1,069 research outputs found

    Dislocation Reduction by Glide in Epitaxial IV-VI Layers on Si Substrates

    Get PDF
    It is explained with a simple model why the reduction of threading dislocation (TD) densities in epitaxial lattice and thermal expansion mismatched IV-VI layers such as PbSe(111) on Si(111) substrates follows a 1/h 2 dependence where h is the thickness of the layer. This is in contrast to the 1/h dependence for III-V and II-VI layers grown on mismatched substrates. The 1/h 2 dependence results since the thermal mismatch strain is mainly reduced by glide and reactions of the TD in their main {100}-type glide system of the NaCl-type IV-VI semiconductors. In addition, multiple thermal cycles lead to further reduction of the TD densities by glide and fusion since fusion does not cause dislocation blockin

    miR-10b Rescues Diabetes and GI Dysmotility Associated with a Leaky Gut

    Get PDF
    Of all microorganisms in the human body, the largest and most complex population resides in the gastrointestinal (GI) tract. The gut microbiota continuously adapts to the host environment and serves multiple critical functions for their hosts, including regulating host immunity, procuring energy from food, and preventing the colonization of pathogens. Mounting evidence has suggested gut immune dysfunction, impaired barrier function, and gut dysmotility play a key role in the development of metabolic disorders and disorders of gut-brain interactions (DGBIs). In reference to the Rome IV criteria, the most common DGBIs, include functional dyspepsia (FD) and irritable bowel syndrome (IBS). Additionally, there is substantial overlap of these disorders and other specific GI motility disorders such as gastroparesis. These disorders are heterogeneous and are intertwined with several proposed pathophysiological mechanisms, such as altered gut motility, intestinal barrier dysfunction, gut immune dysfunction, visceral hypersensitivity, altered GI secretion, presence and degree of bile acid malabsorption, microbial dysbiosis, and alterations to the gut-brain axis. The currently available therapies lack long-term effectiveness and safety for their use to treat motility disorders and DGBIs. Additionally, currently available treatment options simply treat the symptoms and not the pathological mechanism causing the disorder. Pharmacological agents that are developed based on the cellular and molecular mechanisms underlying the pathologies of these disorders might provide the best avenue for future pharmaceutical development. Current advances in RNA-based therapies have substantial promise in treating and preventing many human diseases and disorders through fixing the pathology instead of merely treating the symptomology, like traditional therapeutics. Although many RNA therapeutics have made it to clinical trials, only a few have been FDA-approved thus far. Additionally, the results of clinical trials for RNA therapeutics have been ambivalent to date, with some studies demonstrating potent efficacy, whereas others have limited effectiveness and/or toxicity. Momentum is building in the clinic for RNA therapeutics; future clinical care of human diseases will likely be comprised of promising RNA therapeutics. There has been phenomenal progress in understanding the cellular and molecular mechanisms of DGBIs. However, the precise cellular and molecular pathogeneses of gut dysfunctions are yet enigmatic. Important regulatory mechanisms are mediated through mircoRNAs (miRNAs) and they play an essential role in gut health. miRNAs are small non-coding RNA molecules that post-transcriptionally regulate gene expression by binding to specific mRNA targets to repress their translation and/or promote the target mRNA degradation. Dysregulation of miRNAs might impair gut physiological functions leading to DGBIs and gut motility disorders. Studies have shown miRNAs regulate gut functions such as visceral sensation, gut immune response, GI barrier function, enteric neuronal development, and GI motility. These biological processes are highly relevant to the gut where neuroimmune interactions are key contributors in controlling gut homeostasis and functional defects lead to DGBIs. The therapeutic targeting of miRNAs represents an attractive approach for the treatment of DGBIs because they offer new insights into disease mechanisms and have great potential to be used in the clinic as diagnostic markers and therapeutic targets. Additionally, miRNAs might be beneficial for the treatment of DGBIs because they might be able to return functionality of key cells in the maintenance of normal gut homeostasis such as interstitial cells of Cajal (ICCs), enterochromaffin (EC cells), enteric neurons, smooth muscle cells, gut immune cells, etc. that are normally dysregulated in these conditions. Our previous studies demonstrated that depletion of miR-10b in KIT+ cells has been shown to cause the development of diabetes and gut dysmotility through the KLF11-KIT pathway. Recent studies have also shown that the leaky gut is connected to both diabetes and gut dysmotility; however, there is no direct evidence indicating whether or not the leaky gut is the linking mechanism between these conditions. Here we aimed to elucidate if global loss of miR-10b leads to the development of the leaky gut and if this is the linking mechanism between hyperglycemia and gut dysmotility. First, we created a mir-10b global KO (gKO) mouse model using CRISPR-Mb3Cas12a/Mb3Cpf1. Using both loss-of-function and gain-of-function studies we found that the leaky gut phenotype is a core pathophysiological mechanism linking the hyperglycemic and gut dysmotility phenotypes. Finally, we found that treating the mice with a miR-10b mimic rescues these phenotypes and might have substantial therapeutic potential for the treatment of diabetes, gut dysmotility, and the leaky gut

