ABSTRACT
Engineering offers new educational opportunities for students, yet also poses challenges about how to conceptualize the disciplinary core ideas, crosscutting concepts, and science and ...engineering practices of the disciplinary fields of engineering. In this paper, we draw from empirical studies of engineering in professional and school settings to propose a set of epistemic practices of engineering that can inform curriculum development, teacher education, and research in science and engineering education. We examine the ways that these practices emerge from the work of engineering and serve to guide problem solving across a range of engineering fields. The proposed epistemic practices for education take into consideration social contexts of engineering, the salience of evidence for decision making, the types of tools and strategies used to construct knowledge, and need for creativity and innovation. The article concludes with suggestions for research in engineering education.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Nonsteroidal anti‐inflammatory drugs (NSAIDs) are among the most commonly used analgesics due to their lack of addictive potential. However, NSAIDs have the potential to cause serious ...gastrointestinal, renal, and cardiovascular adverse events. CYP2C9 polymorphisms influence metabolism and clearance of several drugs in this class, thereby affecting drug exposure and potentially safety. We summarize evidence from the published literature supporting these associations and provide therapeutic recommendations for NSAIDs based on CYP2C9 genotype (updates at www.cpicpgx.org).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Phenytoin is an antiepileptic drug with a narrow therapeutic index and large interpatient pharmacokinetic variability, partly due to genetic variation in CYP2C9. Furthermore, the variant allele ...HLA‐B*15:02 is associated with an increased risk of Stevens–Johnson syndrome and toxic epidermal necrolysis in response to phenytoin treatment. We summarize evidence from the published literature supporting these associations and provide therapeutic recommendations for the use of phenytoin based on CYP2C9 and/or HLA‐B genotypes (updates on cpicpgx.org).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The regenerative capacity of the peripheral nervous system declines with age. Why this occurs, however, is unknown. We demonstrate that 24-month-old mice exhibit an impairment of functional recovery ...after nerve injury compared to 2-month-old animals. We find no difference in the intrinsic growth capacity between aged and young sensory neurons in vitro or in their ability to activate growth-associated transcriptional programs after injury. Instead, using age-mismatched nerve transplants in vivo, we show that the extent of functional recovery depends on the age of the nerve graft, and not the age of the host. Molecular interrogation of the sciatic nerve reveals that aged Schwann cells (SCs) fail to rapidly activate a transcriptional repair program after injury. Functionally, aged SCs exhibit impaired dedifferentiation, myelin clearance, and macrophage recruitment. These results suggest that the age-associated decline in axonal regeneration results from diminished Schwann cell plasticity, leading to slower myelin clearance.
•Aged mice exhibit diminished functional recovery after nerve injury•Aged neuronal regeneration responses remain robust•Transplantation of young nerve grafts into old hosts rejuvenates regeneration•Aged Schwann cells exhibit diminished capacity for myelin clearance
Why aging results in diminished peripheral nerve regeneration remains a clinical problem and a biological puzzle. In this issue, Painter et al. demonstrate that Schwann cell injury responses decline with aging, providing key insight into the aging peripheral nervous system.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
ABSTRACT
We investigate the formation of the satellite galaxy population of a Milky Way-mass halo in a very highly resolved magnetohydrodynamic cosmological zoom-in simulation (baryonic mass ...resolution mb = 800 $\rm M_{\odot }$). We show that the properties of the central star-forming galaxy, such as the radial stellar surface density profile and star formation history, are (i) robust to stochastic variations associated with the so-called Butterfly Effect and (ii) well converged over 3.5 orders of magnitude in mass resolution. We find that there are approximately five times as many satellite galaxies at this high resolution compared to a standard ($m_b\sim 10^{4-5}\, \rm M_{\odot }$) resolution simulation of the same system. This is primarily because two-thirds of the high-resolution satellites do not form at standard resolution. A smaller fraction (one-sixth) of the satellites present at high-resolution form and disrupt at standard resolution; these objects are preferentially low-mass satellites on intermediate- to low-eccentricity orbits with impact parameters ≲30 kpc. As a result, the radial distribution of satellites becomes substantially more centrally concentrated at higher resolution, in better agreement with recent observations of satellites around Milky Way-mass haloes. Finally, we show that our galaxy formation model successfully forms ultra-faint galaxies and reproduces the stellar velocity dispersion, half-light radii, and V-band luminosities of observed Milky Way and Local Group dwarf galaxies across six orders of magnitude in luminosity (103–$10^{9}\, \rm L_{\odot }$).
