Integrin β1 cluster stability in the context of cellular mechanosensing and radiosensitivity

The cellular interaction with the extracellular matrix (ECM) modulates many key processes such as proliferation, migration, differentiation and survival. In addition, resistance to ionizing radiation has been found to be higher in cells cultured in presence of a 3D matrix, a process, which has been termed cell-adhesion mediated radio-resistance (CAM-RR). These cells are able to properly organize ECM-binding (extracellular matrix) integrins containing a β1 subunit into firm and stable clusters. Upon irradiation, these clusters are hard to break. On the contrary, cells cultured under standard, monolayer-based conditions are unable to keep this clustered status and are therefore radiosensitive. Radioresistance is thus linked to the ability to maintain a well defined organization of integrins in clusters, making integrin distribution a potential drug target for radiosensitization. With the use of the integrin β1 inhibitory antibody AIIB2, a well-known radiosensitizer, it is possible to induce radiosensitivity and in combination with ionizing radiation (IR) to break integrin β1 clusters of 3D cultured cells. In 2D cultured cells the treatment with AIIB2 completely abolished integrin clustering. As integrins are the key mediators of cell adhesion and mechanosensing, they originate the molecular signaling towards chromatin remodeling in response to a cell’s microenvironment. By following the physical link from integrins up to the nucleus with single molecule localization microscopy, it was found that the disintegration of integrin clusters has a direct impact on this nuclear mechanosensor. Collectively, these results show that, in addition to biochemical also mechanobiological cues and in particular nuclear mechanosensing have to be considered as relevant to uncover the molecular events behind adhesion related radiosensitivity. Therein, 2D cultured cells are highly artificial and do not provide the means to investigate mechanobiological aspects. Not only the involvement of ECM-binding integrins in radioresistance of various tumor types makes them an important target in actual cancer studies, they also contribute to drugresistance, metastasis and angiogenesis. So far, the vast majority of high-content screenings (HCS) use flat cultured, highly artificial monolayer-based 2D cells and standard microscopy techniques. The here achieved results prove that 3D cell cultures and single molecule microscopy are powerful tools for preclinical screenings. It would be possible to combine the virtues of microscopy of the nanoscale with the capability of 3D cultured cells to enhance the predictive value of high-content-screenings (HCS)

Demonstration of Hong-Ou-Mandel interference in an LNOI directional coupler

Interference between single photons is key for many quantum optics experiments and applications in quantum technologies, such as quantum communication or computation. It is advantageous to operate the systems at telecommunication wavelengths and to integrate the setups for these applications in order to improve stability, compactness and scalability. A new promising material platform for integrated quantum optics is lithium niobate on insulator (LNOI). Here, we realise Hong-Ou-Mandel (HOM) interference between telecom photons from an engineered parametric down-conversion source in an LNOI directional coupler. The coupler has been designed and fabricated in house and provides close to perfect balanced beam splitting. We obtain a raw HOM visibility of (93.5+/-0.7)%, limited mainly by the source performance and in good agreement with off-chip measurements. This lays the foundation for more sophisticated quantum experiments in LNOIComment: 7 pages, 6 figure

Diverse perspectives on interdisciplinarity from Members of the College of the Royal Society of Canada

Various multiple-disciplinary terms and concepts (although most commonly interdisciplinarity, which is used herein) are used to frame education, scholarship, research, and interactions within and outside academia. In principle, the premise of interdisciplinarity may appear to have many strengths; yet, the extent to which interdisciplinarity is embraced by the current generation of academics, the benefits and risks for doing so, and the barriers and facilitators to achieving interdisciplinarity, represent inherent challenges. Much has been written on the topic of interdisciplinarity, but to our knowledge there have been few attempts to consider and present diverse perspectives from scholars, artists, and scientists in a cohesive manner. As a team of 57 members from the Canadian College of New Scholars, Artists, and Scientists of the Royal Society of Canada (the College) who self-identify as being engaged or interested in interdisciplinarity, we provide diverse intellectual, cultural, and social perspectives. The goal of this paper is to share our collective wisdom on this topic with the broader community and to stimulate discourse and debate on the merits and challenges associated with interdisciplinarity. Perhaps the clearest message emerging from this exercise is that working across established boundaries of scholarly communities is rewarding, necessary, and is more likely to result in impact. However, there are barriers that limit the ease with which this can occur (e.g., lack of institutional structures and funding to facilitate cross-disciplinary exploration). Occasionally, there can be significant risk associated with doing interdisciplinary work (e.g., lack of adequate measurement or recognition of work by disciplinary peers). Solving many of the world\u27s complex and pressing problems (e.g., climate change, sustainable agriculture, the burden of chronic disease, and aging populations) demands thinking and working across long-standing, but in some ways restrictive, academic boundaries. Academic institutions and key support structures, especially funding bodies, will play an important role in helping to realize what is readily apparent to all who contributed to this paper-that interdisciplinarity is essential for solving complex problems; it is the new norm. Failure to empower and encourage those doing this research will serve as a great impediment to training, knowledge, and addressing societal issues