    Phosphoglycerate Dehydrogenase: Potential Therapeutic Target and Putative Metabolic Oncogene

    Get PDF
    Exemplified by cancer cells' preference for glycolysis, for example, the Warburg effect, altered metabolism in tumorigenesis has emerged as an important aspect of cancer in the past 10–20 years. Whether due to changes in regulatory tumor suppressors/oncogenes or by acting as metabolic oncogenes themselves, enzymes involved in the complex network of metabolic pathways are being studied to understand their role and assess their utility as therapeutic targets. Conversion of glycolytic intermediate 3-phosphoglycerate into phosphohydroxypyruvate by the enzyme phosphoglycerate dehydrogenase (PHGDH)—a rate-limiting step in the conversion of 3-phosphoglycerate to serine—represents one such mechanism. Forgotten since classic animal studies in the 1980s, the role of PHGDH as a potential therapeutic target and putative metabolic oncogene has recently reemerged following publication of two prominent papers near-simultaneously in 2011. Since that time, numerous studies and a host of metabolic explanations have been put forward in an attempt to understand the results observed. In this paper, I review the historic progression of our understanding of the role of PHGDH in cancer from the early work by Snell through its reemergence and rise to prominence, culminating in an assessment of subsequent work and what it means for the future of PHGDH

    Social Affiliation Needs as a Motivator of Risky Online Behaviour

    No full text
    In spite of the risks, people often share large quantities of personal information online. The objective of this research was to gain an understanding as to why people take such risks when engaging with others on social networking sites like Facebook. Initially the existence of online communities had to be established, and consideration given to the possibility that these online communities reflected groups found in the real world. The following hypotheses were then tested using an online survey with Likert Scale questions and freeform questions. This data was then triangulated by and supplemented with data received as a result of semi-structured interviews. Interview and survey questions were informed by a full literature review undertaken on the topic. H1: Humans mimic online behaviours including risky behaviours to gain acceptance in online communities. There was insufficient support for this hypothesis. This may be due to the fact that online and real world groups differ in terms of the way in which they communicate. The five senses are not fully engaged in online communication and there is an absence of body language and other non-verbal communication. This difference may determine that there is less need for social affiliation online than in the real world. H2: The need for personal safety online is secondary to the need for social affiliation. Again there was insufficient support for this hypothesis, and even those with online communities of trusted friends drawn from the real world were concerned for their personal safety and configured their privacy settings. However these people were comfortable sharing personal information online with trusted friends, demonstrating that they were under the illusion that their information was private. H3: Humans reflect the values of their friends on social networks to gain their approval. This hypothesis was well supported and indications were that people were more prepared to share personal information online with those who shared their values. They are also unlikely to share controversial information that violated their personal values. The results of this research were viewed through the lens of "The Online Disinhibition Effect" (Suler, 2004), and recommendations made to companies planning online business

    Social media as an idiosyncratic investment and enhancer of relationship quality and long-term orientation in buyer-supplier relationships

    Get PDF
    Motivation for the research and objectives The purpose of this Master' thesis is to explore the attitudes towards social media collaborations in buyer-supplier relationships (BSR) and to clarify how idiosyncratic investments in social media may enhance the relationship quality and long-term orientation within the dyad. It's suggested also in the literature that firms have to continue to rely on collaborative relationships in order to grow their pie of benefits (eg. Anderson & Jap, 2005). In this study, collaborative buyer-supplier relationships are seen as a creator of competitive advantage. The aim of this research is to contribute to the business marketing by providing new insights about the nature of buyer-supplier relationship and the possibilities of social media. The research strategy and methodology In this study the linkages among of various buyer-supplier relationship-relevant constructs, relationship quality and long-term orientation are hypothesized and assessed. It's recognized that the constructs included in the conceptual model are only a portion of the potentially relevant variables that might have been included. However, the chosen constructs have both theoretical and empirical support and have shown their fit when examining the retail context and the collaborative approach. Hence, trust (1), commitment (2), interdependence (3), communication (4), social media (5), long-term orientation (6) and relationship quality (7) are the constructs that are included in the proposed conceptual framework. The conceptual model is evaluated with confirmatory factor analysis (CFA) and the proposed hypotheses are tested with structural equation modeling (SEM). The sample of the study consisted of 151 suppliers from the action sport and lifestyle brand industry. Suppliers were responding based on the relationship between one retailer buyer. Results All in all, 4 out of 6 hypotheses were supported. The results indicate that commitment and communication have a positive relation to willingness to make idiosyncratic investments in social media. Furthermore, willingness to collaborate also reflects to higher relationship quality and long-term orientation. The relationship between trust and interdependence towards willingness to make idiosyncratic investments in social media weren't statistically significant, hence their importance in social media context cannot be determined based on this study

    Additive Manufacturing of Structural Cores and Washout Tooling for Autoclave Curing of Hybrid Composite Structures

