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- Klionsky, Daniel J., et al.
(author)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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In: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Research review (peer-reviewed)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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- Andersson, Per A., et al.
(author)
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Anger and disgust shape judgments of social sanctions across cultures, especially in high individual autonomy societies
- 2024
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In: Scientific Reports. - : Nature Research. - 2045-2322. ; 14:1
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Journal article (peer-reviewed)abstract
- When someone violates a social norm, others may think that some sanction would be appropriate. We examine how the experience of emotions like anger and disgust relate to the judged appropriateness of sanctions, in a pre-registered analysis of data from a large-scale study in 56 societies. Across the world, we find that individuals who experience anger and disgust over a norm violation are more likely to endorse confrontation, ostracism and, to a smaller extent, gossip. Moreover, we find that the experience of anger is consistently the strongest predictor of judgments of confrontation, compared to other emotions. Although the link between state-based emotions and judgments may seem universal, its strength varies across countries. Aligned with theoretical predictions, this link is stronger in societies, and among individuals, that place higher value on individual autonomy. Thus, autonomy values may increase the role that emotions play in guiding judgments of social sanctions.
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- Eriksson, Kimmo, et al.
(author)
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Perceptions of the appropriate response to norm violation in 57 societies
- 2021
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In: Nature Communications. - : Nature Research. - 2041-1723. ; 12:1
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Journal article (peer-reviewed)abstract
- Norm enforcement may be important for resolving conflicts and promoting cooperation. However, little is known about how preferred responses to norm violations vary across cultures and across domains. In a preregistered study of 57 countries (using convenience samples of 22,863 students and non-students), we measured perceptions of the appropriateness of various responses to a violation of a cooperative norm and to atypical social behaviors. Our findings highlight both cultural universals and cultural variation. We find a universal negative relation between appropriateness ratings of norm violations and appropriateness ratings of responses in the form of confrontation, social ostracism and gossip. Moreover, we find the country variation in the appropriateness of sanctions to be consistent across different norm violations but not across different sanctions. Specifically, in those countries where use of physical confrontation and social ostracism is rated as less appropriate, gossip is rated as more appropriate. Little is known about peoples preferred responses to norm violations across countries. Here, in a study of 57 countries, the authors highlight cultural similarities and differences in peoples perception of the appropriateness of norm violations.
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- Bruhn, Sören, et al.
(author)
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A Generally Applicable Translational Strategy Identifies S100A4 as a Candidate Gene in Allergy
- 2014
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In: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 6:218
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Journal article (peer-reviewed)abstract
- The identification of diagnostic markers and therapeutic candidate genes in common diseases is complicated by the involvement of thousands of genes. We hypothesized that genes co-regulated with a key gene in allergy, IL13, would form a module that could help to identify candidate genes. We identified a T helper 2 (T(H)2) cell module by small interfering RNA-mediated knockdown of 25 putative IL13-regulating transcription factors followed by expression profiling. The module contained candidate genes whose diagnostic potential was supported by clinical studies. Functional studies of human TH2 cells as well as mouse models of allergy showed that deletion of one of the genes, S100A4, resulted in decreased signs of allergy including TH2 cell activation, humoral immunity, and infiltration of effector cells. Specifically, dendritic cells required S100A4 for activating T cells. Treatment with an anti-S100A4 antibody resulted in decreased signs of allergy in the mouse model as well as in allergen-challenged T cells from allergic patients. This strategy, which may be generally applicable to complex diseases, identified and validated an important diagnostic and therapeutic candidate gene in allergy.
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- Eze-Nliam, Chete, et al.
(author)
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Endurance exercise in seniors: Tonic, toxin or neither?
