| 1. |
- Klionsky, Daniel J., et al.
(författare)
-
Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
-
Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
-
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.
|
|
| 2. |
|
|
| 3. |
- Clark, Andrew G., et al.
(författare)
-
Evolution of genes and genomes on the Drosophila phylogeny
- 2007
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 450:7167, s. 203-218
-
Tidskriftsartikel (refereegranskat)abstract
- Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.
|
|
| 4. |
- Ageno, Walter, et al.
(författare)
-
Managing reversal of direct oral anticoagulants in emergency situations Anticoagulation Education Task Force White Paper
- 2016
-
Ingår i: Thrombosis and Haemostasis. - : SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN. - 0340-6245 .- 2567-689X. ; 116:6, s. 1003-1010
-
Tidskriftsartikel (refereegranskat)abstract
- Anticoagulation is the cornerstone of prevention and treatment of venous thromboembolism (VTE) and stroke prevention in patients with atrial fibrillation (AF). However, the mechanisms by which anticoagulants confer therapeutic benefit also increase the risk of bleeding. As such, reversal strategies are critical. Until recently, the direct oral anticoagulants (DOACs) dabigatran, rivaroxaban, apixaban, and edoxaban lacked a specific reversal agent. This report is based on findings from the Anticoagulation Education Task Force, which brought together patient groups and professionals representing different medical specialties with an interest in patient safety and expertise in AF, VTE, stroke, anticoagulation, and reversal agents, to discuss the current status of anticoagulation reversal and fundamental changes in management of bleeding associated with DOACs occasioned by the approval of idarucizumab, a specific reversal agent for dabigatran, as well as recent clinical data on specific reversal agents for factor Xa inhibitors. Recommendations are given for when there is a definite need for a reversal agent (e.g. in cases of life-threatening bleeding, bleeding into a closed space or organ, persistent bleeding despite local haemostatic measures, and need for urgent interventions and/or interventions that carry a high risk for bleeding), when reversal agents may be helpful, and when a reversal agent is generally not needed. Key stakeholders who require 24-7/around-the-clock access to these agents vary among hospitals; however, from a practical perspective the emergency department is recommended as an appropriate location for these agents. Clearly, the advent of new agents requires standardised protocols for treating bleeding on an institutional level.
|
|
| 5. |
- Benze, Susanne, et al.
(författare)
-
On the onset of polar mesospheric cloud seasons as observed by SBUV
- 2012
-
Ingår i: Journal of Geophysical Research. - 0148-0227 .- 2156-2202. ; 117, s. D07104-
-
Tidskriftsartikel (refereegranskat)abstract
- This paper describes an investigation using data from the Solar Backscatter Ultraviolet (SBUV) satellite instruments to explore and understand variations in the timing of the onset of Polar Mesospheric Cloud (PMC) seasons. Previous work has shown that for several recent southern hemisphere (SH) seasons, the PMC season onset was controlled by the timing of the shift from winter to summer zonal wind flow in the SH stratosphere. We extend the analysis of PMC season onset to 28 years of SBUV observations, including both hemispheres. A multiple linear regression analysis of SBUV data from 1984 to 2011 suggests that the SH PMC season onset is delayed by one day for every day that the zonal wind at 65 degrees S and 50 hPa (similar to 20 km) remains in a winter-like state. In addition, we find that the solar cycle plays a role: The SH season onset is delayed by about ten days at solar maximum compared to solar minimum. In the NH, the PMC season onset is delayed by similar to 7 days at solar maximum compared to solar minimum; variations in the NH stratospheric wind, however, are not correlated with the NH onset date. On the other hand, inter-hemispheric teleconnections are important in the NH; a one-day shift in the NH season onset corresponds to a shift of similar to 1.4 m/s in the SH stratospheric wind at 60.0 degrees S and 20 hPa (similar to 26 km). Neither the NH nor the SH season onset date is correlated with the Quasi-Biennial Oscillation, North Atlantic Oscillation, Arctic Oscillation, or El Nino Southern Oscillation.
|
|
| 6. |
- Block, Keith I., et al.
