5) g/l; P = 0·047) and NE (108·8 (sd 0·99) g/l; P = 0·051). Compliance was 84·9 % (KP) and 87·2 % (MN) but delivery 60 %. Adjusting for delivery and compliance, LAZ score at endline was significantly higher in the KP v. MN group (+0·2 LAZ; P = 0·026). A macro- and micronutrient-fortified supplement KP reduced acute infection, improved Hb and demonstrated a dose–response effect on LAZ adjusting consumption for delivery.
To examine the relationship between protein intake and the risk of incident premenstrual syndrome (PMS).
Nested case–control study. FFQ were completed every 4 years during follow-up. Our main analysis assessed protein intake 2–4 years before PMS diagnosis (for cases) or reference year (for controls). Baseline (1991) protein intake was also assessed.
Nurses’ Health Study II (NHS2), a large prospective cohort study of registered female nurses in the USA.
Participants were premenopausal women between the ages of 27 and 44 years (mean: 34 years), without diagnosis of PMS at baseline, without a history of cancer, endometriosis, infertility, irregular menstrual cycles or hysterectomy. Incident cases of PMS (n 1234) were identified by self-reported diagnosis during 14 years of follow-up and validated by questionnaire. Controls (n 2426) were women who did not report a diagnosis of PMS during follow-up and confirmed experiencing minimal premenstrual symptoms.
In logistic regression models adjusting for smoking, BMI, B-vitamins and other factors, total protein intake was not associated with PMS development. For example, the OR for women with the highest intake of total protein 2–4 years before their reference year (median: 103·6 g/d) v. those with the lowest (median: 66·6 g/d) was 0·94 (95 % CI 0·70, 1·27). Additionally, intakes of specific protein sources and amino acids were not associated with PMS. Furthermore, results substituting carbohydrates and fats for protein were also null.
Overall, protein consumption was not associated with risk of developing PMS.
The wheat bZip transcription factor TaABF1 mediates both abscisic acid (ABA)-induced and ABA-suppressed gene expression. As levels of TaABF1 protein do not change in response to ABA, and TaABF1 is in a phosphorylated state in vivo, we investigated whether TaABF1 could be regulated at the post-translational level. In bombarded aleurone cells, a TaABF1 protein carrying phosphomimetic mutations (serine to aspartate) at four sites (S36D, S37D, S113D, S115D) was three to five times more potent than wild-type TaABF1 in activating HVA1, an ABA-responsive gene. The phosphomimetic mutations also increased the ability of TaABF1 to downregulate the ABA-suppressed gene Amy32b. These findings strongly suggest that phosphorylation at these sites increases the transcriptional regulatory activity of TaABF1. In contrast to the activation observed by the quadruple serine to aspartate mutation, a single S113D mutation completely eliminated the ability of TaABF1 to upregulate HVA1 or downregulate Amy32b. Thus phosphorylation of TaABF1 can either stimulate or inhibit the activity of TaABF1 in regulating downstream genes, depending on the site and pattern of phosphorylation. Mutation of S318 and S322 (in the bZIP domain) eliminated the ability of TaABF1 to activate HVA1, but had no effect on the ability of TaABF1 to downregulate Amy32b, suggesting that TaABF1 represses Amy32b expression through a mechanism other than direct DNA binding. An important step towards understanding how ABA and gibberellin (GA) signals are integrated through TaABF1 phosphorylation to regulate downstream gene expression is to clarify the effects of those hormones on the expression of specific genes. In contrast to some other ABA-induced genes, we found that HVA1 induction by ABA or TaABF1 is not inhibited by GA.
