The apocalypse is frequently deployed by political movements, especially contemporary climate activists, to advance their causes. This article develops a framework for defending such invocations of the end of the world. With many other political theorists, I suggest that the apocalypse is a dangerous concept, not least because of its association with authoritarian accounts of history. However, we should not reject the apocalypse. I argue for a form of anti-anti-apocalypticism, using the criticisms directed against the concept as a launchpad to rethink it in viable terms. While acknowledging the value of different ways of defending the apocalypse, I highlight the importance of the causes of apocalyptic movements. Simply put, apocalypses from below are defensible because they have the capacity to clarify the political position of the oppressed and open new political possibilities for the group. By contrast, apocalypses from above, because they fail to fulfill these functions, are not.

Background: Obsessive compulsive disorder (OCD) and major depressive disorder (MDD) are common, often refractory, neuropsychiatric conditions for which new treatment approaches are urgently needed. Magnetic resonance guided focused ultrasound (MRgFUS) is a novel surgical technique permitting incisionless ablative neurosurgery. Methods: We examined the safety profile, clinical response, and imaging correlates of MRgFUS anterior capsulotomy (MRgFUS-AC) in patients with refractory OCD (n=7) and MDD (n = 10). Results: There were no serious adverse clinical or radiographic events. 5/7 OCD patients and 3/10 MDD patients met pre-established clinical response criteria. Neurocognitive performance improved on several measures of executive function (p<0.05). By 6 months, there were significant reductions in cerebral glucose metabolism, and reductions in the bilateral tracts connecting the thalamus with the orbitofrontal cortices, anterior cingulate cortex (p<0.05). Preoperative functional connectivity between the right ventral striatum and hippocampus was predictive of eventual clinical response (p-FDR<0.05). Conclusions: MRgFUS-AC is safe and demonstrates important evidence of efficacy in treatment resistant psychiatric disease, particularly OCD. The procedure was associated with structural and metabolic changes in brain networks implicated in affective regulation, Resting-state fMRI offers the ability to predict response, and potentially select patients most likely to improve.

We present the first Southern-Hemisphere all-sky imager and radio-transient monitoring system implemented on two prototype stations of the low-frequency component of the Square Kilometre Array (SKA-Low). Since its deployment, the system has been used for real-time monitoring of the recorded commissioning data. Additionally, a transient searching algorithm has been executed on the resulting all-sky images. It uses a difference imaging technique to enable identification of a wide variety of transient classes, ranging from human-made radio-frequency interference to genuine astrophysical events. Observations at the frequency 159.375 MHz and higher in a single coarse channel ($\approx$0.926 MHz) were made with 2 s time resolution, and multiple nights were analysed generating thousands of images. Despite having modest sensitivity ($\sim$ few Jy beam–1), using a single coarse channel and 2-s imaging, the system was able to detect multiple bright transients from PSR B0950+08, proving that it can be used to detect bright transients of an astrophysical origin. The unusual, extreme activity of the pulsar PSR B0950+08 (maximum flux density $\sim$155 Jy beam–1) was initially detected in a ‘blind’ search in the 2020 April 10/11 data and later assigned to this specific pulsar. The limitations of our data, however, prevent us from making firm conclusions of the effect being due to a combination of refractive and diffractive scintillation or intrinsic emission mechanisms. The system can routinely collect data over many days without interruptions; the large amount of recorded data at 159.375 and 229.6875 MHz allowed us to determine a preliminary transient surface density upper limit of $1.32 \times 10^{-9} \text{deg}^{-2}$ for a timescale and limiting flux density of 2 s and 42 Jy, respectively. In the future, we plan to extend the observing bandwidth to tens of MHz and improve time resolution to tens of milliseconds in order to increase the sensitivity and enable detections of fast radio bursts below 300 MHz.

We consider the life cycle of an axisymmetric laminar thermal starting from the initial condition of a Gaussian buoyant blob. We find that, as time progresses, the thermal transitions through a number of distinct stages, undergoing several morphological changes before ending up as a vortex ring. Whilst each stage is interesting in its own right, one objective of this study is to set out a consistent mathematical framework under which the entire life cycle can be studied. This allows examination of the transition between the different stages, as well as shedding light on some unsolved questions from previous works. We find that the early stages of formation are key in determining the properties of the final buoyant vortex ring and that, since they occur on a time scale where viscosity has little effect, the final properties of the ring display an independence above a critical Reynolds number. We also find that rings consistently contain the same proportion of the initial heat and have a consistent vorticity flux. By considering the effect of Prandtl number, we show that thermal diffusion can have a significant impact on development, smoothing out the temperature field and inhibiting the generation of vorticity. Finally, by considering the wake left behind as well as the vortex ring that is generated, we observe that the wake can itself roll up to form a second mushroom cap and subsequently a secondary vortex ring that follows the first.

