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| 2. |
- Librado, P., et al.
(author)
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The origins and spread of domestic horses from the Western Eurasian steppes
- 2021
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 598, s. 634-640
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Journal article (peer-reviewed)abstract
- Analysis of 273 ancient horse genomes reveals that modern domestic horses originated in the Western Eurasian steppes, especially the lower Volga-Don region. Domestication of horses fundamentally transformed long-range mobility and warfare(1). However, modern domesticated breeds do not descend from the earliest domestic horse lineage associated with archaeological evidence of bridling, milking and corralling(2-4) at Botai, Central Asia around 3500 bc(3). Other longstanding candidate regions for horse domestication, such as Iberia(5) and Anatolia(6), have also recently been challenged. Thus, the genetic, geographic and temporal origins of modern domestic horses have remained unknown. Here we pinpoint the Western Eurasian steppes, especially the lower Volga-Don region, as the homeland of modern domestic horses. Furthermore, we map the population changes accompanying domestication from 273 ancient horse genomes. This reveals that modern domestic horses ultimately replaced almost all other local populations as they expanded rapidly across Eurasia from about 2000 bc, synchronously with equestrian material culture, including Sintashta spoke-wheeled chariots. We find that equestrianism involved strong selection for critical locomotor and behavioural adaptations at the GSDMC and ZFPM1 genes. Our results reject the commonly held association(7) between horseback riding and the massive expansion of Yamnaya steppe pastoralists into Europe around 3000 bc(8,9) driving the spread of Indo-European languages(10). This contrasts with the scenario in Asia where Indo-Iranian languages, chariots and horses spread together, following the early second millennium bc Sintashta culture(11,12).
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| 3. |
- Brevini, T, et al.
(author)
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FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2
- 2023
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 615:7950, s. 134-
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Journal article (peer-reviewed)abstract
- Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2)1, could represent a new chemoprophylactic approach for COVID-19 that complements vaccination2,3. However, the mechanisms that control the expression of ACE2 remain unclear. Here we show that the farnesoid X receptor (FXR) is a direct regulator of ACE2 transcription in several tissues affected by COVID-19, including the gastrointestinal and respiratory systems. We then use the over-the-counter compound z-guggulsterone and the off-patent drug ursodeoxycholic acid (UDCA) to reduce FXR signalling and downregulate ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. We show that the UDCA-mediated downregulation of ACE2 reduces susceptibility to SARS-CoV-2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. Furthermore, we reveal that UDCA reduces the expression of ACE2 in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes after SARS-CoV-2 infection using retrospective registry data, and confirm these findings in an independent validation cohort of recipients of liver transplants. In conclusion, we show that FXR has a role in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, paving the way for future clinical trials.
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| 4. |
- Chambers, Josephine M., et al.
(author)
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Co-productive agility and four collaborative pathways to sustainability transformations
- 2022
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In: Global Environmental Change. - : Elsevier BV. - 0959-3780 .- 1872-9495. ; 72
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Journal article (peer-reviewed)abstract
- Co-production, the collaborative weaving of research and practice by diverse societal actors, is argued to play an important role in sustainability transformations. Yet, there is still poor understanding of how to navigate the tensions that emerge in these processes. Through analyzing 32 initiatives worldwide that co-produced knowledge and action to foster sustainable social-ecological relations, we conceptualize 'co-productive agility' as an emergent feature vital for turning tensions into transformations. Co-productive agility refers to the willingness and ability of diverse actors to iteratively engage in reflexive dialogues to grow shared ideas and actions that would not have been possible from the outset. It relies on embedding knowledge production within processes of change to constantly recognize, reposition, and navigate tensions and opportunities. Co-productive agility opens up multiple pathways to transformation through: (1) elevating marginalized agendas in ways that maintain their integrity and broaden struggles for justice; (2) questioning dominant agendas by engaging with power in ways that challenge assumptions, (3) navigating conflicting agendas to actively transform interlinked paradigms, practices, and structures; (4) exploring diverse agendas to foster learning and mutual respect for a plurality of perspectives. We explore six process considerations that vary by these four pathways and provide a framework to enable agility in sustainability transformations. We argue that research and practice spend too much time closing down debate over different agendas for change - thereby avoiding, suppressing, or polarizing tensions, and call for more efforts to facilitate better interactions among different agendas.
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| 5. |
- Chambers, Josephine M., et al.
(author)
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Six modes of co-production for sustainability
- 2021
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In: Nature Sustainability. - : Springer Science and Business Media LLC. - 2398-9629. ; 4, s. 983-996
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Journal article (peer-reviewed)abstract
- Co-production includes diverse aims, terminologies and practices. This study explores such diversity by mapping differences in how 32 initiatives from 6 continents co-produce diverse outcomes for the sustainable development of ecosystems at local to global scales. The promise of co-production to address complex sustainability challenges is compelling. Yet, co-production, the collaborative weaving of research and practice, encompasses diverse aims, terminologies and practices, with poor clarity over their implications. To explore this diversity, we systematically mapped differences in how 32 initiatives from 6 continents co-produce diverse outcomes for the sustainable development of ecosystems at local to global scales. We found variation in their purpose for utilizing co-production, understanding of power, approach to politics and pathways to impact. A cluster analysis identified six modes of co-production: (1) researching solutions; (2) empowering voices; (3) brokering power; (4) reframing power; (5) navigating differences and (6) reframing agency. No mode is ideal; each holds unique potential to achieve particular outcomes, but also poses unique challenges and risks. Our analysis provides a heuristic tool for researchers and societal actors to critically explore this diversity and effectively navigate trade-offs when co-producing sustainability.
