The unfolded protein response (UPR) is a protective cellular response activated under conditions of endoplasmic reticulum (ER) stress. The hepatic UPR is activated in several forms of liver disease ...including nonalcoholic fatty liver disease (NAFLD). Recent data defining the role of the UPR in hepatic lipid metabolism have identified molecular mechanisms that may underlie the association between UPR activation and NAFLD. It has become increasingly evident that the IRE1α/Xbp1 pathway of the UPR is critical for hepatic lipid homeostasis, and dysregulation of this evolutionarily conserved pathway is associated with human nonalcoholic steatohepatitis (NASH). Although increasing evidence has delineated the importance of UPR pathway signaling in fatty liver disorders, the regulation of the hepatic UPR in normal physiology and fatty liver disorders remains incompletely understood. Understanding the role of the UPR in hepatic lipid metabolism may lead to the identification of novel therapeutic targets for the treatment of NAFLD.
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Three dimensional (3D) printing is highly amenable to the fabrication of tissue-engineered organs of a repetitive microstructure such as the liver. The creation of uniform and ...geometrically repetitive tissue scaffolds can also allow for the control over cellular aggregation and nutrient diffusion. However, the effect of differing geometries, while controlling for pore size, has yet to be investigated in the context of hepatocyte function. In this study, we show the ability to precisely control pore geometry of 3D-printed gelatin scaffolds. An undifferentiated hepatocyte cell line (HUH7) demonstrated high viability and proliferation when seeded on 3D-printed scaffolds of two different geometries. However, hepatocyte specific functions (albumin secretion, CYP activity, and bile transport) increases in more interconnected 3D-printed gelatin cultures compared to a less interconnected geometry and to 2D controls. Additionally, we also illustrate the disparity between gene expression and protein function in simple 2D culture modes, and that recreation of a physiologically mimetic 3D environment is necessary to induce both expression and function of cultured hepatocytes.
Three dimensional (3D) printing provides tissue engineers the ability spatially pattern cells and materials in precise geometries, however the biological effects of scaffold geometry on soft tissues such as the liver have not been rigorously investigated. In this manuscript, we describe a method to 3D print gelatin into well-defined repetitive geometries that show clear differences in biological effects on seeded hepatocytes. We show that a relatively simple and widely used biomaterial, such as gelatin, can significantly modulate biological processes when fabricated into specific 3D geometries. Furthermore, this study expands upon past research into hepatocyte aggregation by demonstrating how it can be manipulated to enhance protein function, and how function and expression may not precisely correlate in 2D models.
A central question in evolutionary biology is whether sponges or ctenophores (comb jellies) are the sister group to all other animals. These alternative phylogenetic hypotheses imply different ...scenarios for the evolution of complex neural systems and other animal-specific traits
. Conventional phylogenetic approaches based on morphological characters and increasingly extensive gene sequence collections have not been able to definitively answer this question
. Here we develop chromosome-scale gene linkage, also known as synteny, as a phylogenetic character for resolving this question
. We report new chromosome-scale genomes for a ctenophore and two marine sponges, and for three unicellular relatives of animals (a choanoflagellate, a filasterean amoeba and an ichthyosporean) that serve as outgroups for phylogenetic analysis. We find ancient syntenies that are conserved between animals and their close unicellular relatives. Ctenophores and unicellular eukaryotes share ancestral metazoan patterns, whereas sponges, bilaterians, and cnidarians share derived chromosomal rearrangements. Conserved syntenic characters unite sponges with bilaterians, cnidarians, and placozoans in a monophyletic clade to the exclusion of ctenophores, placing ctenophores as the sister group to all other animals. The patterns of synteny shared by sponges, bilaterians, and cnidarians are the result of rare and irreversible chromosome fusion-and-mixing events that provide robust and unambiguous phylogenetic support for the ctenophore-sister hypothesis. These findings provide a new framework for resolving deep, recalcitrant phylogenetic problems and have implications for our understanding of animal evolution.
