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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. |
- Aye, Cho-Cho, et al.
(författare)
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CBL/CAP Is Essential for Mitochondria Respiration Complex I Assembly and Bioenergetics Efficiency in Muscle Cells
- 2023
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 24:4
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Tidskriftsartikel (refereegranskat)abstract
- CBL is rapidly phosphorylated upon insulin receptor activation. Mice whole body CBL depletion improved insulin sensitivity and glucose clearance; however, the precise mechanisms remain unknown. We depleted either CBL or its associated protein SORBS1/CAP independently in myocytes and assessed mitochondrial function and metabolism compared to control cells. CBL- and CAP-depleted cells showed increased mitochondrial mass with greater proton leak. Mitochondrial respiratory complex I activity and assembly into respirasomes were reduced. Proteome profiling revealed alterations in proteins involved in glycolysis and fatty acid degradation. Our findings demonstrate CBL/CAP pathway couples insulin signaling to efficient mitochondrial respiratory function and metabolism in muscle.
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| 4. |
- Rodriguez-Cuenca, Sergio, et al.
(författare)
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Allostatic hypermetabolic response in PGC1α/β heterozygote mouse despite mitochondrial defects
- 2021
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Ingår i: The FASEB Journal. - : John Wiley & Sons. - 0892-6638 .- 1530-6860. ; 35:9
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Tidskriftsartikel (refereegranskat)abstract
- Aging, obesity, and insulin resistance are associated with low levels of PGC1α and PGC1β coactivators and defective mitochondrial function. We studied mice deficient for PGC1α and PGC1β [double heterozygous (DH)] to investigate their combined pathogenic contribution. Contrary to our hypothesis, DH mice were leaner, had increased energy dissipation, a pro-thermogenic profile in BAT and WAT, and improved carbohydrate metabolism compared to wild types. WAT showed upregulation of mitochondriogenesis/oxphos machinery upon allelic compensation of PGC1α4 from the remaining allele. However, DH mice had decreased mitochondrial OXPHOS and biogenesis transcriptomes in mitochondria-rich organs. Despite being metabolically healthy, mitochondrial defects in DH mice impaired muscle fiber remodeling and caused qualitative changes in the hepatic lipidome. Our data evidence first the existence of organ-specific compensatory allostatic mechanisms are robust enough to drive an unexpected phenotype. Second, optimization of adipose tissue bioenergetics is sufficient to maintain a healthy metabolic phenotype despite a broad severe mitochondrial dysfunction in other relevant metabolic organs. Third, the decrease in PGC1s in adipose tissue of obese and diabetic patients is in contrast with the robustness of the compensatory upregulation in the adipose of the DH mice.
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| 5. |
- Andersen, Gregers Stig Tig, et al.
(författare)
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The DEXLIFE study methods : identifying novel candidate biomarkers that predict progression to type 2 diabetes in high risk individuals
- 2014
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Ingår i: Diabetes Research and Clinical Practice. - : Elsevier. - 0168-8227 .- 1872-8227. ; 106:2, s. 383-389
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Tidskriftsartikel (refereegranskat)abstract
- The incidence of type 2 diabetes (T2D) is rapidly increasing worldwide and T2D is likely to affect 592 million people in 2035 if the current rate of progression is continued. Today, patients are diagnosed with T2D based on elevated blood glucose, either directly or indirectly (HbA1c). However, the information on disease progression is limited. Therefore, there is a need to identify novel early markers of glucose intolerance that reflect the underlying biology and the overall physiological, metabolic and clinical characteristics of progression towards diabetes. In the DEXLIFE study, several clinical cohorts provide the basis for a series of clinical, physiological and mechanistic investigations in combination with a range of--omic technologies to construct a detailed metabolic profile of high-risk individuals across multiple cohorts. In addition, an exercise and dietary intervention study is conducted, that will assess the impact on both plasma biomarkers and specific functional tissue-based markers. The DEXLIFE study will provide novel diagnostic and predictive biomarkers which may not only effectively detect the progression towards diabetes in high risk individuals but also predict responsiveness to lifestyle interventions known to be effective in the prevention of diabetes.
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| 6. |
- Bhardwaj, Anshuman, et al.
(författare)
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UAV Imaging of a Martian Brine Analogue Environment in a Fluvio-Aeolian Setting
- 2019
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Ingår i: Remote Sensing. - : MDPI. - 2072-4292. ; 11:18
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Tidskriftsartikel (refereegranskat)abstract
- Understanding extraterrestrial environments and landforms through remote sensing and terrestrial analogy has gained momentum in recent years due to advances in remote sensing platforms, sensors, and computing efficiency. The seasonal brines of the largest salt plateau on Earth in Salar de Uyuni (Bolivian Altiplano) have been inadequately studied for their localized hydrodynamics and the regolith volume transport across the freshwater-brine mixing zones. These brines have recently been projected as a new analogue site for the proposed Martian brines, such as recurring slope lineae (RSL) and slope streaks. The Martian brines have been postulated to be the result of ongoing deliquescence-based salt-hydrology processes on contemporary Mars, similar to the studied Salar de Uyuni brines. As part of a field-site campaign during the cold and dry season in the latter half of August 2017, we deployed an unmanned aerial vehicle (UAV) at two sites of the Salar de Uyuni to perform detailed terrain mapping and geomorphometry. We generated high-resolution (2 cm/pixel) photogrammetric digital elevation models (DEMs) for observing and quantifying short-term terrain changes within the brines and their surroundings. The achieved co-registration for the temporal DEMs was considerably high, from which precise inferences regarding the terrain dynamics were derived. The observed average rate of bottom surface elevation change for brines was ~1.02 mm/day, with localized signs of erosion and deposition. Additionally, we observed short-term changes in the adjacent geomorphology and salt cracks. We conclude that the transferred regolith volume via such brines can be extremely low, well within the resolution limits of the remote sensors that are currently orbiting Mars, thereby making it difficult to resolve the topographic relief and terrain perturbations that are produced by such flows on Mars. Thus, the absence of observable erosion and deposition features within or around most of the proposed Martian RSL and slope streaks cannot be used to dismiss the possibility of fluidized flow within these features
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| 7. |
- Gõmez-Elvira, Javier, et al.