(författare)
-
Designing a broad-spectrum integrative approach for cancer prevention and treatment
- 2015
-
Ingår i: Seminars in Cancer Biology. - : Academic Press. - 1044-579X .- 1096-3650. ; 35, s. S276-S304
-
Forskningsöversikt (refereegranskat)abstract
- Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broadspectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered. (C) 2015 The Authors. Published by Elsevier Ltd.
|
|
| 7. |
|
|
| 8. |
- Janko, Matthew, et al.
(författare)
-
Contemporary Outcomes After Partial Resection of Infected Aortic Grafts
- 2021
-
Ingår i: Annals of Vascular Surgery. - : Elsevier. - 0890-5096 .- 1615-5947. ; 76, s. 202-210
-
Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Aortic graft infection remains a considerable clinical challenge, and it is unclear which variables are associated with adverse outcomes among patients undergoing partial resection.METHODS: A retrospective, multi-institutional study of patients who underwent partial resection of infected aortic grafts from 2002 to 2014 was performed using a standard database. Baseline demographics, comorbidities, operative, and postoperative variables were recorded. The primary outcome was mortality. Descriptive statistics, Kaplan-Meier (KM) survival analysis, and Cox regression analysis were performed.RESULTS: One hundred fourteen patients at 22 medical centers in 6 countries underwent partial resection of an infected aortic graft. Seventy percent were men with median age 70 years. Ninety-seven percent had a history of open aortic bypass graft: 88 (77%) patients had infected aortobifemoral bypass, 18 (16%) had infected aortobiiliac bypass, and 1 (0.8%) had an infected thoracic graft. Infection was diagnosed at a median 4.3 years post-implant. All patients underwent partial resection followed by either extra-anatomic (47%) or in situ (53%) vascular reconstruction. Median follow-up period was 17 months (IQR 1, 50 months). Thirty-day mortality was 17.5%. The KM-estimated median survival from time of partial resection was 3.6 years. There was no significant survival difference between those undergoing in situ reconstruction or extra-anatomic bypass (P = 0.6). During follow up, 72% of repairs remained patent and 11% of patients underwent major amputation. On univariate Cox regression analysis, Candida infection was associated with increased risk of mortality (HR 2.4; P = 0.01) as well as aortoenteric fistula (HR 1.9, P = 0.03). Resection of a single graft limb only to resection of abdominal (graft main body) infection was associated with decreased risk of mortality (HR 0.57, P = 0.04), as well as those with American Society of Anesthesiologists classification less than 3 (HR 0.35, P = 0.04). Multivariate analysis did not reveal any factors significantly associated with mortality. Persistent early infection was noted in 26% of patients within 30 days postoperatively, and 39% of patients were found to have any post-repair infection during the follow-up period. Two patients (1.8%) were found to have a late reinfection without early persistent postoperative infection. Patients with any post-repair infection were older (67 vs. 60 years, P = 0.01) and less likely to have patent repairs during follow up (59% vs. 32%, P = 0.01). Patients with aortoenteric fistula had a higher rate of any post-repair infection (63% vs. 29%, P < 0.01)CONCLUSION: This large multi-center study suggests that patients who have undergone partial resection of infected aortic grafts may be at high risk of death or post-repair infection, especially older patients with abdominal infection not isolated to a single graft limb, or with Candida infection or aortoenteric fistula. Late reinfection correlated strongly with early persistent postoperative infection, raising concern for occult retained infected graft material.
|
|
| 9. |
- Janko, Matthew R., et al.