The structure of the electrical double layer has been debated for well over a century, since it mediates colloidal interactions, regulates surface structure, controls reactivity, sets capacitance, ...and represents the central element of electrochemical supercapacitors. The surface potential of such surfaces generally exceeds the electrokinetic potential, often substantially. Traditionally, a Stern layer of nonspecifically adsorbed ions has been invoked to rationalize the difference between these two potentials; however, the inability to directly measure the surface potential of dispersed systems has rendered quantitative measurements of the Stern layer potential, and other quantities associated with the outer Helmholtz plane, impossible. Here, we use x-ray photoelectron spectroscopy from a liquid microjet to measure the absolute surface potentials of silica nanoparticles dispersed in aqueous electrolytes. We quantitatively determine the impact of specific cations (Li+ , Na+ , K+ , and Cs+ ) in chloride electrolytes on the surface potential, the location of the shear plane, and the capacitance of the Stern layer. We find that the magnitude of the surface potential increases linearly with the hydrated-cation radius. Interpreting our data using the simplest assumptions and most straightforward understanding of Gouy-Chapman-Stern theory reveals a Stern layer whose thickness corresponds to a single layer of water molecules hydrating the silica surface, plus the radius of the hydrated cation. These results subject electrical double-layer theories to direct and falsifiable tests to reveal a physically intuitive and quantitatively verified picture of the Stern layer that is consistent across multiple electrolytes and solution conditions.
Abstract
We present a protocol to prepare extracted DNA for sequencing on the Illumina sequencing platform that has been optimized for ancient and degraded DNA. Our approach, the Santa Cruz Reaction ...or SCR, uses directional splinted ligation of Illumina’s P5 and P7 adapters to convert natively single-stranded DNA and heat denatured double-stranded DNA into sequencing libraries in a single enzymatic reaction. To demonstrate its efficacy in converting degraded DNA molecules, we prepare 5 ancient DNA extracts into sequencing libraries using the SCR and 2 of the most commonly used approaches for preparing degraded DNA for sequencing: BEST, which targets and converts double-stranded DNA, and ssDNA2.0, which targets and converts single-stranded DNA. We then compare the efficiency with which each approach recovers unique molecules, or library complexity, given a standard amount of DNA input. We find that the SCR consistently outperforms the BEST protocol in recovering unique molecules and, despite its relative simplicity to perform and low cost per library, has similar performance to ssDNA2.0 across a wide range of DNA inputs. The SCR is a cost- and time-efficient approach that minimizes the loss of unique molecules and makes accessible a taxonomically, geographically, and a temporally broader sample of preserved remains for genomic analysis.
InElf Queens and Holy FriarsRichard Firth Green investigates an important aspect of medieval culture that has been largely ignored by modern literary scholarship: the omnipresent belief in fairyland.
...Taking as his starting point the assumption that the major cultural gulf in the Middle Ages was less between the wealthy and the poor than between the learned and the lay, Green explores the church's systematic demonization of fairies and infernalization of fairyland. He argues that when medieval preachers inveighed against the demons that they portrayed as threatening their flocks, they were in reality often waging war against fairy beliefs. The recognition that medieval demonology, and indeed pastoral theology, were packed with coded references to popular lore opens up a whole new avenue for the investigation of medieval vernacular culture.
Elf Queens and Holy Friarsoffers a detailed account of the church's attempts to suppress or redirect belief in such things as fairy lovers, changelings, and alternative versions of the afterlife. That the church took these fairy beliefs so seriously suggests that they were ideologically loaded, and this fact makes a huge difference in the way we read medieval romance, the literary genre that treats them most explicitly. The war on fairy beliefs increased in intensity toward the end of the Middle Ages, becoming finally a significant factor in the witch-hunting of the Renaissance.
