The definitive biography and assessment of the wily and formidable prince who unexpectedly became monarch-the most infamous king in British history The reign of Richard III, the last Yorkist king and ...the final monarch of the Plantagenet dynasty, marked a turning point in British history. But despite his lasting legacy, Richard only ruled as king for the final two years of his life. While much attention has been given to his short reign, Michael Hicks explores the whole of Richard's fascinating life and traces the unfolding of his character and career from his early years as the son of a duke to his violent death at the battle of Bosworth. Hicks explores how Richard-villainized for his imprisonment and probable killing of the princes-applied his experience to overcome numerous setbacks and adversaries. Richard proves a complex, conflicted individual whose Machiavellian tact and strategic foresight won him a kingdom. He was a reformer who planned big changes, but lost the opportunity to fulfill them and to retain his crown.
Stem cell niches are composed of dynamic microenvironments that support stem cells over a lifetime. The emerging niche is distinct from the adult because its main role is to support the progenitors ...that build organ systems in development. Emerging niches mature through distinct stages to form the adult niche and enable proper stem cell support. As a model of emerging niches, this review highlights how differences in the skeletal muscle microenvironment influence emerging versus satellite cell (SC) niche formation in skeletal muscle, which is among the most regenerative tissue systems. We contrast how stem cell niches regulate intrinsic properties between progenitor and stem cells throughout development to adulthood. We describe new applications for generating emerging niches from human pluripotent stem cells (hPSCs) using developmental principles and highlight potential applications for regeneration and therapeutics.
Niches coevolve with the maturation of progenitor and stem cells from development through to adulthood.Fetal progenitors in emerging niches are highly expansive, whereas adult niches regulate stem cell quiescence.Fetal progenitors are less able to occupy adult niches during transplantation.Niche formation is stepwise, involving cell–cell contact, followed by cell–extracellular matrix contact, to affect cell polarity and maturation.Emerging niches use similar pathways and mechanisms during regeneration.Understanding niche formation may improve the quality and quantity of stem cells within niches.Supportive cell types in emerging niches are different from homeostatic adult niches.Human pluripotent stem cell lineages can be used to model components of niche development in vitro and in vivo.
This account of the condition now termed complex regional pain syndrome (CRPS) spans approximately 462 years since a description embodying similar clinical features was described by Ambroise Paré in ...1557. While reviewing its historical origins, the text describes why it became necessary to change the taxonomies of two clinical syndromes with similar pathophysiologies to one which acknowledges this aspect but does not introduce any mechanistic overtones. Discussed at length is the role of the sympathetic component of the autonomic nervous system (ANS) and why its dysfunction has both directly and indirectly influenced our understanding of the inflammatory aspects of CRPS. As the following article will show, our knowledge has expanded in an exponential fashion to include musculoskeletal, immune, autoimmune, central and peripheral nervous system and ANS dysfunction, all of which increase the complexity of its clinical management. A burgeoning literature is beginning to shed light on the mechanistic aspects of these syndromes and the increasing evidence of a genetic influence on such factors as autoimmunity, and its importance is also discussed at length. An important aspect that has been missing from the diagnostic criteria is a measure of disease severity. The recent validation of a CRPS Severity Score is also included.
Mutations in DMD disrupt the reading frame, prevent dystrophin translation, and cause Duchenne muscular dystrophy (DMD). Here we describe a CRISPR/Cas9 platform applicable to 60% of DMD patient ...mutations. We applied the platform to DMD-derived hiPSCs where successful deletion and non-homologous end joining of up to 725 kb reframed the DMD gene. This is the largest CRISPR/Cas9-mediated deletion shown to date in DMD. Use of hiPSCs allowed evaluation of dystrophin in disease-relevant cell types. Cardiomyocytes and skeletal muscle myotubes derived from reframed hiPSC clonal lines had restored dystrophin protein. The internally deleted dystrophin was functional as demonstrated by improved membrane integrity and restoration of the dystrophin glycoprotein complex in vitro and in vivo. Furthermore, miR31 was reduced upon reframing, similar to observations in Becker muscular dystrophy. This work demonstrates the feasibility of using a single CRISPR pair to correct the reading frame for the majority of DMD patients.
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•Largest CRISPR/Cas9-mediated deletion of 725 kb of DMD•Reframed DMD hiPSCs differentiated to cardiac and skeletal muscle express dystrophin•Internally deleted dystrophin demonstrates functionality in vitro and in vivo•This single gRNA pair is therapeutically relevant to 60% of DMD mutations
Young et al. demonstrate restoration of the DMD reading frame by CRISPR/Cas9-mediated deletion of up to 725 kb in hiPSCs as a therapeutic strategy for 60% of Duchenne muscular dystrophy patients. The resulting internally deleted protein is shown to be functional in vitro and in vivo.
