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The abundance, temperature, and clustering of metals in the intergalactic medium are important parameters for understanding their cosmic evolution and quantifying their impact on cosmological analysis with the Ly $\alpha$ forest. The properties of these systems are typically measured from individual quasar spectra redward of the quasar's Ly $\alpha$ emission line, yet that approach may provide biased results due to selection effects. We present an alternative approach to measure these properties in an unbiased manner with the two-point statistics commonly employed to quantify large-scale structure. Our model treats the observed flux of a large sample of quasar spectra as a continuous field and describes the one-dimensional, two-point statistics of this field with three parameters per ion: the abundance (column density distribution), temperature (Doppler parameter) and clustering (cloud-cloud correlation function). We demonstrate this approach on multiple ions (e.g., C IV, Si IV, Mg II) with early data from the Dark Energy Spectroscopic Instrument (DESI) and high-resolution spectra from the literature. Our initial results show some evidence that the C IV abundance is higher than previous measurements and evidence for abundance evolution over time. The first full year of DESI observations will have over an order of magnitude more quasar spectra than this study. In a future paper we will use those data to measure the growth of clustering and its impact on the Ly $\alpha$ forest, as well as test other DESI analysis infrastructure such as the pipeline noise estimates and the resolution matrix., Comment: 15 pages, 14 figures, accepted to MNRAS

We derive empirical constraints on the nucleosynthetic yields of nitrogen by incorporating N enrichment into our previously developed and empirically tuned multi-zone galactic chemical evolution model. We adopt a metallicity-independent ("primary") N yield from massive stars and a metallicity-dependent ("secondary") N yield from AGB stars. In our model, galactic radial zones do not evolve along the observed [N/O]-[O/H] relation, but first increase in [O/H] at roughly constant [N/O], then move upward in [N/O] via secondary N production. By $t\approx5$ Gyr, the model approaches an equilibrium [N/O]-[O/H] relation, which traces the radial oxygen gradient. We find good agreement with the [N/O]-[O/H] trend observed in extra-galactic systems if we adopt an IMF-averaged massive star yield $y_\text{N}^\text{CC}=3.6\times10^{-4}$, consistent with predictions for rapidly rotating progenitors, and a fractional AGB yield that is linear in mass and metallicity $y_\text{N}^\text{AGB}=(9\times10^{-4})(M_*/M_\odot)(Z_*/Z_\odot)$. This model reproduces the [N/O]-[O/H] relation found for Milky Way stars in the APOGEE survey, and it reproduces (though imperfectly) the trends of stellar [N/O] with age and [O/Fe]. The metallicity-dependent yield plays the dominant role in shaping the gas-phase [N/O]-[O/H] relation, but the AGB time-delay is required to match the APOGEE stellar age and [O/Fe] trends. If we add $\sim$40\% oscillations to the star formation rate, the model reproduces the scatter in gas-phase [N/O] vs. [O/H] observed in external galaxies by MaNGA. We also construct models using published AGB yields and examine their empirical successes and shortcomings. For all AGB yields we consider, simple stellar populations release half their N after only $\sim$250 Myr., Comment: 21 pages, 10 figures. See Figs. 5, 6, and 9 for key results. Submitted to MNRAS

Galactic haloes in a $\Lambda$-CDM universe are predicted to host today a swarm of debris resulting from cannibalised dwarf galaxies. The chemo-dynamical information recorded in their stellar populations helps elucidate their nature, constraining the assembly history of the Galaxy. Using data from APOGEE and \textit{Gaia}, we examine the chemical properties of various halo substructures, considering elements that sample various nucleosynthetic pathways. The systems studied are Heracles, \textit{Gaia}-Enceladus/Sausage (GES), the Helmi stream, Sequoia, Thamnos, Aleph, LMS-1, Arjuna, I'itoi, Nyx, Icarus, and Pontus. Abundance patterns of all substructures are cross-compared in a statistically robust fashion. Our main findings include: {\it i)} the chemical properties of most substructures studied match qualitatively those of dwarf Milky Way satellites, such as the Sagittarius dSph. Exceptions are Nyx and Aleph, which are chemically similar to disc stars, implying that these substructures were likely formed \textit{in situ}; {\it ii)} Heracles differs chemically from {\it in situ} populations such as Aurora and its inner halo counterparts in a statistically significant way. The differences suggest that the star formation rate was lower in Heracles than in the early Milky Way; {\it iii)} the chemistry of Arjuna, LMS-1, and I'itoi is indistinguishable from that of GES, suggesting a possible common origin; {\it iv)} all three Sequoia samples studied are qualitatively similar. However, only two of those samples present chemistry that is consistent with GES in a statistically significant fashion; {\it v)} the abundance patterns of the Helmi stream and Thamnos are different from all other halo substructures., Comment: Accepted for publication in MNRAS. The revised version contains a detailed comparison of the chemical composition of Heracles against Aurora and its inner halo in situ counterparts as well as a revised discussion of the chemistry of various Sequoia samples in contrast with Gaia-Enceladus/Sausage

