Angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 and the pathophysiology of coronavirus disease 2019 (COVID-19)

Angiotensin‐converting enzyme‐2 (ACE2) has been established as the functional host receptor for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the virus responsible for the current devastating worldwide pandemic of coronavirus disease 2019 (COVID‐19). ACE2 is abundantly expressed in a variety of cells residing in many different human organs. In human physiology, ACE2 is a pivotal counter‐regulatory enzyme to ACE by the breakdown of angiotensin II, the central player in the renin‐angiotensin‐aldosterone system (RAAS) and the main substrate of ACE2. Many factors have been associated with both altered ACE2 expression and COVID‐19 severity and progression, including age, sex, ethnicity, medication and several co‐morbidities, such as cardiovascular disease and metabolic syndrome. Although ACE2 is widely distributed in various human tissues and many of its determinants have been well recognised, ACE2‐expressing organs do not equally participate in COVID‐19 pathophysiology, implying that other mechanisms are involved in orchestrating cellular infection resulting in tissue damage. Reports of pathologic findings in tissue specimens of COVID‐19 patients are rapidly emerging and confirm the established role of ACE2 expression and activity in disease pathogenesis. Identifying pathologic changes caused by SARS‐CoV‐2 infection is crucially important as it has major implications for understanding COVID‐19 pathophysiology and the development of evidence‐based treatment strategies. Currently, many interventional strategies are being explored in ongoing clinical trials, encompassing many drug classes and strategies, including antiviral drugs, biological response modifiers and RAAS inhibitors. Ultimately, prevention is key to combat COVID‐19 and appropriate measures are being taken accordingly, including development of effective vaccines. In this review, we describe the role of ACE2 in COVID‐19 pathophysiology, including factors influencing ACE2 expression and activity in relation to COVID‐19 severity. In addition, we discuss the relevant pathological changes resulting from SARS‐CoV‐2 infection. Finally, we highlight a selection of potential treatment modalities for COVID‐19

A global agenda for advancing freshwater biodiversity research

Global freshwater biodiversity is declining dramatically, and meeting the challenges of this crisis requires bold goals and the mobilisation of substantial resources. While the reasons are varied, investments in both research and conservation of freshwater biodiversity lag far behind those in the terrestrial and marine realms. Inspired by a global consultation, we identify 15 pressing priority needs, grouped into five research areas, in an effort to support informed stewardship of freshwater biodiversity. The proposed agenda aims to advance freshwater biodiversity research globally as a critical step in improving coordinated actions towards its sustainable management and conservation

A global agenda for advancing freshwater biodiversity research

Global freshwater biodiversity is declining dramatically, and meeting the challenges of this crisis requires bold goals and the mobilisation of substantial resources. While the reasons are varied, investments in both research and conservation of freshwater biodiversity lag far behind those in the terrestrial and marine realms. Inspired by a global consultation, we identify 15 pressing priority needs, grouped into five research areas, in an effort to support informed stewardship of freshwater biodiversity. The proposed agenda aims to advance freshwater biodiversity research globally as a critical step in improving coordinated actions towards its sustainable management and conservation.Peer reviewe

Taxonomy based on science is necessary for global conservation

Peer reviewe

Know thine enemy: intra-sexual selection and sympatric speciation in Lake Victoria cichlid fish