    Get PDF
    This paper presents a study combining additive manufactured (AM) elements with carbon fiber-reinforced polymers (CFRP) for the autoclave curing of complex-shaped, lightweight structures. Two approaches were developed: First, structural cores were produced with AM, over-laminated with CFRP, and co-cured in the autoclave. Second, a functional hull is produced with AM, filled with a temperature- and pressure-resistant material, and over-laminated with CFRP. After curing, the filler-material is removed to obtain a hollow lightweight structure. The approaches were applied to hat stiffeners, which were modeled, fabricated, and tested in three-point bending. Results show weight savings by up to 5% compared to a foam core reference. Moreover, the AM element contributes to the mechanical performance of the hat stiffener, which is highlighted by an increase in the specific bending stiffness and the first failure load by up to 18% and 310%. Results indicate that the approaches are appropriate for composite structures with complex geometries

    Exposure to Televised Alcohol Ads and Subsequent Adolescent Alcohol Use

    Get PDF
    Objective: To assess the impact of televised alcohol commercials on adolescents, alcohol use. Methods: Adolescents completed questionnaires about alcohol commercials and alcohol use in a prospective study. Results: A one standard deviation increase in viewing television programs containing alcohol commercials in seventh grade was associated with an excess risk of beer use (44%}, wine/liquor use (34%}, and 3-drlnk episodes (26%} in eighth grade. The strength of associations varied across exposure measures and was most consistent for beer. Conclusions: Although replication is warranted, results showed that exposure was associated with an increased risk of subsequent beer consumption and possibly other consumption variables

    3-4.5 μm continuously tunable single mode VECSEL

    Get PDF
    We present continuously tunable Vertical External Cavity Surface Emitting Lasers (VECSEL) in the mid-infrared. The structure based on IV-VI semiconductors is epitaxially grown on a Si-substrates. The VECSEL emit one single mode, which is mode hop-free tunable over 50-100nm around the center wavelength. In this work, two different devices are presented, emitting at 3.4μm and 3.9μm, respectively. The lasers operate near room temperature with thermoelectric stabilization. They are optically pumped, yielding an output power >10mWp. The axial symmetric emission beam has a half divergence angle of <3.3

    Species-specific differences in the inhibition of 11β-hydroxysteroid dehydrogenase 2 by itraconazole and posaconazole

    Get PDF
    11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) converts active 11β-hydroxyglucocorticoids to their inactive 11-keto forms, thereby preventing inappropriate mineralocorticoid receptor activation by glucocorticoids. Disruption of 11β-HSD2 activity by genetic defects or inhibitors causes the syndrome of apparent mineralocorticoid excess (AME), characterized by hypokalemia, hypernatremia and hypertension. Recently, the azole antifungals itraconazole and posaconazole were identified to potently inhibit human 11β-HSD2, and several case studies described patients with acquired AME. To begin to understand why this adverse drug effect was missed during preclinical investigations, the inhibitory potential of itraconazole, its main metabolite hydroxyitraconazole (OHI) and posaconazole against 11β-HSD2 from human and three commonly used experimental animals was assessed. Whilst human 11β-HSD2 was potently inhibited by all three compounds (IC; 50; values in the nanomolar range), the rat enzyme was moderately inhibited (1.5- to 6-fold higher IC; 50; values compared to human), and mouse and zebrafish 11β-HSD2 were very weakly inhibited (IC; 50; values above 7 μM). Sequence alignment and application of newly generated homology models for human and mouse 11β-HSD2 revealed significant differences in the C-terminal region and the substrate binding pocket. Exchange of the C-terminus and substitution of residues Leu170,Ile172 in mouse 11β-HSD2 by the corresponding residues His170,Glu172 of the human enzyme resulted in a gain of sensitivity to itraconazole and posaconazole, resembling human 11β-HSD2. The results provide an explanation for the observed species-specific 11β-HSD2 inhibition by the studied azole antifungals. The obtained structure-activity relationship information should facilitate future assessments of 11β-HSD2 inhibitors and aid choosing adequate animal models for efficacy and safety studies

    5-μm vertical external-cavity surface-emitting laser (VECSEL) forspectroscopic applications

    Get PDF
    Mid-IR tunable VECSELs (Vertical External-Cavity Surface-Emitting Lasers) emitting at 4-7 μm wavelengths and suitable for spectroscopic sensing applications are described. They are realized with lead-chalcogenide (IV-VI) narrow band gap materials. The active part, a single 0.6-2-μm thick PbTe or PbSe gain layer, is grown onto an epitaxial Bragg mirror consisting of two or three Pb1−y EuyTe/BaF2 quarter-wavelength layer pairs. All layers are deposited by MBE in a single run employing a BaF2 or Si substrate, no further processing is needed. The cavity is completed with an external curved top mirror, which is again realized with an epitaxial Bragg structure. Pumping is performed optically with a 1.5-μm laser. Maximum output power for pulsed operation is currently up to >1 Wp at −173°C and >10 mW at 10°C. In continuous wave (CW) operation, 18 mW at 100 K are reached. Still higher operating temperatures and/or powers are expected with better heat-removal structures and better designs employing QW (Quantum-Wells). Advantages of mid-IR VECSELs compared to edge-emitting lasers are their very good beam quality (circular beam with 15 μm are accessible with Pb1−y XyZ (X=Sr, Eu, Sn, Z=Se, Te) and/or including Q
    • …
    corecore