| 1. |
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| 2. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 3. |
- Fenstermacher, M.E., et al.
(författare)
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DIII-D research advancing the physics basis for optimizing the tokamak approach to fusion energy
- 2022
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Ingår i: Nuclear Fusion. - : IOP Publishing. - 0029-5515 .- 1741-4326. ; 62:4
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Tidskriftsartikel (refereegranskat)abstract
- DIII-D physics research addresses critical challenges for the operation of ITER and the next generation of fusion energy devices. This is done through a focus on innovations to provide solutions for high performance long pulse operation, coupled with fundamental plasma physics understanding and model validation, to drive scenario development by integrating high performance core and boundary plasmas. Substantial increases in off-axis current drive efficiency from an innovative top launch system for EC power, and in pressure broadening for Alfven eigenmode control from a co-/counter-I p steerable off-axis neutral beam, all improve the prospects for optimization of future long pulse/steady state high performance tokamak operation. Fundamental studies into the modes that drive the evolution of the pedestal pressure profile and electron vs ion heat flux validate predictive models of pedestal recovery after ELMs. Understanding the physics mechanisms of ELM control and density pumpout by 3D magnetic perturbation fields leads to confident predictions for ITER and future devices. Validated modeling of high-Z shattered pellet injection for disruption mitigation, runaway electron dissipation, and techniques for disruption prediction and avoidance including machine learning, give confidence in handling disruptivity for future devices. For the non-nuclear phase of ITER, two actuators are identified to lower the L-H threshold power in hydrogen plasmas. With this physics understanding and suite of capabilities, a high poloidal beta optimized-core scenario with an internal transport barrier that projects nearly to Q = 10 in ITER at ∼8 MA was coupled to a detached divertor, and a near super H-mode optimized-pedestal scenario with co-I p beam injection was coupled to a radiative divertor. The hybrid core scenario was achieved directly, without the need for anomalous current diffusion, using off-axis current drive actuators. Also, a controller to assess proximity to stability limits and regulate β N in the ITER baseline scenario, based on plasma response to probing 3D fields, was demonstrated. Finally, innovative tokamak operation using a negative triangularity shape showed many attractive features for future pilot plant operation.
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| 4. |
- Sampson, Joshua N., et al.
(författare)
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Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types
- 2015
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 107:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
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| 5. |
- Wang, Zhaoming, et al.
(författare)
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Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:24, s. 6616-6633
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
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| 6. |
- Sung, Sang Hyun, et al.
(författare)
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Flexible wireless powered drug delivery system for targeted administration on cerebral cortex
- 2018
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Ingår i: Nano Energy. - : ELSEVIER SCIENCE BV. - 2211-2855 .- 2211-3282. ; 51, s. 102-112
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Tidskriftsartikel (refereegranskat)abstract
- The controlled drug delivery devices helps timely drug administrations and maintenance of effective dose to maximize curing effects with minimal side effects. Application of this technology to various body parts has been limited, especially in organs with curved surface, such as the brain and the eye. Herein, we report a flexible drug delivery microdevice (f-DDM) for controlled administration on the curved organ surface. The unique structure of the f-DDM consists of freestanding gold membranes over the multireservoir array was implemented by reversing the typical fabrication order of the reservoir and sealing membrane. We optimized the design of the f-DDM by a finite element analysis to prevent thermal damage during the laser transfer and the applying current density for reliable drug release through an electrochemical analysis. The wireless power transfer system was applied to f-DDM, which shows stable wirelessly powered operation. The f-DDM was flexible enough to be implantable on the curved cerebral cortex and successfully adopted for delivery of two different chemicals or prevention of seizure activity using an anti-epileptic drug. Our study opens a new avenue for the controlled, region-specific, and combinatorial application of drugs, the key factors for precision medicine.
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| 7. |
- Baber, Ashleigh E., et al.
(författare)
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Stabilization of Catalytically Active Cu plus Surface Sites on TitaniumCopper Mixed-Oxide Films**
- 2014
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Ingår i: Angewandte Chemie International Edition. - : Gesellschaft Deutscher Chemiker. - 1433-7851 .- 1521-3773. ; 53:21, s. 5336-5340
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Tidskriftsartikel (refereegranskat)abstract
- The oxidation of CO is the archetypal heterogeneous catalytic reaction and plays a central role in the advancement of fundamental studies, the control of automobile emissions, and industrial oxidation reactions. Copper-based catalysts were the first catalysts that were reported to enable the oxidation of CO at room temperature, but a lack of stability at the elevated reaction temperatures that are used in automobile catalytic converters, in particular the loss of the most reactive Cu+ cations, leads to their deactivation. Using a combined experimental and theoretical approach, it is shown how the incorporation of titanium cations in a Cu2O film leads to the formation of a stable mixed-metal oxide with a Cu+ terminated surface that is highly active for CO oxidation.