Objectives: Prior research has identified numerous genetic (including sex), education, health, and lifestyle factors that predict cognitive decline. Traditional model selection approaches (e.g., backward or stepwise selection) attempt to find one model that best fits the observed data, risking interpretations that only the selected predictors are important. In reality, several predictor combinations may fit similarly well but result in different conclusions (e.g., about size and significance of parameter estimates). In this study, we describe an alternative method, Information-Theoretic (IT) model averaging, and apply it to characterize a set of complex interactions in a longitudinal study on cognitive decline. Methods: Here, we used longitudinal cognitive data from 1256 late–middle aged adults from the Wisconsin Registry for Alzheimer’s Prevention study to examine the effects of sex, apolipoprotein E (APOE) ɛ4 allele (non-modifiable factors), and literacy achievement (modifiable) on cognitive decline. For each outcome, we applied IT model averaging to a set of models with different combinations of interactions among sex, APOE, literacy, and age. Results: For a list-learning test, model-averaged results showed better performance for women versus men, with faster decline among men; increased literacy was associated with better performance, particularly among men. APOE had less of an association with cognitive performance in this age range (∼40–70 years). Conclusions: These results illustrate the utility of the IT approach and point to literacy as a potential modifier of cognitive decline. Whether the protective effect of literacy is due to educational attainment or intrinsic verbal intellectual ability is the topic of ongoing work. (JINS, 2019, 25, 119–133)
Laser-based compact MeV X-ray sources are useful for a variety of applications such as radiography and active interrogation of nuclear materials. MeV X rays are typically generated by impinging the intense laser onto ~mm-thick high-Z foil. Here, we have characterized such a MeV X-ray source from 120 TW (80 J, 650 fs) laser interaction with a 1 mm-thick tantalum foil. Our measurements show X-ray temperature of 2.5 MeV, flux of 3 × 1012 photons/sr/shot, beam divergence of ~0.1 sr, conversion efficiency of ~1%, that is, ~1 J of MeV X rays out of 80 J incident laser, and source size of 80 m. Our measurement also shows that MeV X-ray yield and temperature is largely insensitive to nanosecond laser contrasts up to 10−5. Also, preliminary measurements of similar MeV X-ray source using a double-foil scheme, where the laser-driven hot electrons from a thin foil undergoing relativistic transparency impinging onto a second high-Z converter foil separated by 50–400 m, show MeV X-ray yield more than an order of magnitude lower compared with the single-foil results.
Objectives: A major challenge in cognitive aging is differentiating preclinical disease-related cognitive decline from changes associated with normal aging. Neuropsychological test authors typically publish single time-point norms, referred to here as unconditional reference values. However, detecting significant change requires longitudinal, or conditional reference values, created by modeling cognition as a function of prior performance. Our objectives were to create, depict, and examine preliminary validity of unconditional and conditional reference values for ages 40–75 years on neuropsychological tests. Method: We used quantile regression to create growth-curve–like models of performance on tests of memory and executive function using participants from the Wisconsin Registry for Alzheimer’s Prevention. Unconditional and conditional models accounted for age, sex, education, and verbal ability/literacy; conditional models also included past performance on and number of prior exposures to the test. Models were then used to estimate individuals’ unconditional and conditional percentile ranks for each test. We examined how low performance on each test (operationalized as <7th percentile) related to consensus-conference–determined cognitive statuses and subjective impairment. Results: Participants with low performance were more likely to receive an abnormal cognitive diagnosis at the current visit (but not later visits). Low performance was also linked to subjective and informant reports of worsening memory function. Conclusions: The percentile-based methods and single-test results described here show potential for detecting troublesome within-person cognitive change. Development of reference values for additional cognitive measures, investigation of alternative thresholds for abnormality (including multi-test criteria), and validation in samples with more clinical endpoints are needed. (JINS, 2019, 25, 1–14)
The long-wave, reduced-gravity, shallow-water equations (the semi-geostrophic equations) are used to study the outflow of a river into the ocean. While previous models have studied dynamics driven by gradients in density, the focus here is on the effects of potential vorticity anomaly (PVa). The river water is taken to have the same density as a finite-depth upper layer of oceanic fluid, but the two fluids have different, uniform, potential vorticities. Under these assumptions, the governing equations reduce to two first-order, nonlinear partial differential equations which are integrated numerically for a prescribed efflux of river water and PVa. Results are found to depend strongly on the sign of the PVa, with all fluid turning downstream (in the direction of Kelvin-wave propagation) when the river water has positive PVa and anticyclonic flow upstream of the river mouth when the PVa is negative. In all cases, a nonlinear Kelvin wave propagates at finite speed ahead of the river water. Away from the river mouth, the uniformity of one set of Riemann invariants allows for similarity solutions that describe the shape of the outflow, as well as a theory that predicts properties of the Kelvin wave. A range of behaviours is observed, including flows that develop shocks and flows that continue to expand offshore. The qualitative behaviour of the outflow is strongly correlated with the value of a single dimensionless parameter that expresses the ratio of the speed of the flow driven by the Kelvin wave to that driven by image vorticity.