We create a national-level longitudinal dataset to analyze how children’s participation in public and voucher-assisted housing affects age-26 earnings and adult incarceration. Naïve OLS estimates suggest that returns to subsidized housing participation are negative, but that relationship is driven by household selection into assisted housing. Household fixed effects estimates indicate that additional years of public housing increase earnings by 6.2 percent for females and 6.1 percent for males, while voucher-assisted housing increases earnings by 4.8 percent for females and 2.7 percent for males. Childhood participation in assisted housing also reduces the likelihood of adult incarceration for all household race/ethnicity groups. (JEL I38, J13, J31, K42, R38)

Epithelial-mesenchymal transition (EMT) is a biological process that plays a central role in embryonic development, tissue regeneration, and cancer metastasis. Transforming growth factor-β (TGFβ) is a potent inducer of this cellular transition, comprising transitions from an epithelial state to partial or hybrid EMT state(s), to a mesenchymal state. Recent experimental studies have shown that, within a population of epithelial cells, heterogeneous phenotypical profiles arise in response to different time- and TGFβ dose-dependent stimuli. This offers a challenge for computational models, as most model parameters are generally obtained to represent typical cell responses, not necessarily specific responses nor to capture population variability. In this study, we applied a data-assimilation approach that combines limited noisy observations with predictions from a computational model, paired with parameter estimation. Synthetic experiments mimic the biological heterogeneity in cell states that is observed in epithelial cell populations by generating a large population of model parameter sets. Analysis of the parameters for virtual epithelial cells with biologically significant characteristics (e.g., EMT prone or resistant) illustrates that these sub-populations have identifiable critical model parameters. We perform a series of in silico experiments in which a forecasting system reconstructs the EMT dynamics of each virtual cell within a heterogeneous population exposed to time-dependent exogenous TGFβ dose and either an EMT-suppressing or EMT-promoting perturbation. We find that estimating population-specific critical parameters significantly improved the prediction accuracy of cell responses. Thus, with appropriate protocol design, we demonstrate that a data-assimilation approach successfully reconstructs and predicts the dynamics of a heterogeneous virtual epithelial cell population in the presence of physiological model error and parameter uncertainty.

The Arp 2/3 complex, a nucleator of branched actin, is shown to provide multiple distinct mechanical advantages to migrating glioblastoma cells. These include both decreased substrate stress and increased parallel focal adhesion interactions, preventing failure of cell–-substrate interactions.

Correlative light and electron microscopy (CLEM) methods are powerful methods which combine molecular organization (from light microscopy) with ultrastructure (from electron microscopy). However, CLEM methods pose high cost/difficulty barriers to entry and have very low experimental throughput. Therefore, we have developed anindirectcorrelative light and electron microscopy (iCLEM) pipeline to sidestep the rate limiting steps of CLEM (i.e., preparing and imaging the same samples on multiple microscopes) and correlate multiscale structural data gleaned from separate samples imaged using different modalities by exploiting biological structures identifiable by both light and electron microscopy as intrinsic fiducials.We demonstrate here an application ofiCLEM, where we utilized gap junctions and mechanical junctions between muscle cells in the heart as intrinsic fiducials to correlate ultrastructural measurements from transmission electron microscopy (TEM), and focused ion beam scanning electron microscopy (FIB-SEM) with molecular organization from confocal microscopy and single molecule localization microscopy (SMLM). We further demonstrate howiCLEMcan be integrated with computational modeling to discover structure-function relationships. Thus, we presentiCLEMas a novel approach that complements existing CLEM methods and provides a generalizable framework that can be applied to any set of imaging modalities, provided suitable intrinsic fiducials can be identified.