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| 8. |
- Hyun, Gyu Hwan, et al.
(författare)
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Multivalent Carbohydrate Nanocomposites for Tumor Microenvironment Remodeling to Enhance Antitumor Immunity
- 2023
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Ingår i: ACS Nano. - : American Chemical Society (ACS). - 1936-0851 .- 1936-086X. ; 17:12, s. 11567-11582
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Tidskriftsartikel (refereegranskat)abstract
- Current cancer immunotherapeutic strategies mainly focus on remodeling the tumor microenvironment (TME) to make it favorable for antitumor immunity. Increasing attention has been paid to developing innovative immunomodulatory adjuvants that can restore weakened antitumor immunity by conferring immunogenicity to inflamed tumor tissues. Here, a galactan-enriched nanocomposite (Gal-NC) is developed from native carbohydrate structures through an optimized enzymatic transformation for effective, stable, and biosafe innate immunomodulation. Gal-NC is characterized as a carbohydrate nanoadjuvant with a macrophage-targeting feature. It is composed of repeating galactan glycopatterns derived from heteropolysaccharide structures of plant origin. The galactan repeats of Gal-NC function as multivalent pattern-recognition sites for Toll-like receptor 4 (TLR4). Functionally, Gal-NC-mediated TLR activation induces the repolarization of tumor-associated macrophages (TAMs) toward immunostimulatory/tumoricidal M1-like phenotypes. Gal-NC increases the intratumoral population of cytotoxic T cells, the main effector cells of antitumor immunity, via re-educated TAMs. These TME alterations synergistically enhance the T-cell-mediated antitumor response induced by αPD-1 administration, suggesting that Gal-NC has potential value as an adjuvant for immune checkpoint blockade combination therapies. Thus, the Gal-NC model established herein suggests a glycoengineering strategy to design a carbohydrate-based nanocomposite for advanced cancer immunotherapies.
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| 9. |
- Lara, Patricia, et al.
(författare)
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Refined topology model of the STT3/Stt3 protein subunit of the oligosaccharyltransferase complex
- 2017
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 292:27, s. 11349-11360
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Tidskriftsartikel (refereegranskat)abstract
- The oligosaccharyltransferase complex, localized in the endoplasmic reticulum (ER) of eukaryotic cells, is responsible for the N-linked glycosylation of numerous protein substrates. The membrane protein STT3 is a highly conserved part of the oligosaccharyltransferase and likely contains the active site of the complex. However, understanding the catalytic determinants of this system has been challenging, in part because of a discrepancy in the structural topology of the bacterial versus eukaryotic proteins and incomplete information about the mechanism of membrane integration. Here, we use a glycosylation mapping approach to investigate these questions. We measured the membrane integration efficiency of the mouse STT3-A and yeast Stt3p transmembrane domains (TMDs) and report a refined topology of the N-terminal half of the mouse STT3-A. Our results show that most of the STT3 TMDs are well inserted into the ER membrane on their own or in the presence of the natural flanking residues. However, for the mouse STT3-A hydrophobic domains 4 and 6 and yeast Stt3p domains 2, 3a, 3c, and 6 we measured reduced insertion efficiency into the ER membrane. Furthermore, we mapped the first half of the STT3-A protein, finding two extra hydrophobic domains between the third and the fourthTMD. This result indicates that the eukaryotic STT3 has 13 transmembrane domains, consistent with the structure of the bacterial homolog of STT3 and setting the stage for future combined efforts to interrogate this fascinating system.
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| 10. |
- Park, Sung-Joon, et al.
(författare)
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Autonomous Interfacial Assembly of Polymer Nanofilms via Surfactant-Regulated Marangoni Instability
- 2023
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Ingår i: Nano Letters. - : American Chemical Society (ACS). - 1530-6984 .- 1530-6992. ; 23:11, s. 4822-4829
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Tidskriftsartikel (refereegranskat)abstract
- Interfacialpolymerization (IP) provides a versatile platform forfabricating defect-free functional nanofilms for various applications,including molecular separation, energy, electronics, and biomedicalmaterials. Unfortunately, coupled with complex natural instabilityphenomena, the IP mechanism and key parameters underlying the structuralevolution of nanofilms, especially in the presence of surfactantsas an interface regulator, remain puzzling. Here, we interfaciallyassembled polymer nanofilm membranes at the free water-oilinterface in the presence of differently charged surfactants and comprehensivelycharacterized their structure and properties. Combined with computationalsimulations, an in situ visualization of interfacial film formationdiscovered the critical role of Marangoni instability induced by thesurfactants via various mechanisms in structurally regulating thenanofilms. Despite their different instability-triggering mechanisms,the delicate control of the surfactants enabled the fabrication ofdefect-free, ultra-permselective nanofilm membranes. Our study identifiescritical IP parameters that allow us to rationally design nanofilms,coatings, and membranes for target applications.
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