The production of force and power are inherent properties of skeletal muscle, and regulated by contractile proteins within muscle fibers. However, skeletal muscle integrity and function also require ...strong connections between muscle fibers and their extracellular matrix (ECM). A well-organized and pliant ECM is integral to muscle function and the ability for many different cell populations to efficiently migrate through ECM is critical during growth and regeneration. For many neuromuscular diseases, genetic mutations cause disruption of these cytoskeletal-ECM connections, resulting in muscle fragility and chronic injury. Ultimately, these changes shift the balance from myogenic pathways toward fibrogenic pathways, culminating in the loss of muscle fibers and their replacement with fatty-fibrotic matrix. Hence a common pathological hallmark of muscular dystrophy is prominent fibrosis. This review will cover the salient features of muscular dystrophy pathogenesis, highlight the signals and cells that are important for myogenic and fibrogenic actions, and discuss how fibrosis alters the ECM of skeletal muscle, and the consequences of fibrosis in developing therapies.
•Muscular dystrophy pathology creates an imbalance between myogenic and fibrogenic pathways within skeletal muscle.•Signaling mechanisms promoting fibrosis include TGFβ, myostatin, hypoxia, and mechanical stiffness.•Fibrosis compromises coordination amid satellite cells, inflammatory cells, and fibro/adipogenic progenitors in regeneration.•A major consequence of fibrosis is that it is a barrier to efficient cell-based therapies for muscle disease.•Collagen cross-linking and tissue strain limit extracellular matrix degradation to promote fibrotic progression.
The light sources that power photonic networks are small and scalable, but they also require the incorporation of optical isolators that allow light to pass in one direction only, protecting the ...light source from damaging backreflections. Unfortunately, the size and complex integration of optical isolators makes small-scale and densely integrated photonic networks infeasible. Here, we overcome this limitation by designing a single device that operates both as a coherent light source and as its own optical isolator. Our design relies on high-quality-factor dielectric metasurfaces that exhibit intrinsic chirality. By carefully manipulating the geometry of the constituent silicon metaatoms, we design three-dimensionally chiral modes that act as optical spin-dependent filters. Using spin-polarized Raman scattering together with our chiral metacavity, we demonstrate Raman lasing in the forward direction, while the lasing action is suppressed by over an order of magnitude for reflected light. Our high-Q chiral metasurface design presents a new approach toward compactly isolating integrated light sources by directly tailoring the emission properties of the light source itself.
With landmark films such as Fargo, O Brother Where art Thou?,
Blood Simple, and Raising Arizona, the Coen brothers
have achieved both critical and commercial success. Proving the
existence of a ...viable market for "small" films that are also
intellectually rewarding, their work has exploded generic
conventions amid rich webs of transtextual references.
R. Barton Palmer argues that the Coen oeuvre forms a central
element in what might be called postmodernist filmmaking. Mixing
high and low cultural sources and blurring genres like noir and
comedy, the use of pastiche and anti-realist elements in films such
as The Hudsucker Proxy and Barton Fink clearly
fit the postmodernist paradigm. Palmer argues that for a full
understanding of the Coen brothers' unique position within film
culture, it is important to see how they have developed a new type
of text within general postmodernist practice that Palmer terms
commercial/independent. Analyzing their substantial body of work
from this "generic" framework is the central focus of this
book.
Metasurfaces enable almost complete control of light through ultrathin, subwavelength surfaces by locally and abruptly altering the scattered phase. To date, however, all metasurfaces obey ...time-reversal symmetry, meaning that forward and backward traveling waves will trace identical paths when being reflected, refracted, or diffracted. Here, we use full-field calculations to design a passive metasurface for nonreciprocal transmission of both direct and anomalously refracted near-infrared light over nanoscale optical path lengths. The metasurface consists of a 100 nm-thick, periodically patterned Si slab. Owing to the high-quality-factor resonances of the metasurface and the inherent Kerr nonlinearities of Si, this structure acts as an optical diode for free-space optical signals. This structure also exhibits nonreciprocal anomalous refraction with appropriate patterning to form a phase gradient metasurface. Compared to existing schemes for breaking time-reversal symmetry, our platform enables subwavelength nonreciprocity for arbitrary free-space optical inputs and provides a straightforward path to experimental realization. The concept is also generalizable to other metasurface functions, providing a foundation for one-way lensing and holography.