The transradial approach has increasingly been used for neurointerventions because of the improved safety profile compared with transfemoral. However, it is important to be aware of potential complications such as radial artery (RA) spasm, RA occlusion, pseudoaneurysm, extravasation, arteriovenous fistula, and wrist hematoma as well as their management.To present our institution's experience with the prevention and management of local access site complications associated with the transradial approach for neuroendovascular interventions.We conducted a retrospective analysis of a prospectively maintained database and identified 1524 consecutive neuroendovascular procedures performed using transradial access from April 2018 to February 2021.Among 1524 procedures, local transradial complications occurred in 1.7%. Major complications occurred at a rate of 1.2% including RA extravasation (0.3%), delayed RA occlusion (0.6%), pseudoaneurysm (0.1%), compartment syndrome (0.1%), infection (0.1%), and avulsion of the RA in 0.1% (1 of 1524) with no serious clinical consequence. Although RA occlusion is included in major complications, all cases were asymptomatic and did not require any intervention. Minor complications occurred at a rate of 0.5% including severe RA spasm (0.3%) and hematoma (0.3%). No patient in the cohort died or suffered from permanent disability from a complication related to the transradial approach.Transradial access for neurointervention has a low rate of local complications, particularly when taking appropriate prevention measures. Appropriate management of complications can prevent procedural failure and has low morbidity rates demonstrating the overall safety profile of transradial access even when complications occur.

Spontaneous electrical activity, or automaticity, in the heart is required for normal physiological function. However, irregular automaticity, in particular, originating from the ventricles, can trigger life-threatening cardiac arrhythmias. Thus, understanding mechanisms of automaticity and synchronization is critical. Recent work has proposed that excitable cells coupled via a shared narrow extracellular cleft can mediate coupling, i.e., ephaptic coupling, that promotes automaticity in cell pairs. However, the dynamics of these coupled cells incorporating both ephaptic and gap junction coupling has not been explored. Here, we show that automaticity and synchronization robustly emerges via a Hopf bifurcation from either (i) increasing the fraction of inward rectifying potassium channels (carrying the [Formula: see text] current) at the junctional membrane or (ii) by decreasing the cleft volume. Furthermore, we explore how heterogeneity in the fraction of potassium channels between coupled cells can produce automaticity of both cells or neither cell, or more rarely in only one cell (i.e., automaticity without synchronization). Interestingly, gap junction coupling generally has minor effects, with only slight changes in regions of parameter space of automaticity. This work provides insight into potentially new mechanisms that promote spontaneous activity and, thus, triggers for arrhythmias in ventricular tissue.

During each heartbeat, the propagation of action potentials through the heart coordinates the contraction of billions of individual cardiomyocytes and is thus, a critical life process. Unsurprisingly, intercalated discs, which are cell-cell contact sites specialized to provide electrical and mechanical coupling between adjacent cardiomyocytes, have been the focus of much investigation. Slowed or disrupted propagation leads to potentially life-threatening arrhythmias in a wide range of pathologies, where intercalated disc remodeling is a common finding. Hence, the importance and urgency of understanding intercalated disc structure and its influence on action potential propagation. Surprisingly, however, conventional modeling approaches cannot predict changes in propagation elicited by perturbations that alter intercalated disc ultrastructure or molecular organization, owing to lack of quantitative structural data at subcellular through nano scales. In order to address this critical gap in knowledge, we sought to quantify intercalated disc structure at these finer spatial scales in the healthy adult mouse heart and relate them to function in a chamber-specific manner as a precursor to understanding the impacts of pathological intercalated disc remodeling. Using super-resolution light microscopy, electron microscopy, and computational image analysis, we provide here the first ever systematic, multiscale quantification of intercalated disc ultrastructure and molecular organization. By incorporating these data into a rule-based model of cardiac tissue with realistic intercalated disc structure, and comparing model predictions of electrical propagation with experimental measures of conduction velocity, we reveal that atrial intercalated discs can support faster conduction than their ventricular counterparts, which is normally masked by inter-chamber differences in myocyte geometry. Further, we identify key ultrastructural and molecular organization features underpinning the ability of atrial intercalated discs to support faster conduction. These data provide the first stepping stone to elucidating chamber-specific impacts of pathological intercalated disc remodeling, as occurs in many arrhythmic diseases.