- 2020
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In: Clinical Physiology and Functional Imaging. - : Wiley-Blackwell Publishing Inc.. - 1475-0961 .- 1475-097X. ; 40:5, s. 320-327
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Journal article (peer-reviewed)abstract
- INTRODUCTION: Cardiac adaptation to sustained exercise in the athletes is established. However, exercise-associated effect on the cardiac function of the elderly has to be elucidated. The aim of this study was to analyse left (LV) and right ventricular (RV) characteristics at different levels of chronic exercise in the senior heart.MATERIALS AND METHODS: We studied 178 participants in the World Senior Games (mean age 68 ± 8 years, 86 were men; 48%). Three groups were defined based on the type and intensity of sports: low-, moderate- and high-intensity level. Exclusion criteria were coronary artery disease, atrial fibrillation, valvular heart disease or uncontrolled hypertension. LV and RV size and function were evaluated with an echocardiogram.RESULTS: LV trans-mitral inflow deceleration time decreased in parallel to the intensity of chronic exercise: 242 ± 54 ms in low-, 221 ± 52 ms in moderate- and 215 ± 58 ms in high-intensity level, p = .03. Left atrial volume index (LAVI) was larger in high-intensity group, p = .001. The LAVI remained significantly larger when adjusting for age, gender, heart rate, hypertension and diabetes (p = .002). LV and RV sizes were larger in the high-intensity group. LV ejection fraction and RV systolic function evaluated by tissue Doppler velocity, atrioventricular plane displacement and strain did not differ between groups.CONCLUSION: Left ventricular diastolic filling is not only preserved, but may also be enhanced in long-term, top-level senior athletes. Moreover, LV and RV systolic function remain unchanged at different levels of exercise. This supports the beneficial effects of endurance exercise participation in senior hearts.
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| 9. |
- Link, Verena M, et al.
(author)
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Analysis of Genetically Diverse Macrophages Reveals Local and Domain-wide Mechanisms that Control Transcription Factor Binding and Function.
- 2018
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In: Cell. - Cambridge, United States : Cell Press. - 0092-8674 .- 1097-4172. ; 173:7, s. 1796-1809.e17
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Journal article (peer-reviewed)abstract
- Non-coding genetic variation is a major driver of phenotypic diversity and allows the investigation of mechanisms that control gene expression. Here, we systematically investigated the effects of >50 million variations from five strains of mice on mRNA, nascent transcription, transcription start sites, and transcription factor binding in resting and activated macrophages. We observed substantial differences associated with distinct molecular pathways. Evaluating genetic variation provided evidence for roles of ∼100 TFs in shaping lineage-determining factor binding. Unexpectedly, a substantial fraction of strain-specific factor binding could not be explained by local mutations. Integration of genomic features with chromatin interaction data provided evidence for hundreds of connected cis-regulatory domains associated with differences in transcription factor binding and gene expression. This system and the >250 datasets establish a substantial new resource for investigation of how genetic variation affects cellular phenotypes.
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| 10. |
- Teerlink, John R., et al.
(author)
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Cardiac Myosin Activation with Omecamtiv Mecarbil in Systolic Heart Failure
- 2021
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In: New England Journal of Medicine. - Waltham, MA, United States : MASSACHUSETTS MEDICAL SOC. - 0028-4793 .- 1533-4406. ; 384:2, s. 105-116
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Journal article (peer-reviewed)abstract
- Among patients with heart failure and a reduced ejection fraction, those who received the cardiac myosin activator omecamtiv mecarbil had a lower incidence of a composite of heart-failure events or cardiovascular death at a median of 22 months than those who received placebo. Background The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown. Methods We randomly assigned 8256 patients (inpatients and outpatients) with symptomatic chronic heart failure and an ejection fraction of 35% or less to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes. Results During a median of 21.8 months, a primary-outcome event occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P=0.03). A total of 808 patients (19.6%) and 798 patients (19.4%), respectively, died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). There was no significant difference between groups in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score. At week 24, the change from baseline for the median N-terminal pro-B-type natriuretic peptide level was 10% lower in the omecamtiv mecarbil group than in the placebo group; the median cardiac troponin I level was 4 ng per liter higher. The frequency of cardiac ischemic and ventricular arrhythmia events was similar in the two groups. Conclusions Among patients with heart failure and a reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo. (Funded by Amgen and others; GALACTIC-HF ClinicalTrials.gov number, ; EudraCT number, 2016-002299-28.)
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