Based on a variable-coefficient Kadomtsev–Petviashvili (KP) equation, the topographic effect on the wave interactions between two oblique internal solitary waves is investigated. In the absence of rotation and background shear, the model set-up featuring idealised shoaling topography and continuous stratification is motivated by the large expanse of continental shelf in the South China Sea. When the bottom is flat, the evolution of an initial wave consisting of two branches of internal solitary waves can be categorised into six patterns depending on the respective amplitudes and the oblique angles measured counterclockwise from the transverse axis. Using theoretical multi-soliton solutions of the constant-coefficient KP equation, we select three observed patterns and examine each of them in detail both analytically and numerically. The effect of shoaling topography leads to a complicated structure of the leading waves and the emergence of two types of trailing wave trains. Further, the case when the along-crest width is short compared with the transverse domain of interest is examined and it is found that although the topographic effect can still modulate the wave field, the spreading effect in the transverse direction is dominant.
We developed a decision analytic model to evaluate the impact of a preoperative Staphylococcus aureus decolonization bundle on surgical site infections (SSIs), health-care–associated costs (HCACs), and deaths due to SSI.
Our model population comprised US adults undergoing elective surgery. We evaluated 3 self-administered preoperative strategies: (1) the standard of care (SOC) consisting of 2 disinfectant soap showers; (2) the “test-and-treat” strategy consisting of the decolonization bundle including chlorhexidine gluconate (CHG) soap, CHG mouth rinse, and mupirocin nasal ointment for 5 days) if S. aureus was found at any of 4 screened sites (nasal, throat, axillary, perianal area), otherwise the SOC; and (3) the “treat-all” strategy consisting of the decolonization bundle for all patients, without S. aureus screening. Model parameters were derived primarily from a randomized controlled trial that measured the efficacy of the decolonization bundle for eradicating S. aureus.
Under base-case assumptions, the treat-all strategy yielded the fewest SSIs and the lowest HCACs, followed by the test-and-treat strategy. In contrast, the SOC yielded the most SSIs and the highest HCACs. Consequently, relative to the SOC, the average savings per operation was $217 for the treat-all strategy and $123 for the test-and-treat strategy, and the average savings per per SSI prevented was $21,929 for the treat-all strategy and $15,166 for the test-and-treat strategy. All strategies were sensitive to the probability of acquiring an SSI and the increased risk if SSI if the patient was colonized with SA.
We predict that the treat-all strategy would be the most effective and cost-saving strategy for preventing SSIs. However, because this strategy might select more extensively for mupirocin-resistant S. aureus and cause more medication adverse effects than the test-and-treat approach or the SOC, additional studies are needed to define its comparative benefits and harms.
To determine the efficacy in eradicating Staphylococcus aureus (SA) carriage of a 5-day preoperative decolonization bundle compared to 2 disinfectant soap showers, with both regimens self-administered at home.
Open label, single-center, randomized clinical trial.
Ambulatory orthopedic, urologic, neurologic, colorectal, cardiovascular, and general surgery clinics at a tertiary-care referral center in the United States.
Patients at the University of Minnesota Medical Center planning to have elective surgery and not on antibiotics.
Consenting participants were screened for SA colonization using nasal, throat, axillary, and perianal swab cultures. Carriers of SA were randomized, stratified by methicillin resistance status, to a decolonization bundle group (5 days of nasal mupirocin, chlorhexidine gluconate [CHG] bathing, and CHG mouthwash) or control group (2 preoperative showers with antiseptic soap). Colonization status was reassessed preoperatively. The primary endpoint was absence of SA at all 4 screened body sites.
Of 427 participants screened between August 31, 2011, and August 9, 2016, 127 participants (29.7%) were SA carriers. Of these, 121 were randomized and 110 were eligible for efficacy analysis (57 decolonization bundle group, 53 control group). Overall, 90% of evaluable participants had methicillin-susceptible SA strains. Eradication of SA at all body sites was achieved for 41 of 57 participants (71.9%) in the decolonization bundle group and for 13 of 53 participants (24.5%) in the control group, a difference of 47.4% (95% confidence interval [CI], 29.1%–65.7%; P<.0001).
An outpatient preoperative antiseptic decolonization bundle aimed at 4 body sites was significantly more effective in eradicating SA than the usual disinfectant showers (ie, the control).