Cardiac voltage-gated sodium channel gain-of-function prolongs repolarization in the long-QT syndrome type 3 (LQT3). Previous studies suggest that narrowing the perinexus within the intercalated disc, leading to rapid sodium depletion, attenuates LQT3-associated action potential duration (APD) prolongation. However, it remains unknown whether extracellular sodium concentration modulates APD prolongation during sodium channel gain-of-function. We hypothesized that elevated extracellular sodium concentration and widened perinexus synergistically prolong APD in LQT3. LQT3 was induced with sea anemone toxin (ATXII) in Langendorff-perfused guinea pig hearts (n = 34). Sodium concentration was increased from 145 to 160 mM. Perinexal expansion was induced with mannitol or the sodium channel β1-subunit adhesion domain antagonist (βadp1). Epicardial ventricular action potentials were optically mapped. Individual and combined effects of varying clefts and sodium concentrations were simulated in a computational model. With ATXII, both mannitol and βadp1 significantly widened the perinexus and prolonged APD, respectively. The elevated sodium concentration alone significantly prolonged APD as well. Importantly, the combination of elevated sodium concentration and perinexal widening synergistically prolonged APD. Computational modeling results were consistent with animal experiments. Concurrently elevating extracellular sodium and increasing intercalated disc edema prolongs repolarization more than the individual interventions alone in LQT3. This synergistic effect suggests an important clinical implication that hypernatremia in the presence of cardiac edema can markedly increase LQT3-associated APD prolongation. Therefore, to our knowledge, this is the first study to provide evidence of a tractable and effective strategy to mitigate LQT3 phenotype by means of managing sodium levels and preventing cardiac edema in patients. NEW & NOTEWORTHY This is the first study to demonstrate that the long-QT syndrome type 3 (LQT3) phenotype can be exacerbated or concealed by regulating extracellular sodium concentrations and/or the intercalated disc separation. The animal experiments and computational modeling in the current study reveal a critically important clinical implication: sodium dysregulation in the presence of edema within the intercalated disc can markedly increase the risk of arrhythmia in LQT3. These findings strongly suggest that maintaining extracellular sodium within normal physiological limits may be an effective and inexpensive therapeutic option for patients with congenital or acquired sodium channel gain-of-function diseases.

Many cardiac diseases are characterized by an increased late sodium current, including heart failure, hypertrophic cardiomyopathy, and inherited long QT syndrome type 3 (LQT3). The late sodium current in LQT3 is caused by a gain-of-function mutation in the voltage-gated sodium channel Nav1.5. Despite a well-defined genetic cause of LQT3, treatment remains inconsistent because of incomplete penetrance of the mutation and variability of antiarrhythmic efficacy. Here, we investigate the relationship between LQT3-associated mutation incomplete penetrance and variability in ion channel expression, simulating a population of 1,000 individuals with the O'Hara-Rudy model of the human ventricular myocyte. We first simulate healthy electrical activity (i.e., in the absence of a mutation) and then incorporate heterozygous expression for three LQT3-associated mutations (Y1795C, I1768V, and ΔKPQ), to directly compare the effects of each mutation on individuals across a diverse population. For all mutations, we find that susceptibility, defined by either the presence of an early afterdepolarization (EAD) or prolonged action potential duration (APD), primarily depends on the balance between the conductance of

We develop a hybrid model of galactic chemical evolution that combines a multi-ring computation of chemical enrichment with a prescription for stellar migration and the vertical distribution of stellar populations informed by a cosmological hydrodynamic disc galaxy simulation. Our fiducial model adopts empirically motivated forms of the star formation law and star formation history, with a gradient in outflow mass loading tuned to reproduce the observed metallicity gradient. With this approach, the model reproduces many of the striking qualitative features of the Milky Way disc's abundance structure: (i) the dependence of the [O/Fe]-[Fe/H] distribution on radius $R_\text{gal}$ and midplane distance $|z|$; (ii) the changing shapes of the [O/H] and [Fe/H] distributions with $R_\text{gal}$ and $|z|$; (iii) a broad distribution of [O/Fe] at sub-solar metallicity and changes in the [O/Fe] distribution with $R_\text{gal}$, $|z|$, and [Fe/H]; (iv) a tight correlation between [O/Fe] and stellar age for [O/Fe] $>$ 0.1; (v) a population of young and intermediate-age $\alpha$-enhanced stars caused by migration-induced variability in the Type Ia supernova rate; (vi) non-monotonic age-[O/H] and age-[Fe/H] relations, with large scatter and a median age of $\sim$4 Gyr near solar metallicity. Observationally motivated models with an enhanced star formation rate $\sim$2 Gyr ago improve agreement with the observed age-[Fe/H] and age-[O/H] relations, but worsen agreement with the observed age-[O/Fe] relation. None of our models predict an [O/Fe] distribution with the distinct bimodality seen in the observations, suggesting that more dramatic evolutionary pathways are required. All code and tables used for our models are publicly available through the Versatile Integrator for Chemical Evolution (VICE; https://pypi.org/project/vice)., Comment: 24 pages; 18 figures; to be submitted to MNRAS; comments welcome