In numerical simulations of planetary dynamos there is an abrupt transition in the dynamics of both the velocity and magnetic fields at a‘local’ Rossby number of 0.1. For smaller Rossby numbers there are helical columnar structures aligned with the rotation axis, which efficiently maintain a dipolar field. However, when the thermal forcing is increased, these columns break down and the field becomes multi-polar. Similarly, in rotating turbulence experiments and simulations there is a sharp transition at a Rossby number of ${\sim}0.4$. Again, helical axial columnar structures are found for lower Rossby numbers, and there is strong evidence that these columns are created by inertial waves, at least on short time scales. We perform direct numerical simulations of the flow induced by a layer of buoyant anomalies subject to strong rotation, inspired by the equatorially biased heat flux in convective planetary dynamos. We assess the role of inertial waves in generating columnar structures. At high rotation rates (or weak forcing) we find columnar flow structures that segregate helicity either side of the buoyant layer, whose axial length scale increases linearly, as predicted by the theory of low-frequency inertial waves. As the rotation rate is weakened and the magnitude of the buoyant perturbations is increased, we identify a portion of the flow which is more strongly three-dimensional. We show that the flow in this region is turbulent, and has a Rossby number above a critical value $Ro^{crit}\sim 0.4$, consistent with previous findings in rotating turbulence. We suggest that the discrepancy between the transition value found here (and in rotating turbulence experiments), and that seen in the numerical dynamos ($Ro^{crit}\sim 0.1$), is a result of a different choice of the length scale used to define the local $Ro$. We show that when a proxy for the flow length scale perpendicular to the rotation axis is used in this definition, the numerical dynamo transition lies at $Ro^{crit}\sim 0.5$. Based on this we hypothesise that inertial waves, continually launched by buoyant anomalies, sustain the columnar structures in dynamo simulations, and that the transition documented in these simulations is due to the inability of inertial waves to propagate for $Ro>Ro^{crit}$.

Laser–solid interactions are highly suited as a potential source of high energy X-rays for nondestructive imaging. A bright, energetic X-ray pulse can be driven from a small source, making it ideal for high resolution X-ray radiography. By limiting the lateral dimensions of the target we are able to confine the region over which X-rays are produced, enabling imaging with enhanced resolution and contrast. Using constrained targets we demonstrate experimentally a $(20\pm 3)~\unicode[STIX]{x03BC}\text{m}$ X-ray source, improving the image quality compared to unconstrained foil targets. Modelling demonstrates that a larger sheath field envelope around the perimeter of the constrained targets increases the proportion of electron current that recirculates through the target, driving a brighter source of X-rays.

OBJECTIVES/SPECIFIC AIMS: This study aims to first describe the unique cytokine profile and TGFbeta levels of young children with CF, then understand the pathologic effects of TGFbeta on lung function in a CF animal model. These powerful translational studies linking observations in clinical disease with a transgenic mouse model allow us a unique opportunity to investigate the role of TGFbeta in early CF lung disease. METHODS/STUDY POPULATION: Cytokine levels (TGFbeta, TNFalpha, IL-8, IL-6, HNE, and IL-1beta) in bronchoalveolar lavage fluid (BALF) from CF patients (n = 15) and non-CF control patients (n = 21) under 6 years old were determined by ELISA and Luminex assay. Tracheotomized patients without significant underlying lung disease were chosen as non-CF inflamed control patients, as they had similar levels of neutrophilic inflammation and infection as CF patients. The percentage of BAL neutrophils (% PMNs) in each sample was assessed. The relationships between cytokines were analyzed using linear regression and principal components analysis. In animal studies, CF and non-CF mice (n = 4-5 per group) were treated with intratracheal adenoviral TGFbeta1 vector, an empty vector control, or PBS. After one week, animals were collected; lung function, response to the bronchoconstrictor methacholine, and rescue with albuterol were measured utilizing a FlexiVent machine. Lungs were collected for histology. Immunohistochemistry for alpha-SMA was performed and pictures of all cross-sectional airways were obtained. Burden of ASM was assessed by dividing the square root of alpha-SMA stained airway smooth muscle by the basement membrane perimeter length of each airway. RESULTS/ANTICIPATED RESULTS: Patient characteristics of CF and non-CF inflamed control patients were similar in terms of age (3.6 yrs vs 3.3 yrs respectively, p = 0.49), positive BAL culture (13% vs 14%, p = 0.94), and % PMNs (65% vs 56%, p = 0.64). Despite these similarities, TGFbeta levels were 2-fold higher in CF versus non-CF BAL (p = 0.034). Analysis of BAL cytokines from both patient groups showed that three principal components describe 86% of total variance across the cytokine variables. These components represent different contributions from the cytokines, with TGFbeta, IL6, and % PMNs comprising one component of similarly regulated inflammatory markers. These components can distinguish CF versus non-CF patients with 77% accuracy (area under the curve: 0.77). TGFbeta concentrations were uniquely associated with increased IL-6 in CF samples (r = 0.74; p = 0.0015) but did not demonstrate association with other cytokines. After TGFbeta exposure, CF mice demonstrated greater abnormalities in airway resistance than non-CF mice, with heightened response to methacholine. Importantly, this increase in airway obstruction in CF mice was reversible with albuterol treatment, indicating airway smooth muscle dysfunction as a principal driver of lung function abnormalities. Furthermore, TGFbeta induced an increased ASM burden on lung histology in both CF and non-CF mice (p<0.05). IL-6 levels in the BAL of CF mice showed greater increases after TGFbeta treatment compared to non-CF mice (p<0.05). Empty vector control treatment did not cause lung pathology. DISCUSSION/SIGNIFICANCE OF IMPACT: Young children with CF have a unique pattern of pulmonary inflammation compared to inflamed non-CF control patients. In CF, TGFbeta pulmonary levels are uniquely associated with IL-6, a driver of ASM dysfunction in other pulmonary diseases. We followed up this clinical observation study by investigating the effect of TGFbeta on pulmonary disease in a mouse model. CF mice demonstrate increased pulmonary IL-6, airway obstruction, and ASM dysfunction after TGFbeta exposure. This study provides evidence that TGFbeta is associated with a distinct cytokine pattern that may promote ASM dysfunction in early CF lung disease. Understanding the mechanism of early CF pathophysiology will be critical in developing targeted therapeutics that can prevent early lung damage.