Speciation by sexual selection research has traditionally concentrated on mechanisms for divergence driven via female mate choice (intersexual selection). The pivotal role of competition between members of the same sex (intrasexual selection) has been largely overlooked. In this thesis, I describe a series of experimental studies investigating the role of intrasexual selection in sympatric divergence, using Lake Victoria haplochromine cichlid fish as a model system. Such experiments are needed, as only indirect or descriptive support exists for the hypothesis of male-male competition facilitating sympatric divergence. I also investigate color expression as a result of male-male competition, and ask if the intensity of sexual signaling provides information about the genetic quality of the bearer. Speciation theory suggests that ‘good genes’ mechanism of female mate choice are less likely to drive (sympatric) speciation than purely divergent Fisherian runaway selection (Lande 1981; Payne & Krakauer 1997; Turner & Burrows 1995; Van Doorn et al. 1998; 2004). Under Fisherian runaway selection, population bifurcation may proceed in arbitrary directions, whereas ‘good genes’ sexual selection is less arbritary, leading to the evolution of only those male traits that reliably indicate genetic quality. Identifying the mechanisms that cause sexual selection in haplochromines has important implications for our understanding of sympatric speciation. In chapter 2-7 I studied two recently diverged, ecologically and anatomically similar sympatric cichlid species pairs consisting of P. Pundamilia (Seehausen et al. 1998a) with blue and P. nyererei (Witte-Maas & Witte 1985) with red nuptial coloration. In chapter 3 I also use P. ‘pink anal’ (Seehausen 1996) as a representative of a Pundamilia species with blue nuptial coloration. Red and blue phenotypes are anatomically similar forms that behave like reproductively isolated species in some locations, and like hybridizing incipient species in other locations (Seehausen 1996; Seehausen et al. 1997). Blue phenotypes have a lake-wide distribution whereas red phenotypes have a patchy distribution and always co-occur with blue phenotypes. The blue form has the highest record of sympatric occurrences with other members of the Pundamilia complex (Seehausen 1996; Seehausen & Van Alphen 1999). It seems hence likely that blue represents the ancestral state and that blue populations have been invaded repeatedly and independently by red morphs during speciation (Seehausen 1997; Seehausen & Van Alphen 1999; Seehausen & Schluter 2004). The different populations of Pundamilia were taken as different speciation stages, beginning with an entirely blue population where red males had not been able to gain a foothold yet, to populations where red and blue are hybridizing incipient species, and finally to populations where speciation has been completed with reproductively isolated red and blue species. Own-type biases in aggression (chapter 2 and 3) and differences in aggression level (chapter 2) were measured in wild-caught Pundamilia males using a simulated intruder choice test. Territorial defenders were presented with red and blue stimulus fish, each enclosed in transparent tubes, mimicking intruding rival males, and recorded the aggressive response of the territorial defender. In chapter 2 light manipulations experiments revealed that aggression preferences are based on color differences, suggesting that color is not only important in mate choice, but also in intrasexual signaling. Following up to this chapter, in chapter 3 I tested in blue Pundamilia fish from six different populations whether aggression bias depends on speciation stage. Color-effects on dominance can be measured by staging dyadic combats, mimicking two males disputing over a vacant territory. In chapter 4, I tested the hypothesis that red coloration confers an advantage in direct combat, assisting red phenotypes to invade. To this end, combats were staged between red and blue males under both white and green light condition that effectively eliminates the color difference. How aggression biases come about in Pundamilia is unclear. Chapter 5 investigates the role of learning and genetics in shaping aggression biases in three populations of blue Pundamilia cichlid species. Males were given prolonged experience with red males or only blue males and subsequently subjected to a simulated intruder choice test.

Reconstructing geographical boundary conditions for palaeoclimate modelling during the Cenozoic

Studies on the palaeoclimate and palaeoceanography using numerical model simulations may be considerably dependent on the implemented geographical reconstruction. Because building the palaeogeographic datasets for these models is often a time-consuming and elaborate exercise, palaeoclimate models frequently use reconstructions in which the latest state-of-the-art plate tectonic reconstructions, palaeotopography and -bathymetry, or vegetation have not yet been incorporated. In this paper, we therefore provide a new method to efficiently generate a global geographical reconstruction for the middle-late Eocene. The generalised procedure is also reusable to create reconstructions for other time slices within the Cenozoic, suitable for palaeoclimate modelling. We use a plate-tectonic model to make global masks containing the distribution of land, continental shelves, shallow basins and deep ocean. The use of depth-age relationships for oceanic crust together with adjusted present-day topography gives a first estimate of the global geography at a chosen time frame. This estimate subsequently needs manual editing of areas where existing geological data indicate that the altimetry has changed significantly over time. Certain generic changes (e.g. lowering mountain ranges) can be made relatively easily by defining a set of masks while other features may require a more specific treatment. Since the discussion regarding many of these regions is still ongoing, it is crucial to make it easy for changes to be incorporated without having to redo the entire procedure. In this manner, a complete reconstruction can be made that suffices as a boundary condition for numerical models with a limited effort. This facilitates the interaction between experts in geology and palaeoclimate modelling, keeping reconstructions up to date and improving the consistency between different studies. Moreover, it facilitates model inter-comparison studies and sensitivity tests regarding certain geographical features as newly generated boundary conditions can more easily be incorporated in different model simulations. The workflow is presented covering a middle-late Eocene reconstruction (38ĝ€Ma), using a MatLab script and a complete set of source files that are provided in the supplementary material.Applied Geolog

Timely administration of tocilizumab improves outcome of hospitalized COVID-19 patients

