Spatial linear stability analysis is used to study the axisymmetric screech tones generated by twin converging round nozzles at low supersonic Mach numbers. Vortex-sheet and finite-thickness models allow for identification of the different waves supported by the flow at different conditions. Regions of the frequency–wavenumber domain for which the upstream-propagating guided jet modes are observed to be neutrally stable are observed to vary as a function of solution symmetry, jet separation, $S$, and the velocity profile used. Screech-frequency predictions performed using wavenumbers obtained from both models agree well with experimental data. Predictions obtained from the finite-thickness model better align with the screech tones measured experimentally and so are seen to be an improvement on predictions made with the vortex sheet. Additionally, results from the finite-thickness model predict both symmetric and antisymmetric screech tones for low $S$ that are found in the vortex-sheet model only at greater $S$. The present results indicate that the feedback loop generating these screech tones is similar to that observed for single-jet resonance, with equivalent upstream and downstream modes.

We investigate the intermittency of the coupling behaviour in screeching twin round supersonic jets at low Mach numbers across a range of nozzle spacings. Application of proper orthogonal decomposition combined with time-frequency wavelet analysis and spectral proper orthogonal decomposition shows that intermittency can manifest in twin jets as either a competition between the two symmetries, or the jets uncoupling and recoupling. The time scales on which symmetry switching occurs can vary strongly, ranging from $O(10^2)$ to $O(10^3)$ screech cycles. A transition from one symmetry to another is accompanied by a slight change in the screech frequency ranging from 0.30 % to 0.63 %. It was observed that complete uncoupling occurred only at the largest nozzle spacing of $s/D=6$ and at Mach numbers close to modal staging. When the jets are uncoupled they screech at slightly different frequencies, with a disparity of approximately 0.6 %. The coupling is particularly intermittent in the transition from the A1 to A2 branch, where the A2 mode is first observed, and tends toward steady coupling with increasing Mach number.

OBJECTIVES/GOALS: Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors that are driven by populations of cancer stem cells (CSCs). In this study, we perform an epigenetic-focused functional genomics screen in GBM organoids and identify WDR5 as an essential epigenetic regulator in the SOX2-enriched, therapy resistant cancer stem cell niche. METHODS/STUDY POPULATION: Despite their importance for tumor growth, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We developed a spatially resolved loss-of-function screen in GBM patient-derived organoids to identify essential epigenetic regulators in the SOX2-enriched, therapy resistant niche. Our niche-specific screens identified WDR5, an H3K4 histone methyltransferase responsible for activating specific gene expression, as indispensable for GBM CSC growth and survival. RESULTS/ANTICIPATED RESULTS: In GBM CSC models, WDR5 inhibitors blocked WRAD complex assembly and reduced H3K4 trimethylation and expression of genes involved in CSC-relevant oncogenic pathways. H3K4me3 peaks lost with WDR5 inhibitor treatment occurred disproportionally on POU transcription factor motifs, required for stem cell maintenance and including the POU5F1(OCT4)::SOX2 motif. We incorporated a SOX2/OCT4 motif driven GFP reporter system into our CSC cell models and found that WDR5 inhibitor treatment resulted in dose-dependent silencing of stem cell reporter activity. Further, WDR5 inhibitor treatment altered the stem cell state, disrupting CSC in vitro growth and self-renewal as well as in vivo tumor growth. DISCUSSION/SIGNIFICANCE: Our results unveiled the role of WDR5 in maintaining the CSC state in GBM and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers. This conceptual and experimental framework can be applied to many cancers, and can unmask unique microenvironmental biology and rationally designed combination therapies.

Shock-containing supersonic jets undergoing resonance processes are challenging from both a measurement and simulation perspective. These jets are host to a broad range of complex fluid phenomena: intense acoustic waves, turbulence, wavepackets and strong shock waves. Strong shocks present a challenge to both the experimental and numerical researcher. In the paper of Léon et al. (J. Fluid Mech., vol. 947, 2022, A36), a novel optical technique based on multi-axis digital holographic interferometry is applied to the study of a highly underexpanded screeching jet, producing density measurements of unprecedented clarity and resolution. Where prior studies have been restricted to extrapolating the three-dimensional field from two-dimensional slices or projections, in this work the authors directly measure the three-dimensional helical structure of the wavepacket associated with jet screech.

