The regulatory and catalytic subunits of cAMP-dependent protein kinases are associated with transcriptionally active chromatin during changes in gene expression.

Changes in the association of the catalytic subunit and the regulatory subunits of isozymes I and II of cAMP-dependent protein kinases (RI and RII, respectively) with the transcriptionally active chromatin fraction from rat liver were examined after a glucagon/theophylline injection and also after partial hepatectomy. Chromatin was partitioned into transcriptionally active and bulk, transcriptionally inactive fractions by digestion with micrococcal nuclease under appropriate conditions. In both experimental models, an increased content of catalytic and both RI and RII subunits was observed in chromatin fractions that were enriched in transcriptionally active DNA, particularly in the fraction associated with the residual nuclear matrix-lamina. The changes in the association of the subunits with these fractions paralleled the increases in intracellular cAMP levels and occurred in a time frame compatible with the changes in gene expression. The catalytic subunits could be removed from the nuclear matrix-lamina fraction by salt, whereas the two regulatory subunits remained tightly bound. The data support the concept of a direct role of the regulatory subunits of cAMP-dependent protein kinases in the induction of gene expression. However, we were unable to confirm that RII possessed an intrinsic topoisomerase activity

Identification of a new cAMP response element-binding factor by southwestern blotting.

We have identified in mammalian cells a novel cyclic AMP response element (CRE)-binding protein of molecular mass 47 kDa. This protein was not recognized by either the CREB-327/341 or c-Jun antisera, and its tissue distribution did not overlap with those of the CREB and Jun families. For example, hepatoma and placental tissue did not contain the 47-kDa DNA-binding protein, but did contain the CREB isoforms. On the other hand, S49 lymphoma cells contained a high level of the 47-kDa DNA-binding protein but did not contain a 47-kDa Jun-related protein which was found in normal liver and hepatoma. This new 47-kDa factor bound to the CRE in the dephosphorylated form, and phosphorylation of the protein by the catalytic subunit of protein kinase A completely abolished its DNA-binding activity. The isoforms of the CREB-327/341 family, on the other hand, bound to DNA in the phosphorylated form, and alkaline phosphatase treatment reduced significantly their interaction with CRE sequence. This reverse effect of phosphorylation/dephosphorylation on the DNA-binding property of this new 47-kDa protein in particular distinguishes it from other known CREB factors and suggests that the protein might play a unique role in the regulation of cAMP-mediated transcription

The Possible Roles of the Dentate Granule Cell's Leptin and Other Ciliary Receptors in Alzheimer's Neuropathology

Dentate-gyral granule cells in the hippocampus plus dentate gyrus memory-recording/retrieving machine, unlike most other neurons in the brain, are continuously being generated in the adult brain with the important task of separating overlapping patterns of data streaming in from the outside world via the entorhinal cortex. This "adult neurogenesis" is driven by tools in the mature granule cell's cilium. Here we report our discovery of leptin's LepRb receptor in this cilium. In addition, we discuss how ciliary LepRb signaling might be involved with ciliary p75NTR and SSTR3 receptors in adult neurogenesis and memory formation as well as attenuation of Alzheimer's neuropathology by reducing the production of its toxic amyloid-\u3b2-derived drivers

Studies of the adduct formed on interacting cisplatin with human apotransferrin: Synthesis, in vitro binding kinetics, in vivo pharmacokinetics and biodistribution in the rat.

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30716/1/0000362.pd

Biological, clinical and population relevance of 95 loci for blood lipids.