Through the case of the salmon aquaculture sector in Chile, the risks involved in the development of a non-traditional export sector are reviewed, in order to point to failings (lessons not learned) ...and opportunities (lessons learned, new plans), and the changing scales of stakeholder interactions. In particular the paper highlights the ways in which sustainability considerations have gained ground in terms of evaluating sectoral development and what is expected from this development. These considerations have emerged as a result of the increasing globalisation of the sector, through investment, exports and international ‘attention’ from an increasingly diverse set of stakeholders. These sustainability considerations have generated a range of conflicts linked to these diverse actors. The actors are local, national and global, operating through alliances to bring pressure on others. The conflicts relate to environmental quality, foreign direct investment (FDI), local socio-economic development, regional development, national economic strategies, and new globalised issues relating to the production and consumption of foodstuffs. The contemporary panorama in the sector is significantly different from the early origins in the 1980s under the dictatorship – the period of ‘the socio-ecological silence’ – also different from the 1990s period of economic expansion – ‘the economic imperative’. Over the past twenty-five years, the Chilean aquaculture sector has evolved from experimental production to a major global industry. Regulatory frameworks and civil society awareness and mobilisation have struggled to ‘catch up’ with the dynamism of the sector, however the gap has reduced and the future of the sector within the contemporary context of ‘glocal’ sustainability is now under the microscope: the ‘sustainable globalisation perspective’. The collapse of the sector during the period 2008–2010 as a consequence of the ISA virus is a key moment with production severely diminished. The way out of the crisis, via new legislation and inspection regimes, will create a new structure of aquaculture governance. Nevertheless, the crisis marks a turning point in the industry, revealing the weaknesses built into the former productive system.
PurposeWhole-exome and whole-genome sequencing have transformed the discovery of genetic variants that cause human Mendelian disease, but discriminating pathogenic from benign variants remains a ...daunting challenge. Rarity is recognized as a necessary, although not sufficient, criterion for pathogenicity, but frequency cutoffs used in Mendelian analysis are often arbitrary and overly lenient. Recent very large reference datasets, such as the Exome Aggregation Consortium (ExAC), provide an unprecedented opportunity to obtain robust frequency estimates even for very rare variants.MethodsWe present a statistical framework for the frequency-based filtering of candidate disease-causing variants, accounting for disease prevalence, genetic and allelic heterogeneity, inheritance mode, penetrance, and sampling variance in reference datasets.ResultsUsing the example of cardiomyopathy, we show that our approach reduces by two-thirds the number of candidate variants under consideration in the average exome, without removing true pathogenic variants (false-positive rate<0.001).ConclusionWe outline a statistically robust framework for assessing whether a variant is "too common" to be causative for a Mendelian disorder of interest. We present precomputed allele frequency cutoffs for all variants in the ExAC dataset.
Many human proteins contain domains that vary in size or copy number because of variable numbers of tandem repeats (VNTRs) in protein-coding exons. However, the relationships of VNTRs to most ...phenotypes are unknown because of difficulties in measuring such repetitive elements. We developed methods to estimate VNTR lengths from whole-exome sequencing data and impute VNTR alleles into single-nucleotide polymorphism haplotypes. Analyzing 118 protein-altering VNTRs in 415,280 UK Biobank participants for association with 786 phenotypes identified some of the strongest associations of common variants with human phenotypes, including height, hair morphology, and biomarkers of health. Accounting for large-effect VNTRs further enabled fine-mapping of associations to many more protein-coding mutations in the same genes. These results point to cryptic effects of highly polymorphic common structural variants that have eluded molecular analyses to date.
The novel coronavirus pandemic, also known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has placed an immense strain on healthcare systems across the entire world. Consequently, ...multiple federal and state governments have placed restrictions on hospitals such as limiting “elective surgery” and recommending social or physical distancing. We review the literature on several areas that have been affected including surgical selection, inpatient care, and physician well-being. These areas affecting inpatient paradigms include surgical priority, physical or social distancing, file sharing for online clinical communications, and physician wellness. During this crisis, it is important that orthopaedic departments place an emphasis on personnel safety and slowing the spread of the virus so that the department can still maintain vital functions. Physical distancing and emerging technologies such as inpatient telemedicine and online file sharing applications can enable orthopaedic programs to still function while attempting to protect medical staff and patients from the novel coronavirus spread. This literature review sought to provide evidence-based guidance to orthopaedic departments during an unprecedented time. Orthopaedic surgeons should follow the Centers for Disease Control and Prevention guidelines, wear personal protective equipment (PPE) when appropriate, have teams created using physical distancing, understand the departmentʼs policy on elective surgery, and engage in routines which enhance physician wellness.
Abstract Skeletal muscle and bone rely on a number of growth factors to undergo development, modulate growth, and maintain physiological strength. A major player in these actions is insulin-like ...growth factor I (IGF-I). However, because this growth factor can directly enhance muscle mass and bone density, it alters the state of the musculoskeletal system indirectly through mechanical crosstalk between these two organ systems. Thus, there are clearly synergistic actions of IGF-I that extend beyond the direct activity through its receptor. This review will cover the production and signaling of IGF-I as it pertains to muscle and bone, the chemical and mechanical influences that arise from IGF-I activity, and the potential for therapeutic strategies based on IGF-I. This article is part of a Special Issue entitled “Muscle Bone Interactions”.
George Cukor Pomerance, Murray; Palmer, R. Barton
07/2015
eBook
A critical analysis of the films and career of George Cukor. George Cukor: Hollywood Master is the first book to focus on the career of director George Cukor, one of classic Hollywood's most ...important figures, with films such as The Women , Adam's Rib , Born Yesterday , Gaslight , and A Star is Born to his credit. The various essays in this volume, all written by prominent experts in the field, offer critical discussions of every feature film Cukor directed and include a rich trove of valuable information about their production histories. This is the first book devoted to one of the most beloved figures from the American cinema's golden age.
PDF