(författare)
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Curiosity's rover environmental monitoring station : Overview of the first 100 sols
- 2014
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Ingår i: Journal of Geophysical Research - Planets. - 2169-9097 .- 2169-9100. ; 119:7, s. 1680-1688
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Tidskriftsartikel (refereegranskat)abstract
- In the first 100 Martian solar days (sols) of the Mars Science Laboratory mission, the Rover Environmental Monitoring Station (REMS) measured the seasonally evolving diurnal cycles of ultraviolet radiation, atmospheric pressure, air temperature, ground temperature, relative humidity, and wind within Gale Crater on Mars. As an introduction to several REMS-based articles in this issue, we provide an overview of the design and performance of the REMS sensors and discuss our approach to mitigating some of the difficulties we encountered following landing, including the loss of one of the two wind sensors. We discuss the REMS data set in the context of other Mars Science Laboratory instruments and observations and describe how an enhanced observing strategy greatly increased the amount of REMS data returned in the first 100 sols, providing complete coverage of the diurnal cycle every 4 to 6 sols. Finally, we provide a brief overview of key science results from the first 100 sols. We found Gale to be very dry, never reaching saturation relative humidities, subject to larger diurnal surface pressure variations than seen by any previous lander on Mars, air temperatures consistent with model predictions and abundant short timescale variability, and surface temperatures responsive to changes in surface properties and suggestive of subsurface layering. Key Points Introduction to the REMS results on MSL mission Overiview of the sensor information Overview of operational constraints
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| 8. |
- Hamilton, Victoria E., et al.
(författare)
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Observations and preliminary science results from the first 100 sols of MSL Rover Environmental Monitoring Station ground temperature sensor measurements at Gale Crater
- 2014
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Ingår i: Journal of Geophysical Research - Planets. - : John Wiley & Sons. - 2169-9097 .- 2169-9100. ; 119:4, s. 745-770
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Tidskriftsartikel (refereegranskat)abstract
- We describe preliminary results from the first 100 sols of ground temperature measurements along the Mars Science Laboratory's traverse from Bradbury Landing to Rocknest in Gale. The ground temperature data show long-term increases in mean temperature that are consistent with seasonal evolution. Deviations from expected temperature trends within the diurnal cycle are observed and may be attributed to rover and environmental effects. Fits to measured diurnal temperature amplitudes using a thermal model suggest that the observed surfaces have thermal inertias in the range of 265-375?J m-2 K-1 s-1/2, which are within the range of values determined from orbital measurements and are consistent with the inertias predicted from the observed particle sizes on the uppermost surface near the rover. Ground temperatures at Gale Crater appear to warm earlier and cool later than predicted by the model, suggesting that there are multiple unaccounted for physical conditions or processes in our models. Where the Mars Science Laboratory (MSL) descent engines removed a mobile layer of dust and fine sediments from over rockier material, the diurnal temperature profile is closer to that expected for a homogeneous surface, suggesting that the mobile materials on the uppermost surface may be partially responsible for the mismatch between observed temperatures and those predicted for materials having a single thermal inertia. Models of local stratigraphy also implicate thermophysical heterogeneity at the uppermost surface as a potential contributor to the observed diurnal temperature cycle. Key Points Diurnal ground temperatures vary with location Diurnal temperature curves are not well matched by a homogeneous thermal model GTS data are consistent with a varied stratigraphy and thermophysical properties.
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| 9. |
- Hernández-Alvarez, María Isabel, et al.
(författare)
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Deficient Endoplasmic Reticulum-Mitochondrial Phosphatidylserine Transfer Causes Liver Disease
- 2019
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Ingår i: Cell. - : Cell Press. - 0092-8674 .- 1097-4172. ; 177:4, s. 881-895.e17
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Tidskriftsartikel (refereegranskat)abstract
- Non-alcoholic fatty liver is the most common liver disease worldwide. Here, we show that the mitochondrial protein mitofusin 2 (Mfn2) protects against liver disease. Reduced Mfn2 expression was detected in liver biopsies from patients with non-alcoholic steatohepatitis (NASH). Moreover, reduced Mfn2 levels were detected in mouse models of steatosis or NASH, and its re-expression in a NASH mouse model ameliorated the disease. Liver-specific ablation of Mfn2 in mice provoked inflammation, triglyceride accumulation, fibrosis, and liver cancer. We demonstrate that Mfn2 binds phosphatidylserine (PS) and can specifically extract PS into membrane domains, favoring PS transfer to mitochondria and mitochondrial phosphatidylethanolamine (PE) synthesis. Consequently, hepatic Mfn2 deficiency reduces PS transfer and phospholipid synthesis, leading to endoplasmic reticulum (ER) stress and the development of a NASH-like phenotype and liver cancer. Ablation of Mfn2 in liver reveals that disruption of ER-mitochondrial PS transfer is a new mechanism involved in the development of liver disease.
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