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD

Results from a new efficacy and safety analysis of the REGENERATE trial of obeticholic acid for treatment of pre-cirrhotic fibrosis due to non-alcoholic steatohepatitis

BACKGROUND &amp; AIMS: Obeticholic acid (OCA) is a first-in-class farnesoid X receptor agonist and antifibrotic agent in development for the treatment of pre-cirrhotic liver fibrosis due to non-alcoholic steatohepatitis (NASH). We aimed to validate the original 18-month liver biopsy analysis from the phase III REGENERATE trial of OCA for the treatment of NASH with a consensus panel analysis, provide additional histology data in a larger population, and evaluate safety from &gt;8,000 total patient-years' exposure with nearly 1,000 participants receiving study drug for &gt;4 years.METHODS: Digitized whole-slide images were evaluated independently by panels of three pathologists using the NASH Clinical Research Network scoring system. Primary endpoints were (1) ≥1 stage improvement in fibrosis with no worsening of NASH or (2) NASH resolution with no worsening of fibrosis. Safety was assessed by laboratory values and adverse events.RESULTS: Prespecified efficacy analyses included 931 participants. The proportion of participants achieving a ≥1 stage improvement in fibrosis with no worsening of NASH was 22.4% for OCA 25 mg vs. 9.6% for placebo (p &lt;0.0001). More participants receiving OCA 25 mg vs. placebo achieved NASH resolution with no worsening of fibrosis (6.5% vs. 3.5%, respectively; p = 0.093). Histology data in a larger population of 1,607 participants supported these results. Safety data included 2,477 participants. The incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, and deaths was not substantively different across treatment groups. Pruritus was the most common TEAE. Rates of adjudicated hepatic, renal, and cardiovascular events were low and similar across treatment groups.CONCLUSIONS: These results confirm the antifibrotic effect of OCA 25 mg. OCA was generally well tolerated over long-term dosing. These data support a positive benefit:risk profile in patients with pre-cirrhotic liver fibrosis due to NASH.IMPACT AND IMPLICATIONS: Patients with non-alcoholic steatohepatitis (NASH) often have liver scarring (fibrosis), which causes an increased risk of liver-related illness and death. Preventing progression of fibrosis to cirrhosis or reversing fibrosis are the main goals of drug development for NASH. In this clinical trial of obeticholic acid (OCA) in patients with NASH (REGENERATE), we reaffirmed our previous results demonstrating that OCA was superior to placebo in improving fibrosis using a more rigorous consensus panel analysis of liver biopsies taken at month 18. We also showed that OCA treatment resulted in dose-dependent reductions of serum liver biochemistries and liver stiffness measurements compared with placebo, even in participants in whom histologic fibrosis did not change at 18 months, providing evidence that the benefit of OCA extends beyond what is captured by the ordinal NASH CRN scoring system. OCA was well tolerated with a favorable safety profile supporting a positive benefit: risk profile in patients with pre-cirrhotic liver fibrosis due to NASH.</p

Bayesian methods for instrumental variable analysis with genetic instruments (‘Mendelian randomization’): example with urate transporter SLC2A9 as an instrumental variable for effect of urate levels on metabolic syndrome

The ‘Mendelian randomization’ approach uses genotype as an instrumental variable to distinguish between causal and non-causal explanations of biomarker–disease associations. Classical methods for instrumental variable analysis are limited to linear or probit models without latent variables or missing data, rely on asymptotic approximations that are not valid for weak instruments and focus on estimation rather than hypothesis testing. We describe a Bayesian approach that overcomes these limitations, using the JAGS program to compute the log-likelihood ratio (lod score) between causal and non-causal explanations of a biomarker–disease association. To demonstrate the approach, we examined the relationship of plasma urate levels to metabolic syndrome in the ORCADES study of a Scottish population isolate, using genotype at six single-nucleotide polymorphisms in the urate transporter gene SLC2A9 as an instrumental variable. In models that allow for intra-individual variability in urate levels, the lod score favouring a non-causal over a causal explanation was 2.34. In models that do not allow for intra-individual variability, the weight of evidence against a causal explanation was weaker (lod score 1.38). We demonstrate the ability to test one of the key assumptions of instrumental variable analysis—that the effects of the instrument on outcome are mediated only through the intermediate variable—by constructing a test for residual effects of genotype on outcome, similar to the tests of ‘overidentifying restrictions’ developed for classical instrumental variable analysis. The Bayesian approach described here is flexible enough to deal with any instrumental variable problem, and does not rely on asymptotic approximations that may not be valid for weak instruments. The approach can easily be extended to combine information from different study designs. Statistical power calculations show that instrumental variable analysis with genetic instruments will typically require combining information from moderately large cohort and cross-sectional studies of biomarkers with information from very large genetic case–control studies

The emerging structure of the Extended Evolutionary Synthesis: where does Evo-Devo fit in?