Optical manipulations of genetically defined cell types have generated significant insights into the dynamics of neural circuits. While optogenetic activation has been relatively straightforward, ...rapid and reversible synaptic inhibition has proven more elusive. Here, we leveraged the natural ability of inhibitory presynaptic GPCRs to suppress synaptic transmission and characterize parapinopsin (PPO) as a GPCR-based opsin for terminal inhibition. PPO is a photoswitchable opsin that couples to Gi/o signaling cascades and is rapidly activated by pulsed blue light, switched off with amber light, and effective for repeated, prolonged, and reversible inhibition. PPO rapidly and reversibly inhibits glutamate, GABA, and dopamine release at presynaptic terminals. Furthermore, PPO alters reward behaviors in a time-locked and reversible manner in vivo. These results demonstrate that PPO fills a significant gap in the neuroscience toolkit for rapid and reversible synaptic inhibition and has broad utility for spatiotemporal control of inhibitory GPCR signaling cascades.
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•Parapinopsin (PPO) is a photoswitchable Gi-coupled opsin activated by blue light•At cell bodies, PPO inhibits neuronal activity to suppress reward-seeking behaviors•PPO reversibly inhibits neurotransmitter release at axon terminals•Photoinhibition of projections in vivo rapidly and reversibly alters mouse behavior
Optical approaches to rapidly and reversibly inhibit neuronal projections have lagged behind those for activation. Copits et al. identify a photoswitchable GPCR-based opsin that couples to inhibitory effectors. This opsin leverages the natural ability of presynaptic GPCRs to inhibit transmitter release, providing an alternative strategy to manipulate distinct synaptic projections.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Neuroinflammation is associated with a broad spectrum of neurodegenerative and psychiatric diseases. The core process in neuroinflammation is activation of microglia, the innate immune cells of the ...brain. We measured the neuroinflammatory response produced by a systemic administration of theEscherichia colilipopolysaccharide (LPS; also called endotoxin) in humans with the positron emission tomography (PET) radiotracer 11CPBR28, which binds to translocator protein, a molecular marker that is up-regulated by microglial activation. In addition, inflammatory cytokines in serum and sickness behavior profiles were measured before and after LPS administration to relate brain microglial activation with systemic inflammation and behavior. Eight healthy male subjects each had two 120-min 11CPBR28 PET scans in 1 d, before and after an LPS challenge. LPS (1.0 ng/kg, i.v.) was administered 180 min before the second 11CPBR28 scan. LPS administration significantly increased 11CPBR28 binding 30–60%, demonstrating microglial activation throughout the brain. This increase was accompanied by an increase in blood levels of inflammatory cytokines, vital sign changes, and sickness symptoms, well-established consequences of LPS administration. To our knowledge, this is the first demonstration in humans that a systemic LPS challenge induces robust increases in microglial activation in the brain. This imaging paradigm to measure brain microglial activation with 11CPBR28 PET provides an approach to test new medications in humans for their putative antiinflammatory effects.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Neutralization of the omicron variant was assessed in serum samples obtained from persons who had received an mRNA-1273 booster. After the standard two-dose vaccine regimen, these titers were ...approximately 35 times lower than those against the D614G variant. However, boosters increased omicron neutralization by a factor of 20 — to levels that correlate with clinical resistance to infection.
Engineering design provides unique ways to include epistemic tools to support collaborative sense‐making, reasoning with evidence, and assessing knowledge. Engineering design processes often require ...students to apply science concepts to solve problems. We draw from five engineering curricular units that engaged students in specific epistemic practices of engineering: constructing models and prototypes, making trade‐offs between criteria and constraints, and communicating through uses of conventionalized verbal, written, and symbolic models. Through analysis of curriculum products, student artifacts, and classroom discourse, we show how engaging in such practices requires the use of epistemic tools that shape, and are shaped by, the knowledge construction work of the members of the classrooms. The epistemic tools foster creating, sharing, and assessing knowledge claims. Six principles of practice for education demonstrate how such tools can be educative. These principles evince how epistemic tools support goal‐directed, concerted activity that can support the learning of disciplinary knowledge and practice and offer the potential to increase student agency.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The recent successes of immunotherapy have shifted the paradigm in cancer treatment, but because only a percentage of patients are responsive to immunotherapy, it is imperative to identify factors ...impacting outcome. Obesity is reaching pandemic proportions and is a major risk factor for certain malignancies, but the impact of obesity on immune responses, in general and in cancer immunotherapy, is poorly understood. Here, we demonstrate, across multiple species and tumor models, that obesity results in increased immune aging, tumor progression and PD-1-mediated T cell dysfunction which is driven, at least in part, by leptin. However, obesity is also associated with increased efficacy of PD-1/PD-L1 blockade in both tumor-bearing mice and clinical cancer patients. These findings advance our understanding of obesity-induced immune dysfunction and its consequences in cancer and highlight obesity as a biomarker for some cancer immunotherapies. These data indicate a paradoxical impact of obesity on cancer. There is heightened immune dysfunction and tumor progression but also greater anti-tumor efficacy and survival after checkpoint blockade which directly targets some of the pathways activated in obesity.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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