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| 6. |
- Peterziel, H, et al.
(author)
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Drug sensitivity profiling of 3D tumor tissue cultures in the pediatric precision oncology program INFORM
- 2022
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In: NPJ precision oncology. - : Springer Science and Business Media LLC. - 2397-768X. ; 6:1, s. 94-
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Journal article (peer-reviewed)abstract
- The international precision oncology program INFORM enrolls relapsed/refractory pediatric cancer patients for comprehensive molecular analysis. We report a two-year pilot study implementing ex vivo drug sensitivity profiling (DSP) using a library of 75–78 clinically relevant drugs. We included 132 viable tumor samples from 35 pediatric oncology centers in seven countries. DSP was conducted on multicellular fresh tumor tissue spheroid cultures in 384-well plates with an overall mean processing time of three weeks. In 89 cases (67%), sufficient viable tissue was received; 69 (78%) passed internal quality controls. The DSP results matched the identified molecular targets, including BRAF, ALK, MET, and TP53 status. Drug vulnerabilities were identified in 80% of cases lacking actionable (very) high-evidence molecular events, adding value to the molecular data. Striking parallels between clinical courses and the DSP results were observed in selected patients. Overall, DSP in clinical real-time is feasible in international multicenter precision oncology programs.
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| 7. |
- Smiseth, Otto A, et al.
(author)
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Multimodality imaging in patients with heart failure and preserved ejection fraction : an expert consensus document of the European Association of Cardiovascular Imaging.
- 2022
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In: European Heart Journal Cardiovascular Imaging. - : Oxford University Press (OUP). - 2047-2404 .- 2047-2412. ; 23:2, s. e34-e61
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Journal article (peer-reviewed)abstract
- Nearly half of all patients with heart failure (HF) have a normal left ventricular (LV) ejection fraction (EF) and the condition is termed heart failure with preserved ejection fraction (HFpEF). It is assumed that in these patients HF is due primarily to LV diastolic dysfunction. The prognosis in HFpEF is almost as severe as in HF with reduced EF (HFrEF). In contrast to HFrEF where drugs and devices are proven to reduce mortality, in HFpEF there has been limited therapy available with documented effects on prognosis. This may reflect that HFpEF encompasses a wide range of different pathological processes, which multimodality imaging is well placed to differentiate. Progress in developing therapies for HFpEF has been hampered by a lack of uniform diagnostic criteria. The present expert consensus document from the European Association of Cardiovascular Imaging (EACVI) provides recommendations regarding how to determine elevated LV filling pressure in the setting of suspected HFpEF and how to use multimodality imaging to determine specific aetiologies in patients with HFpEF.
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| 8. |
- Almeida, Ana G., et al.
(author)
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Multimodality imaging of myocardial viability : an expert consensus document from the European Association of Cardiovascular Imaging (EACVI)
- 2021
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In: European Heart Journal Cardiovascular Imaging. - : Oxford University Press. - 2047-2404 .- 2047-2412. ; 22:8, s. E97-E125
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Journal article (peer-reviewed)abstract
- In clinical decision making, myocardial viability is defined as myocardium in acute or chronic coronary artery disease and other conditions with contractile dysfunction but maintained metabolic and electrical function, having the potential to improve dysfunction upon revascularization or other therapy. Several pathophysiological conditions may coexist to explain this phenomenon. Cardiac imaging may allow identification of myocardial viability through different principles, with the purpose of prediction of therapeutic response and selection for treatment. This expert consensus document reviews current insight into the underlying pathophysiology and available methods for assessing viability. In particular the document reviews contemporary viability imaging techniques, including stress echocardiography, single photon emission computed tomography, positron emission tomography, cardiovascular magnetic resonance, and computed tomography and provides clinical recommendations for how to standardize these methods in terms of acquisition and interpretation. Finally, it presents clinical scenarios where viability assessment is clinically useful.
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| 9. |
- Gerber, Julia P., et al.
(author)
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Aberrant chromatin landscape following loss of the H3.3 chaperone Daxx in haematopoietic precursors leads to Pu.1-mediated neutrophilia and inflammation
- 2021
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In: Nature Cell Biology. - : Springer Science and Business Media LLC. - 1465-7392 .- 1476-4679. ; 23:12, s. 1224-1239
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Journal article (peer-reviewed)abstract
- Defective silencing of retrotransposable elements has been linked to inflammageing, cancer and autoimmune diseases. However, the underlying mechanisms are only partially understood. Here we implicate the histone H3.3 chaperone Daxx, a retrotransposable element repressor inactivated in myeloid leukaemia and other neoplasms, in protection from inflammatory disease. Loss of Daxx alters the chromatin landscape, H3.3 distribution and histone marks of haematopoietic progenitors, leading to engagement of a Pu.1-dependent transcriptional programme for myelopoiesis at the expense of B-cell differentiation. This causes neutrophilia and inflammation, predisposing mice to develop an autoinflammatory skin disease. While these molecular and phenotypic perturbations are in part reverted in animals lacking both Pu.1 and Daxx, haematopoietic progenitors in these mice show unique chromatin and transcriptome alterations, suggesting an interaction between these two pathways. Overall, our findings implicate retrotransposable element silencing in haematopoiesis and suggest a cross-talk between the H3.3 loading machinery and the pioneer transcription factor Pu.1.
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