The crustal domains of the Alboran Basin (Western Mediterranean)

The Alboran Basin in the westernmost Mediterranean hosts the orogenic boundary between the Iberian and African plates. Although numerous geophysical studies of crustal structure onshore Iberia have been carried out during the last decade, the crustal structure of the Alboran Basin has comparatively been poorly studied. We analyze crustal‐scale images of a grid of new and reprocessed multichannel seismic profiles showing the tectonic structure and variations in the reflective character of the crust of the basin. The nature of the distinct domains has been ground‐truthed using available basement samples from drilling and dredging. Our results reveal four different crustal types ‐domains‐ of the Alboran Basin: a) a thin continental crust underneath the West Alboran and Malaga basins, which transitions to b) a magmatic arc crust in the central part of the Alboran Sea and the East Alboran Basin, c) the North‐African continental crust containing the Pytheas and Habibas sub‐basins, and d) the oceanic crust in the transition towards the Algero‐Balearic Basin. The Alboran Basin crust is configured in a fore‐arc basin (West Alboran and Malaga basins), a magmatic arc (central and East Alboran), and a back‐arc system in the easternmost part of the East Alboran Basin and mainly Algero‐Balearic Basin. The North‐African continental crust is influenced by arc‐related magmatism along its edge, and was probably affected by strike‐slip tectonics during westward migration of the Miocene subduction system. The distribution of active tectonic structures in the current compressional setting generally corresponds to boundaries between domains, possibly representing inherited lithospheric‐scale weak structures

Diverse perspectives on interdisciplinarity from the Members of the College of the Royal Society of Canada

Various multiple-disciplinary terms and concepts (although most commonly “interdisciplinarity”, which is used herein) are used to frame education, scholarship, research, and interactions within and outside academia. In principle, the premise of interdisciplinarity may appear to have many strengths; yet, the extent to which interdisciplinarity is embraced by the current generation of academics, the benefits and risks for doing so, and the barriers and facilitators to achieving interdisciplinarity represent inherent challenges. Much has been written on the topic of interdisciplinarity, but to our knowledge there have been few attempts to consider and present diverse perspectives from scholars, artists, and scientists in a cohesive manner. As a team of 57 members from the Canadian College of New Scholars, Artists, and Scientists of the Royal Society of Canada (the College) who self-identify as being engaged or interested in interdisciplinarity, we provide diverse intellectual, cultural, and social perspectives. The goal of this paper is to share our collective wisdom on this topic with the broader community and to stimulate discourse and debate on the merits and challenges associated with interdisciplinarity. Perhaps the clearest message emerging from this exercise is that working across established boundaries of scholarly communities is rewarding, necessary, and is more likely to result in impact. However, there are barriers that limit the ease with which this can occur (e.g., lack of institutional structures and funding to facilitate cross-disciplinary exploration). Occasionally, there can be significant risk associated with doing interdisciplinary work (e.g., lack of adequate measurement or recognition of work by disciplinary peers). Solving many of the world’s complex and pressing problems (e.g., climate change, sustainable agriculture, the burden of chronic disease, and aging populations) demand thinking and working across long-standing, but in some ways restrictive, academic boundaries. Academic institutions and key support structures, especially funding bodies, will play an important role in helping to realize what is readily apparent to all who contributed to this paper—that interdisciplinarity is essential for solving complex problems; it is the new norm. Failure to empower and encourage those doing this research will serve as a great impediment to training, knowledge, and addressing societal issues

