Age-related macular degeneration (AMD), a progressive condition that is untreatable in up to 90% of patients, is a leading cause of blindness in the elderly worldwide. The two forms of AMD, wet and ...dry, are classified based on the presence or absence of blood vessels that have disruptively invaded the retina, respectively. A detailed understanding of the molecular mechanisms underlying wet AMD has led to several robust FDA-approved therapies. In contrast, there are no approved treatments for dry AMD. In this review, we provide insight into the critical effector pathways mediating each form of the disease. A recurring theme that spans most aspects of AMD pathogenesis is defective immune modulation in the classically immune-privileged ocular haven. Interestingly, the latest advances in AMD research also highlight common molecular disease pathways with other neurodegenerative disorders. Finally, the therapeutic potential of intervening at known mechanistic steps of AMD pathogenesis is discussed.
Age-related macular degeneration (AMD) is a progressive blindness condition that is untreatable in up to 90% of patients. Ambati and Fowler review our molecular understanding of the wet and dry forms of this disorder, placing this work in the context of the latest clinical data and possible therapeutic strategies.
High-throughput transcriptomic profiling approaches have revealed that alternative splicing (AS) of precursor mRNAs, a fundamental process by which cells expand their transcriptomic diversity, is ...particularly widespread in the nervous system. AS events detected in the brain are more highly conserved than those detected in other tissues, suggesting that they more often provide conserved functions. Our understanding of the mechanisms and functions of neural AS events has significantly advanced with the coupling of various computational and experimental approaches. These studies indicate that dynamic regulation of AS in the nervous system is critical for modulating protein-protein interactions, transcription networks, and multiple aspects of neuronal development. Furthermore, several underappreciated classes of AS with the aforementioned roles in neuronal cells have emerged from unbiased, global approaches. Collectively, these findings emphasize the importance of characterizing neural AS in order to gain new insight into pathways that may be altered in neurological diseases and disorders.
Alternative splicing generates vast isoform diversity in the nervous system. Raj and Blencowe review how high-throughput profiling, computational approaches, animal models, and biochemical methods have provided remarkable new insights into the complexity and function of the neural-regulated alternative splicing landscape.
High-throughput sequencing-based methods and their applications in the study of transcriptomes have revolutionized our understanding of alternative splicing. Networks of functionally coordinated and ...biologically important alternative splicing events continue to be discovered in an ever-increasing diversity of cell types in the context of physiologically normal and disease states. These studies have been complemented by efforts directed at defining sequence codes governing splicing and their cognate trans-acting factors, which have illuminated important combinatorial principles of regulation. Additional studies have revealed critical roles of position-dependent, multivalent protein-RNA interactions that direct splicing outcomes. Investigations of evolutionary changes in RNA binding proteins, splice variants, and associated cis elements have further shed light on the emergence, mechanisms, and functions of splicing networks. Progress in these areas has emphasized the need for a coordinated, community-based effort to systematically address the functions of individual splice variants associated with normal and disease biology.
Ule and Blencowe review recent insights into the biological significance of splicing regulatory networks and the mechanistic principles of regulation. They describe the roles of position-dependent, multivalent protein-RNA interactions that direct splicing outcomes, including regulation of cryptic exons, and conclude by discussing the emergence and evolution of alternative splicing.
Currency Power Cohen, Benjamin J
2015, 2015., 20150901, 2015-09-01
eBook
Overview: Monetary rivalry is a fact of life in the world economy. Intense competition between international currencies like the US dollar, Europe's euro, and the Chinese yuan is profoundly ...political, going to the heart of the global balance of power. But what exactly is the relationship between currency and power, and what does it portend for the geopolitical standing of the United States, Europe, and China? Popular opinion holds that the days of the dollar, long the world's dominant currency, are numbered. By contrast, Currency Power argues that the current monetary rivalry still greatly favors America's greenback. Benjamin Cohen shows why neither the euro nor the yuan will supplant the dollar at the top of the global currency hierarchy. Cohen presents an innovative analysis of currency power and emphasizes the importance of separating out the various roles that international money might have. After systematically exploring the links between currency internationalization and state power, Cohen turns to the state of play among today's top currencies. The greenback, he contends, is the "indispensable currency"--The one that the world can't do without. Only the dollar is backed by all the economic and political resources that make a currency powerful. Meanwhile, the euro is severely handicapped by structural defects in the design of its governance mechanisms, and the yuan suffers from various practical limitations in both finance and politics. Contrary to today's growing opinion, Currency Power demonstrates that the dollar will continue to be the leading global currency for some time to come.