(författare)
-
In situ bypass and extra-anatomic bypass procedures result in similar survival in patients with secondary aortoenteric fistulas
- 2021
-
Ingår i: Journal of Vascular Surgery. - : Elsevier. - 0741-5214 .- 1097-6809. ; 73:1, s. 210-221.e1
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: The optimal revascularization modality in secondary aortoenteric fistula (SAEF) remains unclear in the literature. The purpose of this investigation was to determine the revascularization approach associated with the lowest morbidity and mortality using real-world data in patients with SAEF. Methods: A retrospective, multi-institutional study of SAEF from 2002 to 2014 was performed using a standardized database. Baseline demographics, comorbidities, and operative and postoperative variables were recorded. The primary outcome was long-term mortality. Descriptive statistics, Kaplan-Meier survival analysis, and univariate and multivariate analyses were performed. Results: During the study period, 182 patients at 34 institutions from 11 countries presented with SAEF (median age, 72 years; 79% male). The initial aortic procedures that resulted in SAEF were 138 surgical grafts (76%) and 42 endografts (23%), with 2 unknown; 102 of the SAEFs (56%) underwent complete excision of infected aortic graft material, followed by in situ (in-line) bypass (ISB), including antibiotic-soaked prosthetic graft (53), autogenous femoral vein (neoaortoiliac surgery; 17), cryopreserved allograft (28), and untreated prosthetic grafts (4). There were 80 patients (44%) who underwent extra-anatomic bypass (EAB) with infected graft excision. Overall median Kaplan-Meier estimated survival was 319 days (interquartile range, 20-2410 days). Stratified by EAB vs ISB, there was no significant difference in Kaplan-Meier estimated survival (P = .82). In comparing EAB vs ISB, EAB patients were older (74 vs 70 years; P = .01), had less operative hemorrhage (1200 mL vs 2000 mL; P = .04), were more likely to initiate dialysis within 30 days postoperatively (15% vs 5%; P = .02), and were less likely to experience aorta-related hemorrhage within 30 days postoperatively (3% aortic stump dehiscence vs 11% anastomotic rupture; P = .03). There were otherwise no significant differences in presentation, comorbidities, and intraoperative or postoperative variables. Multivariable Cox regression showed that the duration of antibiotic use (hazard ratio, 0.92; 95% confidence interval, 0.86-0.98; P = .01) and rifampin use at time of discharge (hazard ratio, 0.20; 95% confidence interval, 0.05-0.86; P = .03) independently decreased mortality. Conclusions: These data suggest that ISB does not offer a survival advantage compared with EAB and does not decrease the risk of postoperative aorta-related hemorrhage. After repair, <50% of SAEF patients survive 10-months. Each week of antibiotic use decreases mortality by 8%. Further study with risk modeling is imperative for this population. (J Vasc Surg 2021;73:210-21.)
|
|
| 10. |
- Janko, Matthew R., et al.
(författare)
-
In-situ bypass is associated with superior infection-free survival compared with extra-anatomic bypass for the management of secondary aortic graft infections without enteric involvement
- 2022
-
Ingår i: Journal of Vascular Surgery. - : Elsevier. - 0741-5214 .- 1097-6809. ; 76:2, s. 546-
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: The optimal revascularization modality following complete resection of aortic graft infection (AGI) without enteric involvement remains unclear. The purpose of this investigation is to determine the revascularization approach associated with the lowest morbidity and mortality using real-world data in patients undergoing complete excision of AGI. Methods: A retrospective, multi-institutional study of AGI from 2002 to 2014 was performed using a standardized database. Baseline demographics, comorbidities, and perioperative variables were recorded. The primary outcome was infection-free survival. Descriptive statistics, Kaplan-Meier survival analysis, and univariate and multivariable analyses were performed. Results: A total of 241 patients at 34 institutions from seven countries presented with AGI during the study period (median age, 68 years; 75% male). The initial aortic procedures that resulted in AGI were 172 surgical grafts (71%), 66 endografts (27%), and three unknown (2%). Of the patients, 