Critical attention to Wilfrid Sellars’s “Philosophy and the Scientific Image of Man” (PSIM) has focused on the dubious Peircean optimism about scientific convergence that underwrites Sellars’s talk ...of “the” scientific image. Sellars’s ultimate Peircean ontology has led Willem deVries, for instance, to accuse him of being a naturalistic “monistic visionary.” But this complaint of monism misplays the status of the ideal end of science in Sellars’s thinking. I propose a novel reading of PSIM, foregrounding its opening methodological re ections. On this reading, the central point of the paper is to accuse figures like Wittgenstein and Strawson, whom I call “analytical quietists,” of taking the unity of intellectual endeavor as somehow given. Such unity as is forthcoming is, Sellars tells us, a task. I conclude by noting that a structurally similar accusation of too easily presumed unity emerges at the end of the paper, against a familiar sort of anti-relativistic moral theorizing. Thus, Sellars’s conception of the task of philosophy is, at least potentially, a point of surprising ethico-political significance as well.
Human pluripotent stem cells (hPSCs) can be directed to differentiate into skeletal muscle progenitor cells (SMPCs). However, the myogenicity of hPSC-SMPCs relative to human fetal or adult satellite ...cells remains unclear. We observed that hPSC-SMPCs derived by directed differentiation are less functional in vitro and in vivo compared to human satellite cells. Using RNA sequencing, we found that the cell surface receptors ERBB3 and NGFR demarcate myogenic populations, including PAX7 progenitors in human fetal development and hPSC-SMPCs. We demonstrated that hPSC skeletal muscle is immature, but inhibition of transforming growth factor-β signalling during differentiation improved fusion efficiency, ultrastructural organization and the expression of adult myosins. This enrichment and maturation strategy restored dystrophin in hundreds of dystrophin-deficient myofibres after engraftment of CRISPR-Cas9-corrected Duchenne muscular dystrophy human induced pluripotent stem cell-SMPCs. The work provides an in-depth characterization of human myogenesis, and identifies candidates that improve the in vivo myogenic potential of hPSC-SMPCs to levels that are equal to directly isolated human fetal muscle cells.
Analogy has played an important role in developing modern mathematics. However, it is unclear to what extent students are granted opportunities to productively reason by analogy. This article ...proposes a set of lessons for introducing topics in ring theory that allow students to engage with the process of reasoning by analogy while exploring new (to the students) mathematics. In this way, students come to creatively establish new concepts that they may take ownership of. I provide insights from previous implementations and conclude by reflecting on what has (and has not) worked well in my experience with implementing the lesson.
This analysis uses a difference-in-differences approach to examine the impact of the Regional Cities Initiative (RCI) on economic development outcomes in counties that participated in the program ...relative to those that did not participate. The RCI was a place-based economic development program that was implemented in Indiana beginning in 2015. Through a competitive process, this program provided funding for projects meant to improve the quality of life in three regions of the state. The results indicate that participating counties had higher gross domestic product growth and higher employment growth than nonparticipating counties. There is limited evidence that the program had a positive impact on population growth. There were no discernable effects on house prices or earnings.
Dorsal root ganglion stimulation (DRG-S) involves the electrical modulation of the somata of afferent neural fibers to treat chronic pain. DRG-S has demonstrated clinical efficacy at frequencies ...lower than typically used with spinal cord stimulation (SCS). In a clinical study, we found that the frequency of DRG-S can be tapered to a frequency as low as 4 Hz with no loss of efficacy. This review discusses possible mechanisms of action underlying effective pain relief with very low-frequency DRG-S.
We performed a literature review to explore the role of frequency in neural transmission and the corresponding relevance of frequency settings with neuromodulation.
Sensory neural transmission is a frequency-modulated system, with signal frequency determining which mechanisms are activated in the dorsal horn. In the dorsal horn, low-frequency signaling (<20 Hz) activates inhibitory processes while higher frequencies (>25 Hz) are excitatory. Physiologically, low-threshold mechanoreceptors (LTMRs) fibers transmit or modulate innocuous mechanical touch at frequencies as low as 0.5-5 Hz, while nociceptive fibers transmit pain at high frequencies. We postulate that very low-frequency DRG-S, at least partially, harnesses LTMRs and the native endogenous opioid system. Utilizing lower stimulation frequency decreases the total energy delivery used for DRG-S, extends battery life, and facilitates the development of devices with smaller generators.
This paper presents a single-point Material Point Method (MPM) for large deformation problems in two-phase porous media such as soils. Many MPM formulations are known to produce numerical ...oscillations and inaccuracies in the simulated results, largely due to numerical integration and stress recovery performed at non-ideal locations, cell crossing errors, and mass moving from one background grid cell to another. The same drawbacks lead to even worse consequences in the presence of an interstitial fluid phase, especially when undrained/incompressible conditions are approached. In this study, an explicit stabilised MPM, based on the Generalised Interpolation Material Point (GIMP) method with Selective Reduced Integration (SRI), is proposed to mitigate typical numerical oscillations in (nearly) incompressible coupled problems. It includes two additional features to improve stress and pore pressure recovery, namely (i) patch recovery of pore pressure increments based on a Moving Least Squares Approximation, and (ii) two-phase extension of the Composite Material Point Method for effective stress recovery. The combination of components leads to a new method named GC-SRI-patch. After a detailed description of the approach, its effectiveness is verified through analysing various consolidation problems, with emphasis on the representation of pore pressures in time and space.
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