Knowledge of the effects of burial depth and burial duration on seed viability and, consequently, seedbank persistence of Palmer amaranth (Amaranthus palmeri S. Watson) and waterhemp [Amaranthus tuberculatus (Moq.) J. D. Sauer] ecotypes can be used for the development of efficient weed management programs. This is of particular interest, given the great fecundity of both species and, consequently, their high seedbank replenishment potential. Seeds of both species collected from five different locations across the United States were investigated in seven states (sites) with different soil and climatic conditions. Seeds were placed at two depths (0 and 15 cm) for 3 yr. Each year, seeds were retrieved, and seed damage (shrunken, malformed, or broken) plus losses (deteriorated and futile germination) and viability were evaluated. Greater seed damage plus loss averaged across seed origin, burial depth, and year was recorded for lots tested at Illinois (51.3% and 51.8%) followed by Tennessee (40.5% and 45.1%) and Missouri (39.2% and 42%) for A. palmeri and A. tuberculatus, respectively. The site differences for seed persistence were probably due to higher volumetric water content at these sites. Rates of seed demise were directly proportional to burial depth (α=0.001), whereas the percentage of viable seeds recovered after 36 mo on the soil surface ranged from 4.1% to 4.3% compared with 5% to 5.3% at the 15-cm depth for A. palmeri and A. tuberculatus, respectively. Seed viability loss was greater in the seeds placed on the soil surface compared with the buried seeds. The greatest influences on seed viability were burial conditions and time and site-specific soil conditions, more so than geographical location. Thus, management of these weed species should focus on reducing seed shattering, enhancing seed removal from the soil surface, or adjusting tillage systems.
J. F. Cooper, NASA Goddard Space Flight Center Greenbelt, Maryland, USA,
R. E. Johnson, University of Virginia Charlottesville, Virginia, USA,
P. Kollmann, Johns Hopkins University Applied Physics Laboratory Laurel, Maryland, USA,
E. Roussos, Max Planck Institute for Solar System Studies Göttingen, GERMANY,
E. C. Sittler, NASA Goddard Space Flight Center Greenbelt, Maryland, USA
Ring systems around magnetized planets are expected to have varied interactions with the magnetic fields, hot plasma, and energetic particles of the associated magnetospheres. In our solar system all the giant planets, Jupiter to Neptune, have magnetospheres with embedded rings. Each ring system and its associated moons have strong interactions with their radiation environments (the most intense of which is at Jupiter). Such interactions both erode diffuse rings (such as the E ring of Saturn) and supply plasma and energetic particles to the magnetosphere and its radiation belts. Compositional and structural measurements of rings are enabled by these interactions, such as the information obtained by detection of the secondary neutron and gamma-ray emissions produced by galactic cosmic ray (GCR) interactions with the rings. It is also notable that Earth has both a magnetosphere with radiation belts, and an artificial ring system of satellites and debris, that continuously interact. Konradi (1988) even projected that the high energy trapped protons of the inner Van Allen Belt should now be experiencing significant depletion by this interaction, and we will later discuss the possible evidence for this. Magnetized exoplanets with rings would have similar interactions.
The ring systems of Jupiter and Saturn have been explored by multiple spacecraft. The Jovian ring environment was first explored in situ in 1974 by Pioneer 11, which subsequently flew under Saturn's main rings in 1979. After passing through the Saturn ring plane near the G ring in 1981, Voyager 2 encountered Uranus in 1986 and then Neptune in 1989, but in neither case were the rings and arcs of these two ice giant planets traversed. The Galileo Probe passed across the Jovian ring in December 1995 en route to the first direct penetration into Jupiter's atmosphere. The Cassini Orbiter crossed over the Saturn A and B rings in mid-2004 (Figure 14.1) as part of the Saturn Orbital Insertion (SOI). Cassini will again traverse the main rings during its Grand Finale orbit phase many times, crossing the ring plane just inwards of the D ring, prior to final atmospheric entry in 2017. With the exception of the Cassini Plasma Spectrometer (CAPS) instrument, turned off in 2012 due to electrical problems, Cassini will continue to operate through the final observations.
A study of the propagation of a mode-2 internal solitary wave over a slope-shelf topography is presented. The methodology is based on a variable-coefficient Korteweg–de Vries (vKdV) equation, using both analysis and numerical simulations, and simulations using the MIT general circulation model (MITgcm). Two configurations are considered. One is a mode-2 internal solitary wave propagating up the slope, from one three-layer system to another three-layer system. Depending on the height of the shelf, which determines the variation of the nonlinear coefficient of the vKdV equation, this can be classified into two cases. First, the case of a polarity change, in which the coefficient of the quadratic nonlinear term changes sign at a certain critical point on the slope, and second, the case with no such polarity change. In both these cases there is a small transfer of energy from the mode-2 wave to mode-1 waves. The other configuration is when the lower layer in the three-layer system goes to zero at a transition point on the slope, and beyond that point, there is a two-layer fluid system. A mode-2 internal solitary wave propagating up the slope cannot exist past this transition point. Instead it is extinguished and replaced by a mode-1 bore and trailing wave packet which moves onto the shelf.