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Understanding, diagnosing, and treating Myalgic encephalomyelitis/chronic fatigue syndrome - State of the art: Report of the 2nd international meeting at the Charité fatigue center.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a devastating disease affecting millions of people worldwide. Due to the 2019 pandemic of coronavirus disease (COVID-19), we are facing a significant increase of ME/CFS prevalence. On May 11th to 12th, 2023, the second international ME/CFS conference of the Charité Fatigue Center was held in Berlin, Germany, focusing on pathomechanisms, diagnosis, and treatment. During the two-day conference, more than 100 researchers from various research fields met on-site and over 700 attendees participated online to discuss the state of the art and novel findings in this field. Key topics from the conference included: the role of the immune system, dysfunction of endothelial and autonomic nervous system, and viral reactivation. Furthermore, there were presentations on innovative diagnostic measures and assessments for this complex disease, cutting-edge treatment approaches, and clinical studies. Despite the increased public attention due to the COVID-19 pandemic, the subsequent rise of Long COVID-19 cases, and the rise of funding opportunities to unravel the pathomechanisms underlying ME/CFS, this severe disease remains highly underresearched. Future adequately funded research efforts are needed to further explore the disease etiology and to identify diagnostic markers and targeted therapies

Integrin β1 cluster stability in the context of cellular mechanosensing and radiosensitivity

The cellular interaction with the extracellular matrix (ECM) modulates many key processes such as proliferation, migration, differentiation and survival. In addition, resistance to ionizing radiation has been found to be higher in cells cultured in presence of a 3D matrix, a process, which has been termed cell-adhesion mediated radio-resistance (CAM-RR). These cells are able to properly organize ECM-binding (extracellular matrix) integrins containing a β1 subunit into firm and stable clusters. Upon irradiation, these clusters are hard to break. On the contrary, cells cultured under standard, monolayer-based conditions are unable to keep this clustered status and are therefore radiosensitive. Radioresistance is thus linked to the ability to maintain a well defined organization of integrins in clusters, making integrin distribution a potential drug target for radiosensitization. With the use of the integrin β1 inhibitory antibody AIIB2, a well-known radiosensitizer, it is possible to induce radiosensitivity and in combination with ionizing radiation (IR) to break integrin β1 clusters of 3D cultured cells. In 2D cultured cells the treatment with AIIB2 completely abolished integrin clustering. As integrins are the key mediators of cell adhesion and mechanosensing, they originate the molecular signaling towards chromatin remodeling in response to a cell’s microenvironment. By following the physical link from integrins up to the nucleus with single molecule localization microscopy, it was found that the disintegration of integrin clusters has a direct impact on this nuclear mechanosensor. Collectively, these results show that, in addition to biochemical also mechanobiological cues and in particular nuclear mechanosensing have to be considered as relevant to uncover the molecular events behind adhesion related radiosensitivity. Therein, 2D cultured cells are highly artificial and do not provide the means to investigate mechanobiological aspects. Not only the involvement of ECM-binding integrins in radioresistance of various tumor types makes them an important target in actual cancer studies, they also contribute to drugresistance, metastasis and angiogenesis. So far, the vast majority of high-content screenings (HCS) use flat cultured, highly artificial monolayer-based 2D cells and standard microscopy techniques. The here achieved results prove that 3D cell cultures and single molecule microscopy are powerful tools for preclinical screenings. It would be possible to combine the virtues of microscopy of the nanoscale with the capability of 3D cultured cells to enhance the predictive value of high-content-screenings (HCS)

Integrin β1 cluster stability in the context of cellular mechanosensing and radiosensitivity