The 2020 presidential election brought expanded vote-by-mail opportunities, a rise in attacks on this process’s integrity, and the implementation of novel programs such as California’s Where’s My Ballot? system to ensure confidence in mail balloting. Can heightening awareness of this ballot-tracking system and other election protections alleviate fraud concerns and raise turnout? We assess whether messages reinforcing election integrity increased participation in the 2020 election through a large-scale voter mobilization field experiment. California registrants were mailed a letter that described either existing safeguards to prevent vote-by-mail fraud or the ability to track one’s ballot and ensure that it was counted. Analysis of state voter records reveals that neither message increased turnout over a simple election reminder or even no contact, even among subgroups where larger effects might be expected. In the context of a high-profile, high-turnout presidential election, assurances about ballot and electoral integrity did not increase turnout.

The shame system appears to be natural selection's solution to the adaptive problem of information-triggered reputational damage. Over evolutionary time, this problem would have led to a coordinated set of adaptations – the shame system – designed to minimise the spread of negative information about the self and the likelihood and costs of being socially devalued by others. This information threat theory of shame can account for much of what we know about shame and generate precise predictions. Here, we analyse the behavioural configuration that people adopt stereotypically when ashamed – slumped posture, downward head tilt, gaze avoidance, inhibition of speech – in light of shame's hypothesised function. This behavioural configuration may have differentially favoured its own replication by (a) hampering the transfer of information (e.g. diminishing audiences’ tendency to attend to or encode identifying information – shame camouflage) and/or (b) evoking less severe devaluative responses from audiences (shame display). The shame display hypothesis has received considerable attention and empirical support, whereas the shame camouflage hypothesis has to our knowledge not been advanced or tested. We elaborate on this hypothesis and suggest directions for future research on the shame pose.

This paper describes the mechanism underpinning modal staging behaviour in screeching jets. An upstream-propagating subsonic guided-jet mode is shown to be active in all stages of screech. Axial variation of shock-cell spacing manifests in the spectral domain as a series of suboptimal peaks. It is demonstrated that the guided-jet mode may be energized by interactions of the Kelvin–Helmholtz wavepacket with not only the primary shock wavenumber peak, but also suboptimal peaks; interaction with suboptimals is shown to be responsible for closing the resonance loop in multiple stages of jet screech. A consideration of the full spectral representation of the shocks reconciles several of the classical models and results for jet screech that had heretofore been paradoxical. It is demonstrated that there are multiple standing waves present in the near field of screeching jets, corresponding to the superposition of the various waves active in these jets. Multimodal behaviour is explored for jets in a range of conditions, demonstrating that multiple peaks in the frequency spectra can be due to either changes in which peak of the shock spectra the Kelvin–Helmholtz wavepacket is interacting with, or a change in azimuthal mode, or both. The absence of modal staging in high-aspect-ratio non-axisymmetric jets is also explained in the context of the aforementioned mechanism. The paper closes with a new proposed theory for frequency selection in screeching jets, based on the observation that these triadic interactions appear to underpin selection of the guided-jet mode wavelength in all measured cases.

An investigation of shock diffraction through a non-quiescent background medium is presented using both experimental and numerical techniques. Unlike diffracting shocks in quiescent media, a spatial distortion of the shock front occurs, producing a region of constant shock angle. An example of this process arises in the exhaust from a pulse-detonation combustor. As the background velocity is increased, such as through the inclusion of a converging nozzle at the exhaust, the spatial distortion becomes more apparent. Numerical simulations using a compressible Euler solver demonstrate that the distortion is not due to the geometrical influence of the nozzle, but rather is a function of the magnitude of the background flow velocity. The distortion is studied using a modified geometrical shock dynamics formulation which includes the background flow and is validated against experiments. A simple model is presented to predict the shock distortion angle in the weak-shock limit. Finally, the axial decay behaviour of the shock is investigated and it is shown that the advection of the shock by the background flow delays the arrival of the head and tail of the expansion characteristic at the centreline. This leads to an increase in the rate of decay of the shock Mach number as the background flow velocity is increased.