The microbiota plays an essential role in the education, development, and function of the immune system, both locally and systemically. Emerging experimental and epidemiological evidence highlights a ...crucial cross-talk between the intestinal microbiota and the lungs, termed the 'gut-lung axis'. Changes in the constituents of the gut microbiome, through either diet, disease or medical interventions (such as antibiotics) is linked with altered immune responses and homeostasis in the airways. The importance of the gut-lung axis has become more evident following the identification of several gut microbe-derived components and metabolites, such as short-chain fatty acids (SCFAs), as key mediators for setting the tone of the immune system. Recent studies have supported a role for SCFAs in influencing hematopoietic precursors in the bone marrow-a major site of innate and adaptive immune cell development. Here, we review the current understanding of host-microbe cross-talk along the gut-lung axis. We highlight the importance of SCFAs in shaping and promoting bone marrow hematopoiesis to resolve airway inflammation and to support a healthy homeostasis.
The unprecedented ability of computations to probe atomic-level details of catalytic systems holds immense promise for the fundamentals-based bottom-up design of novel heterogeneous catalysts, which ...are at the heart of the chemical and energy sectors of industry. Here, we critically analyze recent advances in computational heterogeneous catalysis. First, we will survey the progress in electronic structure methods and atomistic catalyst models employed, which have enabled the catalysis community to build increasingly intricate, realistic, and accurate models of the active sites of supported transition-metal catalysts. We then review developments in microkinetic modeling, specifically mean-field microkinetic models and kinetic Monte Carlo simulations, which bridge the gap between nanoscale computational insights and macroscale experimental kinetics data with increasing fidelity. We finally review the advancements in theoretical methods for accelerating catalyst design and discovery. Throughout the review, we provide ample examples of applications, discuss remaining challenges, and provide our outlook for the near future.
The rational development
of fast-ion-conducting solid electrolytes
for all-solid-state lithium-ion batteries requires understanding the
key structural and chemical principles that give some materials ...their
exceptional ionic conductivities. For the lithium argyrodites Li
6
PS
5
X (X = Cl, Br, or I), the choice of the halide,
X, strongly affects the ionic conductivity, giving room-temperature
ionic conductivities for X = {Cl,Br} that are ×10
3
higher than for X = I. This variation has been attributed to differing
degrees of S/X anion disorder. For X = {Cl,Br}, the S/X anions are
substitutionally disordered, while for X = I, the anion substructure
is fully ordered. To better understand the role of substitutional
anion disorder in enabling fast lithium-ion transport, we have performed
a first-principles molecular dynamics study of Li
6
PS
5
I and Li
6
PS
5
Cl with varying amounts
of S/X anion-site disorder. By considering the S/X anions as a tetrahedrally
close-packed substructure, we identify three partially occupied lithium
sites that define a contiguous three-dimensional network of face-sharing
tetrahedra. The active lithium-ion diffusion pathways within this
network are found to depend on the S/X anion configuration. For anion-disordered
systems, the active site–site pathways give a percolating three-dimensional
diffusion network; whereas for anion-ordered systems, critical site–site
pathways are inactive, giving a disconnected diffusion network with
lithium motion restricted to local orbits around S positions. Analysis
of the lithium substructure and dynamics in terms of the lithium coordination
around each sulfur site highlights a mechanistic link between substitutional
anion disorder and lithium disorder. In anion-ordered systems, the
lithium ions are pseudo-ordered, with preferential 6-fold coordination
of sulfur sites. Long-ranged lithium diffusion would disrupt this
SLi
6
pseudo-ordering, and is, therefore, disfavored. In
anion-disordered systems, the pseudo-ordered 6-fold S–Li coordination
is frustrated because of Li–Li Coulombic repulsion. Lithium
positions become disordered, giving a range of S–Li coordination
environments. Long-ranged lithium diffusion is now possible with no
net change in S–Li coordination numbers. This gives rise to
superionic lithium transport in the anion-disordered systems, effected
by a concerted string-like diffusion mechanism.
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