172 (71%) underwent complete excision of infected aortic graft material followed by in situ (in-line) bypass (ISB), including antibiotic-treated prosthetic graft (35%), autogenous femoral vein (neo-aortoiliac surgery) (24%), and cryopreserved allograft (41%). Sixty-nine patients (29%) underwent extra-anatomic bypass (EAB). Overall median Kaplan-Meier estimated survival was 5.8 years. Perioperative mortality was 16%. When stratified by ISB vs EAB, there was a significant difference in Kaplan-Meier estimated infection-free survival (2910 days; interquartile range, 391-3771 days vs 180 days; interquartile range, 27-3750 days; P <.001). There were otherwise no significant differences in presentation, comorbidities, or perioperative variables. Multivariable Cox regression showed lower infection-free survival among patients with EAB (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.6-3.6; P <.001), polymicrobial infection (HR, 2.2; 95% CI, 1.4-3.5; P = .001), methicillin-resistant Staphylococcus aureus infection (HR, 1.7; 95% CI, 1.1-2.7; P = .02), as well as the protective effect of omental/muscle flap coverage (HR, 0.59; 95% CI, 0.37-0.92; P = .02). Conclusions: After complete resection of AGI, perioperative mortality is 16% and median overall survival is 5.8 years. EAB is associated with nearly a two and one-half-fold higher reinfection/mortality compared with ISB. Omental and/or muscle flap coverage of the repair appear protective.
|
|
| 11. |
- Magnusson, Charlotte, et al.
(författare)
-
Stroke and universal design
- 2018
-
Ingår i: Transforming our World Through Design, Diversity and Education - Proceedings of Universal Design and Higher Education in Transformation Congress 2018. - 1879-8365 .- 0926-9630. - 9781614999225 ; 256, s. 854-861
-
Konferensbidrag (refereegranskat)abstract
- Universal Design (UD) is usually stated to be “for all ages and abilities”. Given that stroke is a major source of disability, it is important that UD recommendations take stroke-specific problems into account. Within the framework of EU project STARR, we have investigated user requirements of stroke survivors. In this project we have used a mix of interviews, focus groups, design workshops and technology tests to come up with a set of design recommendations, which we present as a first step towards universal design recommendations which are inclusive for stroke survivors. Our general recommendations are: make it fun, do not make people fail, empower and encourage. The technology needs to be highly adaptable to different sets of abilities. Safety, but also aesthetics and simplicity is important, but it is pointed out that designs should not be “childish” – this can be felt to be degrading. It is important to be able to see and follow your progress and win small victories often. Consider social applications and activities –being able to connect to others in the same situation can enable discussions and provide peer support. More stroke consequence specific recommendations are to design to allow one-sided use (hemiplegia), avoid sensory and activity overload (fatigue), complement speech with images (aphasia), limit demand on memory, support learning and avoid errors (memory problems), and include multiple modalities in your design (reduced vision or hearing).
|
|
| 12. |
- Rassmus-Gröhn, Kirsten, et al.
(författare)
-
Conjuring up new technology – using magic objects in co-ideation with stroke survivors
- 2017
-
Ingår i: AAATE conference proceedings. - 9781614997979 - 9781614997986 ; 242, s. 429-436
-
Konferensbidrag (refereegranskat)abstract
- Ideation means to generate ideas, and when involving non-designers in these activities they need to be informed about the scope of the possibilities without limiting their imagination. This is a general challenge, which becomes particularly important when it comes to advanced technology ideation together with participants that may not have in-depth knowledge of technological designs and solutions. In this study, we supported the ideation process by presenting a kit of magic objects (consisting of cards and physical props) to stroke survivors participating in a co-design workshop carried out within the STARR EU project. The kit was seen to generally work well, but improvements are suggested for the introduction, the design of the cards and the number of objects used.
|
|
| 13. |
- Slemmon, J Randall, et al.