Introduction The aim of this study was to determine the efficacy of early tocilizumab treatment for hospitalized patients with COVID-19 disease. Methods Open-label randomized phase II clinical trial investigating tocilizumab in patients with proven COVID-19 admitted to the general ward and in need of supplemental oxygen. The primary endpoint of the study was 30-day mortality with a prespecified 2-sided significance level of α = 0.10. A post-hoc analysis was performed for a combined endpoint of mechanical ventilation or death at 30 days. Secondary objectives included comparing the duration of hospital stay, ICU admittance and duration of ICU stay and the duration of mechanical ventilation. Results A total of 354 patients (67% men; median age 66 years) were enrolled of whom 88% received dexamethasone. Thirty-day mortality was 19% (95% CI 14%-26%) in the standard arm versus 12% (95% CI: 8%-18%) in the tocilizumab arm, hazard ratio (HR) = 0.62 (90% CI 0.39–0.98; p = 0.086). 17% of patients were admitted to the ICU in each arm (p = 0.89). The median stay in the ICU was 14 days (IQR 9–28) in the standard arm versus 9 days (IQR 5–14) in the tocilizumab arm (p = 0.014). Mechanical ventilation or death at thirty days was 31% (95% CI 24%-38%) in the standard arm versus 21% (95% CI 16%-28%) in the tocilizumab arm, HR = 0.65 (95% CI 0.42–0.98; p = 0.042). Conclusions This randomized phase II study supports efficacy for tocilizumab when given early in the disease course in hospitalized patients who need oxygen support, especially when concomitantly treated with dexamethasone

Timely administration of tocilizumab improves outcome of hospitalized COVID-19 patients

INTRODUCTION: The aim of this study was to determine the efficacy of early tocilizumab treatment for hospitalized patients with COVID-19 disease. METHODS: Open-label randomized phase II clinical trial investigating tocilizumab in patients with proven COVID-19 admitted to the general ward and in need of supplemental oxygen. The primary endpoint of the study was 30-day mortality with a prespecified 2-sided significance level of α = 0.10. A post-hoc analysis was performed for a combined endpoint of mechanical ventilation or death at 30 days. Secondary objectives included comparing the duration of hospital stay, ICU admittance and duration of ICU stay and the duration of mechanical ventilation. RESULTS: A total of 354 patients (67% men; median age 66 years) were enrolled of whom 88% received dexamethasone. Thirty-day mortality was 19% (95% CI 14%-26%) in the standard arm versus 12% (95% CI: 8%-18%) in the tocilizumab arm, hazard ratio (HR) = 0.62 (90% CI 0.39-0.98; p = 0.086). 17% of patients were admitted to the ICU in each arm (p = 0.89). The median stay in the ICU was 14 days (IQR 9-28) in the standard arm versus 9 days (IQR 5-14) in the tocilizumab arm (p = 0.014). Mechanical ventilation or death at thirty days was 31% (95% CI 24%-38%) in the standard arm versus 21% (95% CI 16%-28%) in the tocilizumab arm, HR = 0.65 (95% CI 0.42-0.98; p = 0.042). CONCLUSIONS: This randomized phase II study supports efficacy for tocilizumab when given early in the disease course in hospitalized patients who need oxygen support, especially when concomitantly treated with dexamethasone. TRIAL REGISTRATION: https://www.trialregister.nl/trial/8504

Timely administration of tocilizumab improves outcome of hospitalized COVID-19 patients

Introduction The aim of this study was to determine the efficacy of early tocilizumab treatment for hospitalized patients with COVID-19 disease. Methods Open-label randomized phase II clinical trial investigating tocilizumab in patients with proven COVID-19 admitted to the general ward and in need of supplemental oxygen. The primary endpoint of the study was 30-day mortality with a prespecified 2-sided significance level of α = 0.10. A post-hoc analysis was performed for a combined endpoint of mechanical ventilation or death at 30 days. Secondary objectives included comparing the duration of hospital stay, ICU admittance and duration of ICU stay and the duration of mechanical ventilation. Results A total of 354 patients (67% men; median age 66 years) were enrolled of whom 88% received dexamethasone. Thirty-day mortality was 19% (95% CI 14%-26%) in the standard arm versus 12% (95% CI: 8%-18%) in the tocilizumab arm, hazard ratio (HR) = 0.62 (90% CI 0.39–0.98; p = 0.086). 17% of patients were admitted to the ICU in each arm (p = 0.89). The median stay in the ICU was 14 days (IQR 9–28) in the standard arm versus 9 days (IQR 5–14) in the tocilizumab arm (p = 0.014). Mechanical ventilation or death at thirty days was 31% (95% CI 24%-38%) in the standard arm versus 21% (95% CI 16%-28%) in the tocilizumab arm, HR = 0.65 (95% CI 0.42–0.98; p = 0.042). Conclusions This randomized phase II study supports efficacy for tocilizumab when given early in the disease course in hospitalized patients who need oxygen support, especially when concomitantly treated with dexamethasone