The ability of morphine to alleviate pain is mediated through a heterotrimeric guanine nucleotide binding protein (G protein)-coupled heptahelical receptor (GPCR), the mu opioid receptor (muOR). The efficiency of GPCR signaling is tightly regulated and ultimately limited by the coordinated phosphorylation of the receptors by specific GPCR kinases and the subsequent interaction of the phosphorylated receptors with beta-arrestin 1 and beta-arrestin 2. Functional deletion of the beta-arrestin 2 gene in mice resulted in remarkable potentiation and prolongation of the analgesic effect of morphine, suggesting that muOR desensitization was impaired. These results provide evidence in vivo for the physiological importance of beta-arrestin 2 in regulating the function of a specific GPCR, the muOR. Moreover, they suggest that inhibition of beta-arrestin 2 function might lead to enhanced analgesic effectiveness of morphine and provide potential new avenues for the study and treatment of pain, narcotic tolerance, and dependence.
Islet transplantation for type 1 diabetes treatment has been limited by the need for lifelong immunosuppression regimens. This challenge has prompted the development of macroencapsulation devices (MEDs) to immunoprotect the transplanted islets. While promising, conventional MEDs are faced with insufficient transport of oxygen, glucose, and insulin because of the reliance on passive diffusion. Hence, these devices are constrained to two-dimensional, wafer-like geometries with limited loading capacity to maintain cells within a distance of passive diffusion. We hypothesized that convective nutrient transport could extend the loading capacity while also promoting cell viability, rapid glucose equilibration, and the physiological levels of insulin secretion. Here, we showed that convective transport improves nutrient delivery throughout the device and affords a three-dimensional capsule geometry that encapsulates 9.7-fold-more cells than conventional MEDs. Transplantation of a convection-enhanced MED (ceMED) containing insulin-secreting β cells into immunocompetent, hyperglycemic rats demonstrated a rapid, vascular-independent, and glucose-stimulated insulin response, resulting in early amelioration of hyperglycemia, improved glucose tolerance, and reduced fibrosis. Finally, to address potential translational barriers, we outlined future steps necessary to optimize the ceMED design for long-term efficacy and clinical utility.
New! enhanced beta 4
Working with PDFs becomes faster and more comfortable. The update adds undo/redo to highlighting, underlining, or striking through, and no longer changes the PDF tool mode after selecting another annotation. To make the application more responsive, beta 4 saves modified PDFs in the background and works around limitations in macOS Mojave. PDFs aside, DEVONthink 3 Beta 4 improves also converting sheets to other file formats and printing them as tables or forms. Markdown fans can now use the :colon: syntax for adding emojis.
Of course, beta 4 comes with bug fixes and performance enhancements, too. It speeds up searching PDFs, working with EPUB books, saving formatted notes, viewing documents in the web interface, and overall responsiveness.
More subtle are the numerous changes to the search engine which now better supports Asian languages, indexes also PDF and RTF attachments, and highlights search hits more precisely. Its enhanced search language allows prefixes for mouse-less specific searching, and filters quickly focus the displayed items on tags, dates, marks, or geolocation.
DEVONthink 3 can be downloaded for free from the DEVONtechnologies website. The public beta does not require a valid license key but to use email archiving and text recognition beyond the trial limits it needs to be properly licensed. After the public beta phase DEVONthink 3 will require a license key for one of the three available editions which can be purchased starting today:
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Our previous finding indicated M. circinelloides strain CBS 277.49 as a dominant producer of β-carotene than M. circinelloides strain WJ11 [21]. So, in the current investigation, strain CBS 277.49 was nominated as a suitable candidate. This study was aimed at optimizing the production of β-carotene by screening different carbon sources and chemical modulators to divert metabolic flux of acetyl-CoA and FPP from fatty acid synthesis (FAS) and sterol synthesis pathways towards the mevalonate pathway. Based on a well-established fact that acetyl-CoA is a shared precursor for terpenoid and fatty acid biosynthesis [22], it was proposed that decreased fatty acid production might result in the transfer of more acetyl-CoA to the carotenoid biosynthesis pathway in CBS 277.49. Since both sterols and carotenoid biosynthesis pathway share intermediate farnesyl diphosphate (FPP), redirecting FPP towards the mevalonate pathway could increase the biosynthesis of β-carotene by using an ergosterol inhibitor (Figure 1). To confirm our hypothesis, cerulenin was used to block the FAS pathway and ketoconazole was used to inhibit ergosterol biosynthesis in M. circinelloides for enhanced β-carotene production. There are two different aspects that we considered to achieve substantial β-carotene production by CBS 277.49: (1) optimization of medium components by screening different carbon sources and C/N ratios and (2) redirection of metabolic flux towards the mevalonate pathway by using inhibitors of the FAS and sterol pathway, individually or in combination. Many studies have been conducted for the enrichment of β-carotene in different microorganisms. To date, an optimization study of β-carotene biosynthesis in Mucor using statistical analysis has not been studied extensively and required further comprehensive exploration. So, to the best of our knowledge, this is the first study to optimize the production of β-carotene in CBS 277.49 by diverting metabolic flux towards the mevalonate pathway from the FAS and ergosterol synthesis pathway using inhibitors of the mentioned pathways.
Pancreatic β-cells are the primary source of physiologically-relevant insulin and defects in their function cause diabetes and hyperinsulinism. Several groups have reported evidence for the presence of cells resembling β-cells among the differentiated derivatives formed in EBs of HESC [1], [2]. Others have also found enhanced differentiation of such cells from HESC and mouse embryonic stem cells (MESC) after culturing EBs in media that selectively promote the growth of neuroectodermal cells [3], [4], [5], [6]. As some of these techniques have proved unreliable and difficult to replicate [7], [8], attention has switched to testing whether specific signalling pathways that guide the appearance of β-cells during embryonic development can be applied to MESC or HESC in vitro.
During embryonic development, the pancreatic primordium arises from the posterior foregut region of the definitive endoderm, in a step that is dependent upon the transcription factor Pdx1. Thus, homozygous knock-out mice lacking Pdx1 develop the pancreatic buds but fail to form a pancreas [9], [10]. Subsequently, Pdx1 expression down-regulates and fate restriction of various cells in the pancreatic primordium results in the formation of distinct exocrine and endocrine cells [11]. Building on these observations, D'Amour et al [12] found that after inducing definitive endoderm differentiation from HESC, the subsequent exposure to retinoic acid and an inhibitor of hedgehog signalling could lead to the formation of cells expressing insulin. On the other hand, although Lavon et al [13] found that over-expression of Pdx1 in HESC enhanced pancreatic endocrine cell differentiation in EBs, they failed to find evidence of β-cell formation in vitro. We speculated that signals induced downstream of definitive endoderm might be, at least in part, more potent to trigger subsequent signal cascades that culminate with the pancreatic β-cell formation. 2ff7e9595c
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