(författare)
-
Impact of cerebrospinal fluid matrix on the detection of Alzheimer's disease with Aβ42 and influence of disease on the total-Aβ42/Aβ40 ratio.
- 2015
-
Ingår i: Journal of neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 135:5, s. 1049-1058
-
Tidskriftsartikel (refereegranskat)abstract
- The 42 amino acid fragment of amyloid β (Aβ1-42) in cerebrospinal fluid (CSF) has continued to be important for detecting cerebral β-amyloidosis in Alzheimer's disease (AD). However, there are impediments to our ability to fully understand this measurement, including matrix interference and changes linked to APOE ε4 genotype. The current study investigated matrix interference as a contributing factor for detecting AD in APOE ε4-negative patients by comparing total extractable Aβ1-42 to free Aβ1-42. It also examined the ratio of total Aβ1-42 to Aβ1-40, since changes relative to other Aβ peptides may provide a measurement of cerebral β-amyloidosis that is neutral to changes in APP metabolism. Total Aβ1-42 lost diagnostic power for detecting AD, confirming a role for matrix in the diagnostic. However, when total Aβ1-42/Aβ1-40 was examined, the separation between groups was reestablished. This result was confirmed in a second sample set of unknown APOE status. These results confirmed that matrix interference in some CSF samples appears to contribute to identifying AD patients and this can be compensated by using a total extracted Aβ1-42/Aβ1-40 ratio when matrix interference is small. It may be preferable to employ a total Aβ1-42/Aβ1-40 measurement, since this could minimize variability due to matrix and compensate for across patient differences. This article is protected by copyright. All rights reserved.
|
|
| 14. |
- Stephens, Lucas, et al.
(författare)
-
Archaeological assessment reveals Earth’s early transformation through land use
- 2019
-
Ingår i: Science. - : American Association for the Advancement of Science. - 0036-8075 .- 1095-9203. ; 365:6456, s. 897-902
-
Tidskriftsartikel (refereegranskat)abstract
- Humans began to leave lasting impacts on Earth’s surface starting 10,000 to 8000 years ago. Through a synthetic collaboration with archaeologists around the globe, Stephens et al. compiled a comprehensive picture of the trajectory of human land use worldwide during the Holocene (see the Perspective by Roberts). Hunter-gatherers, farmers, and pastoralists transformed the face of Earth earlier and to a greater extent than has been widely appreciated, a transformation that was essentially global by 3000 years before the present.Science, this issue p. 897; see also p. 865Environmentally transformative human use of land accelerated with the emergence of agriculture, but the extent, trajectory, and implications of these early changes are not well understood. An empirical global assessment of land use from 10,000 years before the present (yr B.P.) to 1850 CE reveals a planet largely transformed by hunter-gatherers, farmers, and pastoralists by 3000 years ago, considerably earlier than the dates in the land-use reconstructions commonly used by Earth scientists. Synthesis of knowledge contributed by more than 250 archaeologists highlighted gaps in archaeological expertise and data quality, which peaked for 2000 yr B.P. and in traditionally studied and wealthier regions. Archaeological reconstruction of global land-use history illuminates the deep roots of Earth’s transformation and challenges the emerging Anthropocene paradigm that large-scale anthropogenic global environmental change is mostly a recent phenomenon.
|
|
| 15. |
- Wang, Li-San, et al.
(författare)
-
Rarity of the Alzheimer Disease-Protective APP A673T Variant in the United States.
- 2015
-
Ingår i: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 72:2
-
Tidskriftsartikel (refereegranskat)abstract
- Recently, a rare variant in the amyloid precursor protein gene (APP) was described in a population from Iceland. This variant, in which alanine is replaced by threonine at position 673 (A673T), appears to protect against late-onset Alzheimer disease (AD). We evaluated the frequency of this variant in AD cases and cognitively normal controls to determine whether this variant will significantly contribute to risk assessment in individuals in the United States.
|
|
