Parallel Play McDonald, Rory M.; Eisenhardt, Kathleen M.
Administrative science quarterly,
06/2020, Letnik:
65, Številka:
2
Journal Article
Recenzirano
Prior research has advanced several explanations for entrepreneurial success in nascent markets but leaves a key imperative unexplored: the business model. By studying five ventures in a nascent ...financial-technology market, we develop a novel theoretical framework for understanding how entrepreneurs effectively design business models: parallel play. Similar to parallel play by preschoolers, entrepreneurs engaged in parallel play interweave action, cognition, and timing to accelerate learning about a novel world. Specifically, they (1) borrow from peers and focus on established substitutes for their services or products, (2) test assumptions, then commit to a broad business-model template, and (3) pause before elaborating the activity system. The insights from our framework contribute to research on optimal distinctiveness and to the learning and evolutionary-adjustment literatures. More broadly, we blend organization theory with a fresh theoretical lens—business-model processes—to highlight how organizations actually work and create value.
Leakage from blood vessels into tissues is governed by mechanisms that control endothelial barrier function to maintain homeostasis. Dysregulated endothelial permeability contributes to many ...conditions and can influence disease morbidity and treatment. Diverse approaches used to study endothelial permeability have yielded a wealth of valuable insights. Yet, ongoing questions, technical challenges, and unresolved controversies relating to the mechanisms and relative contributions of barrier regulation, transendothelial sieving, and transport of fluid, solutes, and particulates complicate interpretations in the context of vascular physiology and pathophysiology. Here, we describe recent in vivo findings and other advances in understanding endothelial barrier function with the goal of identifying and reconciling controversies over cellular and molecular processes that regulate the vascular barrier in health and disease.
In the microcirculation, endothelial permeability varies from least in arterioles to greatest in venules and is regulated in an organ-specific manner to control the extravasation of fluid, solutes, and large molecules.Inflammatory factors increase vascular permeability by inducing the formation of focal endothelial gaps that can be transient in acute inflammation or sustained in chronic conditions.Gap formation requires changes in the organization of tight junctions and adherens junctions that join endothelial cells and create a barrier.Adherens junction opening requires phosphorylation, loss of homophilic interactions, and internalization of VE-cadherin accompanied by changes in the cortical cytoskeleton.Sustained hyperpermeability in pathologic conditions can lead to edema, reduced vascular perfusion, impaired drug delivery, and exaggerated disease severity.
Disorders of bone remodeling Feng, Xu; McDonald, Jay M
Annual review of pathology,
01/2011, Letnik:
6
Journal Article
Recenzirano
Odprti dostop
The skeleton provides mechanical support for stature and locomotion, protects vital organs, and controls mineral homeostasis. A healthy skeleton must be maintained by constant bone modeling to carry ...out these crucial functions throughout life. Bone remodeling involves the removal of old or damaged bone by osteoclasts (bone resorption) and the subsequent replacement of new bone formed by osteoblasts (bone formation). Normal bone remodeling requires a tight coupling of bone resorption to bone formation to guarantee no alteration in bone mass or quality after each remodeling cycle. However, this important physiological process can be derailed by a variety of factors, including menopause-associated hormonal changes, age-related factors, changes in physical activity, drugs, and secondary diseases, which lead to the development of various bone disorders in both women and men. We review the major diseases of bone remodeling, emphasizing our current understanding of the underlying pathophysiological mechanisms.
The Universe's largest galaxies reside at the centres of galaxy clusters and are embedded in hot gas that, if left undisturbed, would cool quickly and create many more new stars than are actually ...observed. Cooling can be regulated by feedback from accretion of cooling gas onto the central black hole, but requires an accretion rate finely tuned to the thermodynamic state of the hot gas. Theoretical models in which cold clouds precipitate out of the hot gas via thermal instability and accrete onto the black hole exhibit the necessary tuning. Recent observational evidence shows that the abundance of cold gas in the centres of clusters increases rapidly near the predicted threshold for instability. Here we report observations showing that this precipitation threshold extends over a large range in cluster radius, cluster mass and cosmic time. We incorporate the precipitation threshold into a framework of theoretical models for the thermodynamic state of hot gas in galaxy clusters. According to that framework, precipitation regulates star formation in some giant galaxies, while thermal conduction prevents star formation in others if it can compensate for radiative cooling and shut off precipitation.
We present a study of 107 galaxies, groups, and clusters spanning ∼3 orders of magnitude in mass, ∼5 orders of magnitude in central galaxy star formation rate (SFR), ∼4 orders of magnitude in the ...classical cooling rate ( ) of the intracluster medium (ICM), and ∼5 orders of magnitude in the central black hole accretion rate. For each system in this sample, we measure the ICM cooling rate, , using archival Chandra X-ray data and acquire the SFR and systematic uncertainty in the SFR by combining over 330 estimates from dozens of literature sources. With these data, we estimate the efficiency with which the ICM cools and forms stars, finding % for systems with M yr−1. For these systems, we measure a slope in the SFR- relation greater than unity, suggesting that the systems with the strongest cool cores are also cooling more efficiently. We propose that this may be related to, on average, higher black hole accretion rates in the strongest cool cores, which could influence the total amount (saturating near the Eddington rate) and dominant mode (mechanical versus radiative) of feedback. For systems with M yr−1, we find that the SFR and are uncorrelated and show that this is consistent with star formation being fueled at a low (but dominant) level by recycled ISM gas in these systems. We find an intrinsic log-normal scatter in SFR at a fixed of 0.52 0.06 dex (1 rms), suggesting that cooling is tightly self-regulated over very long timescales but can vary dramatically on short timescales. There is weak evidence that this scatter may be related to the feedback mechanism, with the scatter being minimized (∼0.4 dex) for systems for which the mechanical feedback power is within a factor of two of the cooling luminosity.