OBJECTIVES/SPECIFIC AIMS: Transforming growth factor-beta (TGFβ) is a genetic modifier of cystic fibrosis (CF) lung disease. TGFβ’s pulmonary levels in young CF patients and its mechanism of action in CF are unknown. We examined TGFβ levels in children with CF and investigated responses of human airway epithelial cells (AECs) and mice to TGFβ. METHODS/STUDY POPULATION: TGFβ levels in bronchoalveolar lavage fluid from CF patients (n=15) and non-CF control patients (n=21)<6 years old were determined by ELISA. CF mice and non-CF mice were intratracheally treated with an adenoviral TGFβ1 vector or PBS; lungs were collected for analysis at day 7. Human CF and non-CF AECs were treated with TGFβ or PBS for 24 hours then collected for analysis. RESULTS/ANTICIPATED RESULTS: Young CF patients had higher bronchoalveolar lavage fluid TGFβ than non-CF controls (p=0.03). Mouse lungs exposed to TGFβ demonstrated inflammation, goblet cell hyperplasia, and decreased CFTR expression. CF mice had greater TGFβ-induced lung mechanics abnormalities than controls; both CF human AECs and CF mice showed higher TGFβ induced MAPK and PI3K signaling compared with controls. DISCUSSION/SIGNIFICANCE OF IMPACT: For the first time, we show increased TGFβ levels very early in CF. TGFβ drives CF lung abnormalities in mouse and human models; CF models are more sensitive to TGFβ’s effects. Understanding the role of TGFβ in promoting CF lung disease is critical to developing patient specific treatments.

The distribution of kinetic helicity in a dipolar planetary dynamo is central to the success of that dynamo. Motivated by the helicity distributions observed in numerical simulations of the Earth’s dynamo, we consider the relationship between the kinetic helicity, $h=\boldsymbol{u}\boldsymbol{\cdot }\unicode[STIX]{x1D735}\times \boldsymbol{u}$, and the buoyancy field that acts as a source of helicity, where $\boldsymbol{u}$ is velocity. We show that, in the absence of a magnetic field, helicity evolves in accordance with the equation $\unicode[STIX]{x2202}h/\unicode[STIX]{x2202}t=-\unicode[STIX]{x1D735}\boldsymbol{\cdot }\boldsymbol{F}+S_{h}$, where the flux, $\boldsymbol{F}$, represents the transport of helicity by inertial waves, and the helicity source, $S_{h}$, involves the product of the buoyancy and the velocity fields. In the numerical simulations it is observed that the helicity outside the tangent cylinder is predominantly negative in the north and positive in the south, a feature which the authors had previously attributed to the transport of helicity by waves (Davidson & Ranjan, Geophys. J. Intl, vol. 202, 2015, pp. 1646–1662). It is also observed that there is a strong spatial correlation between the distribution of $h$ and of $S_{h}$, with $S_{h}$ also predominantly negative in the north and positive in the south. This correlation tentatively suggests that it is the in situ generation of helicity by buoyancy that establishes the distribution of $h$ outside the tangent cylinder, rather than the dispersal of helicity by waves, as had been previously argued by the authors. However, although $h$ and $S_{h}$ are strongly correlated, there is no such correlation between $\unicode[STIX]{x2202}h/\unicode[STIX]{x2202}t$ and $S_{h}$, as might be expected if the distribution of $h$ were established by an in situ generation mechanism. We explain these various observations by showing that inertial waves interact with the buoyancy field in such a way as to induce a source $S_{h}$ which has the same sign as the helicity in the local wave flux, and that the sign of $h$ is simply determined by the direction of that flux. We conclude that the observed distributions of $h$ and $S_{h}$ outside the tangent cylinder are consistent with the transport of helicity by waves.