This paper explores the screech closure mechanism for different axisymmetric modes in shock-containing jets. While many of the discontinuities in tonal frequency exhibited by screeching jets can be associated with a change in the azimuthal mode, there has to date been no satisfactory explanation for the existence of multiple axisymmetric modes at different frequencies. This paper provides just such an explanation. As shown in previous works, specific wavenumbers arise from the interaction of waves in the flow with the shocks. This provides new paths for driving upstream-travelling waves that can potentially close the resonance loop. Predictions using locally parallel and spatially periodic linear stability analyses and the wavenumber spectrum of the shock-cell structure suggest that the A1 mode resonance is closed by a wave generated when the Kelvin–Helmholtz mode interacts with the leading wavenumber of the shock-cell structure. The A2 mode is closed by a wave that arises owing to the interaction between the Kelvin–Helmholtz wave and a secondary wavenumber peak, which arises from the spatial variation of the shock-cell wavelength. The predictions are shown to closely match experimental data, and possible justifications for the dominance of each mode are provided based on the growth rates of the absolute instability.

We present an analysis of the linear stability characteristics of shock-containing jets. The flow is linearised around a spatially periodic mean, which acts as a surrogate for a mean flow with a shock-cell structure, leading to a set of partial differential equations with periodic coefficients in space. Disturbances are written using the Floquet ansatz and Fourier modes in the streamwise direction, leading to an eigenvalue problem for the Floquet exponent. The characteristics of the solution are directly compared with the locally parallel case, and some of the features are similar. The inclusion of periodicity induces minor changes in the growth rate and phase velocity of the relevant modes for small shock amplitudes. On the other hand, the eigenfunctions are now subject to modulation related to the periodicity of the flow. Analysis of the spatio-temporal growth rates led to the identification of a saddle point between the Kelvin–Helmholtz mode and the guided jet mode, characterising an absolute instability mechanism. Frequencies and mode shapes related to the saddle points for two conditions (associated with axisymmetric and helical modes) are compared with screech frequencies and the most energetic coherent structures of screeching jets, resulting in a good agreement for both. The analysis shows that a periodic shock-cell structure has an impulse response that grows upstream, leading to oscillator behaviour. The results suggest that screech can occur in the absence of a nozzle, and that the upstream reflection condition is not essential for screech frequency selection. Connections to previous models are also discussed.

Background: Despite significant morbidity and mortality, estimates of the burden of healthcare-associated viral respiratory infections (HA-VRI) for noninfluenza infections are limited. Of the studies assessing the burden of respiratory syncytial virus (RSV), cases are typically classified as healthcare associated if a positive test result occurred after the first 3 days following admission, which may miss healthcare exposures prior to admission. Utilizing an expanded definition of healthcare-associated RSV, we assessed the estimates of disease prevalence. Methods: This study included laboratory-confirmed cases of RSV in adult and pediatric patients admitted to acute-care hospitals in a catchment area of 8 counties in Tennessee identified between October 1, 2016, and April 30, 2019. Surveillance information was abstracted from hospital and state laboratory databases, hospital infection control databases, reportable condition databases, and electronic health records as a part of the Influenza Hospitalization Surveillance Network by the Emerging Infections Program. Cases were defined as healthcare-associated RSV if laboratory confirmation of infection occurred (1) on or after hospital day 4 (ie, “traditional definition”) or (2) between hospital day 0 and 3 in patients transferred from a chronic care facility or with a recent discharge from another acute-care facility in the 7 days preceding the current index admission (ie, “enhanced definition”). The proportion of laboratory-confirmed RSV designated as HA-VRI using both the traditional definition as well as with the added enhanced definition were compared. Results: We identified 900 cases of RSV in hospitalized patients over the study period. Using the traditional definition for HA-VRI, only 41 (4.6%) were deemed healthcare associated. Adding the cases identified using the enhanced definition, an additional 12 cases (1.3%) were noted in patients transferred from a chronic care facility for the current acute-care admission and 17 cases (1.9%) were noted in patients with a prior acute-care admission in the preceding 7 days. Using our expanded definition, the total proportion of healthcare-associated RSV in this cohort was 69 (7.7%) of 900 compared to 13.1% of cases for influenza (Figure 1). Although the burden of HA-VRI due to RSV was less than that of influenza, when stratified by age, the rate increased to 11.7% for those aged 50–64 years and to 10.1% for those aged ≥65 years (Figure 2). Conclusions: RSV infections are often not included in estimates of HA-VRI, but the proportion of cases that are healthcare associated are substantial. Typical surveillance methods likely underestimate the burden of disease related to RSV, especially for those aged ≥50 years.