Pharmaceuticals and personal care products (PPCPs) are found in measureable quantities within the aquatic environment. Selective serotonin reuptake inhibitor (SSRI) antidepressants are one class of ...pharmaceutical compound that has received a lot of attention. Consistent with most PPCPs, the pharmacokinetics and physiological impacts of SSRI treatment have been well-studied in small mammals and humans and this, combined with the evolutionary conservation of the serotonergic system across vertebrates, allows for the read-across of known SSRI effects in mammals to potential SSRI impacts on aquatic organisms. Using an Adverse Outcome Pathway (AOP) framework, this review examines the similarities and differences between the mammalian and teleost fish SSRI target, the serotonin transporter (SERT; SLC6A4), and the downstream impacts of elevated extracellular serotonin (5-HT; 5-hydroxytryptamine), the consequence of SERT inhibition, on organ systems and physiological processes within teleost fish. This review also intends to reveal potentially understudied endpoints for SSRI toxicity based on what is known to be controlled by 5-HT in fish.
Advances in understanding the role of vascular endothelial growth factor (VEGF) in normal physiology are giving insight into the basis of adverse effects attributed to the use of VEGF inhibitors in ...clinical oncology. These effects are typically downstream consequences of suppression of cellular signalling pathways important in the regulation and maintenance of the microvasculature. Downregulation of these pathways in normal organs can lead to vascular disturbances and even regression of blood vessels, which could be intensified by concurrent pathological conditions. These changes are generally manageable and pose less risk than the tumours being treated, but they highlight the properties shared by tumour vessels and the vasculature of normal organs.
Selective inhibition of vascular endothelial growth factor (VEGF) increases the efficacy of chemotherapy and has beneficial effects on multiple advanced cancers, but response is often limited and the ...disease eventually progresses. Changes in the tumour microenvironment--hypoxia among them--that result from vascular pruning, suppressed angiogenesis and other consequences of VEGF inhibition can promote escape and tumour progression. New therapeutic approaches that target pathways that are involved in the escape mechanisms add the benefits of blocking tumour progression to those of slowing tumour growth by inhibiting angiogenesis.
We present a multiwavelength morphological analysis of star-forming clouds and filaments in the central (≲50 kpc) regions of 16 low-redshift (z < 0.3) cool core brightest cluster galaxies. New Hubble ...Space Telescope imaging of far-ultraviolet continuum emission from young (≲10 Myr), massive (≳5 M⊙) stars reveals filamentary and clumpy morphologies, which we quantify by means of structural indices. The FUV data are compared with X-ray, Lyα, narrow-band Hα, broad-band optical/IR, and radio maps, providing a high spatial resolution atlas of star formation locales relative to the ambient hot (∼107–8 K) and warm ionized (∼104 K) gas phases, as well as the old stellar population and radio-bright active galactic nucleus (AGN) outflows. Nearly half of the sample possesses kpc-scale filaments that, in projection, extend towards and around radio lobes and/or X-ray cavities. These filaments may have been uplifted by the propagating jet or buoyant X-ray bubble, or may have formed in situ by cloud collapse at the interface of a radio lobe or rapid cooling in a cavity's compressed shell. The morphological diversity of nearly the entire FUV sample is reproduced by recent hydrodynamical simulations in which the AGN powers a self-regulating rain of thermally unstable star-forming clouds that precipitate from the hot atmosphere. In this model, precipitation triggers where the cooling-to-free-fall time ratio is t
cool/t
ff ∼ 10. This condition is roughly met at the maximal projected FUV radius for more than half of our sample, and clustering about this ratio is stronger for sources with higher star formation rates.
We propose a novel method to constrain turbulence and bulk motions in massive galaxies, galaxy groups, and clusters, exploring both simulations and observations. As emerged in the recent picture of ...top-down multiphase condensation, hot gaseous halos are tightly linked to all other phases in terms of cospatiality and thermodynamics. While hot halos (∼107 K) are perturbed by subsonic turbulence, warm (∼104 K) ionized and neutral filaments condense out of the turbulent eddies. The peaks condense into cold molecular clouds (<100 K) raining in the core via chaotic cold accretion (CCA). We show that all phases are tightly linked in terms of the ensemble (wide-aperture) velocity dispersion along the line of sight. The correlation arises in complementary long-term AGN feedback simulations and high-resolution CCA runs, and is corroborated by the combined Hitomi and new Integral Field Unit measurements in the Perseus cluster. The ensemble multiphase gas distributions (from the UV to the radio band) are characterized by substantial spectral line broadening ( v,los 100-200 ) with a mild line shift. On the other hand, pencil-beam detections (as H i absorption against the AGN backlight) sample the small-scale clouds displaying smaller broadening and significant line shifts of up to several 100 (for those falling toward the AGN), with increased scatter due to the turbulence intermittency. We present new ensemble v,los of the warm H +N ii gas in 72 observed cluster/group cores: the constraints are consistent with the simulations and can be used as robust proxies for the turbulent velocities, in particular for the challenging hot plasma (otherwise requiring extremely long X-ray exposures). Finally, we show that the physically motivated criterion C tcool/teddy 1 best traces the condensation extent region and the presence of multiphase gas in observed clusters and groups. The ensemble method can be applied to many available spectroscopic data sets and can substantially advance our understanding of multiphase halos in light of the next-generation multiwavelength missions.
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