The cellular interaction with the extracellular matrix (ECM) modulates many key processes such as proliferation, migration, differentiation and survival. In addition, resistance to ionizing radiation has been found to be higher in cells cultured in presence of a 3D matrix, a process, which has been termed cell-adhesion mediated radio-resistance (CAM-RR). These cells are able to properly organize ECM-binding (extracellular matrix) integrins containing a β1 subunit into firm and stable clusters. Upon irradiation, these clusters are hard to break. On the contrary, cells cultured under standard, monolayer-based conditions are unable to keep this clustered status and are therefore radiosensitive. Radioresistance is thus linked to the ability to maintain a well defined organization of integrins in clusters, making integrin distribution a potential drug target for radiosensitization. With the use of the integrin β1 inhibitory antibody AIIB2, a well-known radiosensitizer, it is possible to induce radiosensitivity and in combination with ionizing radiation (IR) to break integrin β1 clusters of 3D cultured cells. In 2D cultured cells the treatment with AIIB2 completely abolished integrin clustering. As integrins are the key mediators of cell adhesion and mechanosensing, they originate the molecular signaling towards chromatin remodeling in response to a cell’s microenvironment. By following the physical link from integrins up to the nucleus with single molecule localization microscopy, it was found that the disintegration of integrin clusters has a direct impact on this nuclear mechanosensor. Collectively, these results show that, in addition to biochemical also mechanobiological cues and in particular nuclear mechanosensing have to be considered as relevant to uncover the molecular events behind adhesion related radiosensitivity. Therein, 2D cultured cells are highly artificial and do not provide the means to investigate mechanobiological aspects. Not only the involvement of ECM-binding integrins in radioresistance of various tumor types makes them an important target in actual cancer studies, they also contribute to drugresistance, metastasis and angiogenesis. So far, the vast majority of high-content screenings (HCS) use flat cultured, highly artificial monolayer-based 2D cells and standard microscopy techniques. The here achieved results prove that 3D cell cultures and single molecule microscopy are powerful tools for preclinical screenings. It would be possible to combine the virtues of microscopy of the nanoscale with the capability of 3D cultured cells to enhance the predictive value of high-content-screenings (HCS)

Integrin β1 cluster stability in the context of cellular mechanosensing and radiosensitivity

The cellular interaction with the extracellular matrix (ECM) modulates many key processes such as proliferation, migration, differentiation and survival. In addition, resistance to ionizing radiation has been found to be higher in cells cultured in presence of a 3D matrix, a process, which has been termed cell-adhesion mediated radio-resistance (CAM-RR). These cells are able to properly organize ECM-binding (extracellular matrix) integrins containing a β1 subunit into firm and stable clusters. Upon irradiation, these clusters are hard to break. On the contrary, cells cultured under standard, monolayer-based conditions are unable to keep this clustered status and are therefore radiosensitive. Radioresistance is thus linked to the ability to maintain a well defined organization of integrins in clusters, making integrin distribution a potential drug target for radiosensitization. With the use of the integrin β1 inhibitory antibody AIIB2, a well-known radiosensitizer, it is possible to induce radiosensitivity and in combination with ionizing radiation (IR) to break integrin β1 clusters of 3D cultured cells. In 2D cultured cells the treatment with AIIB2 completely abolished integrin clustering. As integrins are the key mediators of cell adhesion and mechanosensing, they originate the molecular signaling towards chromatin remodeling in response to a cell’s microenvironment. By following the physical link from integrins up to the nucleus with single molecule localization microscopy, it was found that the disintegration of integrin clusters has a direct impact on this nuclear mechanosensor. Collectively, these results show that, in addition to biochemical also mechanobiological cues and in particular nuclear mechanosensing have to be considered as relevant to uncover the molecular events behind adhesion related radiosensitivity. Therein, 2D cultured cells are highly artificial and do not provide the means to investigate mechanobiological aspects. Not only the involvement of ECM-binding integrins in radioresistance of various tumor types makes them an important target in actual cancer studies, they also contribute to drugresistance, metastasis and angiogenesis. So far, the vast majority of high-content screenings (HCS) use flat cultured, highly artificial monolayer-based 2D cells and standard microscopy techniques. The here achieved results prove that 3D cell cultures and single molecule microscopy are powerful tools for preclinical screenings. It would be possible to combine the virtues of microscopy of the nanoscale with the capability of 3D cultured cells to enhance the predictive value of high-content-screenings (HCS)