Long-range and highly accurate de novo assembly from short-read data is one of the most pressing challenges in genomics. Recently, it has been shown that read pairs generated by proximity ligation of ...DNA in chromatin of living tissue can address this problem, dramatically increasing the scaffold contiguity of assemblies. Here, we describe a simpler approach ("Chicago") based on in vitro reconstituted chromatin. We generated two Chicago data sets with human DNA and developed a statistical model and a new software pipeline ("HiRise") that can identify poor quality joins and produce accurate, long-range sequence scaffolds. We used these to construct a highly accurate de novo assembly and scaffolding of a human genome with scaffold N50 of 20 Mbp. We also demonstrated the utility of Chicago for improving existing assemblies by reassembling and scaffolding the genome of the American alligator. With a single library and one lane of Illumina HiSeq sequencing, we increased the scaffold N50 of the American alligator from 508 kbp to 10 Mbp.
High-throughput short-read sequencing has revolutionized how transcriptomes are quantified and annotated. However, while Illumina short-read sequencers can be used to analyze entire transcriptomes ...down to the level of individual splicing events with great accuracy, they fall short of analyzing how these individual events are combined into complete RNA transcript isoforms. Because of this shortfall, long-distance information is required to complement short-read sequencing to analyze transcriptomes on the level of full-length RNA transcript isoforms. While long-read sequencing technology can provide this long-distance information, there are issues with both Pacific Biosciences (PacBio) and Oxford Nanopore Technologies (ONT) long-read sequencing technologies that prevent their widespread adoption. Briefly, PacBio sequencers produce low numbers of reads with high accuracy, while ONT sequencers produce higher numbers of reads with lower accuracy. Here, we introduce and validate a long-read ONT-based sequencing method. At the same cost, our Rolling Circle Amplification to Concatemeric Consensus (R2C2) method generates more accurate reads of full-length RNA transcript isoforms than any other available long-read sequencing method. These reads can then be used to generate isoform-level transcriptomes for both genome annotation and differential expression analysis in bulk or single-cell samples.
We define a me‐too drug as a pharmacologically active compound that is structurally related to a first‐in‐class compound, regarded as belonging to the same therapeutic class as the original compound, ...and used for the same therapeutic purposes, but which may differ in some respects, such as specificity of pharmacological action, adverse reactions profile, or drug–drug interactions. We also offer definitions of related terms, including follow‐on drug and first‐in‐class. The therapeutic advantages of me‐too drugs may include improved target specificity, reduced risks of off‐target adverse reactions and drug–drug interactions, increased chance of benefit in some patients, and improved drug delivery and pharmacokinetics. Me‐too drugs can also demonstrate incremental innovation. Their availability may help in coping with drug shortages. However, they may occasionally cause unexpected adverse reactions that are not class effects. Tricyclic antidepressants, β‐blockers, and statins illustrate the diversity of me‐too drugs. Earlier compounds may be as effective as later ones, or more so. Tricyclic antidepressants have similar chemical structures, and compounds introduced after the first‐in‐class compound (imipramine) mostly offered little in the way of innovative features, but continue to be prescribed. In contrast, me‐too β‐blockers introduced after the first‐in‐class compound, pronethalol, have diverse structures and display several innovative features. Stereoisomers and biosimilars/biobetters provide special examples of me‐too drugs. Although many me‐too drugs offer no significant advantages over their predecessors, over 60% of the drugs listed on the World Health Organization's essential list are me‐toos. Different countries may choose different me‐too drugs when constructing essential medicines lists, partly explaining transnational differences between them.
Financial Expertise as an Arms Race GLODE, VINCENT; GREEN, RICHARD C.; LOWERY, RICHARD
The Journal of finance (New York),
October 2012, Letnik:
67, Številka:
5
Journal Article
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We show that firms intermediating trade have incentives to overinvest in financial expertise. In our model, expertise improves firms' ability to estimate value when trading a security. Expertise ...creates asymmetric information, which, under normal circumstances, works to the advantage of the expert as it deters opportunistic bargaining by counterparties. This advantage is neutralized in equilibrium, however, by offsetting investments by competitors. Moreover, when volatility rises the adverse selection created by expertise triggers breakdowns in liquidity, destroying gains to trade and thus the benefits that firms hope to gain through high levels of expertise.
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