The Extended Evolutionary Synthesis (EES) debate is gaining ground in contemporary evolutionary biology. In parallel, a number of philosophical standpoints have emerged in an attempt to clarify what exactly is represented by the EES. For Massimo Pigliucci, we are in the wake of the newest instantiation of a persisting Kuhnian paradigm; in contrast, Telmo Pievani has contended that the transition to an EES could be best represented as a progressive reformation of a prior Lakatosian scientific research program, with the extension of its Neo-Darwinian core and the addition of a brand-new protective belt of assumptions and auxiliary hypotheses. Here, we argue that those philosophical vantage points are not the only ways to interpret what current proposals to ‘extend’ the Modern Synthesis-derived ‘standard evolutionary theory’ (SET) entail in terms of theoretical change in evolutionary biology. We specifically propose the image of the emergent EES as a vast network of models and interweaved representations that, instantiated in diverse practices, are connected and related in multiple ways. Under that assumption, the EES could be articulated around a paraconsistent network of evolutionary theories (including some elements of the SET), as well as models, practices and representation systems of contemporary evolutionary biology, with edges and nodes that change their position and centrality as a consequence of the co-construction and stabilization of facts and historical discussions revolving around the epistemic goals of this area of the life sciences. We then critically examine the purported structure of the EES—published by Laland and collaborators in 2015—in light of our own network-based proposal. Finally, we consider which epistemic units of Evo-Devo are present or still missing from the EES, in preparation for further analyses of the topic of explanatory integration in this conceptual framework

The genomes of two key bumblebee species with primitive eusocial organization

Background: The shift from solitary to social behavior is one of the major evolutionary transitions. Primitively eusocial bumblebees are uniquely placed to illuminate the evolution of highly eusocial insect societies. Bumblebees are also invaluable natural and agricultural pollinators, and there is widespread concern over recent population declines in some species. High-quality genomic data will inform key aspects of bumblebee biology, including susceptibility to implicated population viability threats. Results: We report the high quality draft genome sequences of Bombus terrestris and Bombus impatiens, two ecologically dominant bumblebees and widely utilized study species. Comparing these new genomes to those of the highly eusocial honeybee Apis mellifera and other Hymenoptera, we identify deeply conserved similarities, as well as novelties key to the biology of these organisms. Some honeybee genome features thought to underpin advanced eusociality are also present in bumblebees, indicating an earlier evolution in the bee lineage. Xenobiotic detoxification and immune genes are similarly depauperate in bumblebees and honeybees, and multiple categories of genes linked to social organization, including development and behavior, show high conservation. Key differences identified include a bias in bumblebee chemoreception towards gustation from olfaction, and striking differences in microRNAs, potentially responsible for gene regulation underlying social and other traits. Conclusions: These two bumblebee genomes provide a foundation for post-genomic research on these key pollinators and insect societies. Overall, gene repertoires suggest that the route to advanced eusociality in bees was mediated by many small changes in many genes and processes, and not by notable expansion or depauperation

Achieving a quantum smart workforce

Interest in building dedicated Quantum Information Science and Engineering (QISE) education programs has greatly expanded in recent years. These programs are inherently convergent, complex, often resource intensive and likely require collaboration with a broad variety of stakeholders. In order to address this combination of challenges, we have captured ideas from many members in the community. This manuscript not only addresses policy makers and funding agencies (both public and private and from the regional to the international level) but also contains needs identified by industry leaders and discusses the difficulties inherent in creating an inclusive QISE curriculum. We report on the status of eighteen post-secondary education programs in QISE and provide guidance for building new programs. Lastly, we encourage the development of a comprehensive strategic plan for quantum education and workforce development as a means to make the most of the ongoing substantial investments being made in QISE.Comment: 18 pages, 2 figures, 1 tabl