Funding: No

Disclosures: None

Figure 1.

Figure 2.

Background: Healthcare-associated transmission of influenza leads to significant morbidity, mortality, and cost. Most studies classify healthcare-associated viral respiratory infections (HA-VRI) as those with a positive test result after the first 3 days following admission, which does not account for healthcare exposures prior to admission. Utilizing an expanded definition of healthcare-associated influenza, we aimed to improve the estimates of disease prevalence on a population level. Methods: This study included laboratory-confirmed cases of influenza in adult and pediatric patients admitted to any acute-care hospital in a catchment area of 8 counties Tennessee identified between October 1, 2012, and April 30, 2019. Surveillance information was abstracted from hospital and state laboratory databases, hospital infection control practitioner databases, reportable condition databases, and electronic health records as a part of the Influenza Hospitalization Surveillance Network (FluSurv-NET) by the Centers for Disease Control and Prevention (CDC) Emerging Infections Program (EIP). Cases were defined as healthcare-associated influenza laboratory confirmation of infection occurred (1) on or after hospital day 4 (“traditional definition”), or (2) between hospital days 0 and 3 in patients transferred from a chronic care facility or with a recent discharge from another acute-care facility in the 7 days preceding the current index admission (ie, enhanced definition). The proportion of laboratory-confirmed influenza designated as HA-VRI using both the traditional definition as well as with the added enhanced definition were compared. Data were imported into Stata software for analysis. Results: We identified 5,904 cases of laboratory-confirmed influenza in hospitalized patients over the study period. Using the traditional definition for HA-VRI, only 147 (2.5%, seasonal range 1.3%–3.4%) were deemed healthcare associated (Figure 1). Adding the cases identified using the enhanced definition, an additional 317 (5.4%, range 2.3%–6.7%) cases were noted in patients transferred from a chronic care facility for the current acute-care admission and 336 cases (5.7%; range, 4.1%–7.4%) were noted in patients with a prior acute-care facility admission in the preceding 7 days. Using our expanded definition, the total proportion of healthcare-associated influenza in this cohort was 772 of 5,904 (13.1%; range, 10.6%–14.8%). Conclusion: HA-VRI due to influenza is an underrecognized infection in hospitalized patients. Limiting surveillance assessment of this important outcome to just those patients with a positive influenza test after hospital day 3 captured only 19% of possible healthcare-associated influenza infections across 7 influenza seasons. These results suggest that the traditionally used definitions of healthcare-associated influenza underestimate the true burden of cases.

Funding: No

Disclosures: None

Figure 1.

The present work focuses on the study of the resonance and coupling of an underexpanded circular twin-jet system operating at a nozzle pressure ratio of $5.0$. Particle image velocimetry data from previous work were revisited, and a symmetry-imposed proper orthogonal decomposition (POD) was performed. It is shown that the system is dominated by a single POD mode pair symmetric about the internozzle plane, and the resonance loop is modulated by a third POD mode related to shear thickness modulation. A spatial Fourier transform of the leading POD mode pair leads to the identification of the peak wavenumbers and radial shapes of the different waves at play in the screech phenomenon. Locally parallel linear stability analysis around the experimental mean flow is also performed, in order to provide clarification of the mode ‘locking’ mechanism, i.e. the selection of the global mode associated with screech. It is shown that the characteristics of the Kelvin–Helmholtz wavepackets alone are not sufficient to explain the coupling observed in the experimental data. A consideration of the upstream-travelling guided jet mode offers an explanation; only specific symmetries of upstream modes can be supported in the frequency range at which resonance occurs. Results from stability analysis point to structures at frequencies and wavenumbers close to those found experimentally, and their spatial structures show excellent agreement with the POD modes. The present results suggest that the resonance loop is closed by an upstream-travelling guided jet mode for the twin-jet system at high nozzle pressure ratio.