A Zebrafish Compound Screen Reveals Modulation of Neutrophil Reverse Migration as an Anti-Inflammatory Mechanism

Diseases of failed inflammation resolution are common and largely incurable. Therapeutic induction of inflammation resolution is an attractive strategy to bring about healing without increasing susceptibility to infection. However, therapeutic targeting of inflammation resolution has been hampered by a lack of understanding of the underlying molecular controls. To address this drug development challenge, we developed an in vivo screen for proresolution therapeutics in a transgenic zebrafish model. Inflammation induced by sterile tissue injury was assessed for accelerated resolution in the presence of a library of known compounds. Of the molecules with proresolution activity, tanshinone IIA, derived from a Chinese medicinal herb, potently induced inflammation resolution in vivo both by induction of neutrophil apoptosis and by promoting reverse migration of neutrophils. Tanshinone IIA blocked proinflammatory signals in vivo, and its effects are conserved in human neutrophils, supporting a potential role in treating human inflammation and providing compelling evidence of the translational potential of this screening strategy

The Cholecystectomy As A Day Case (CAAD) Score: A Validated Score of Preoperative Predictors of Successful Day-Case Cholecystectomy Using the CholeS Data Set

Background Day-case surgery is associated with significant patient and cost benefits. However, only 43% of cholecystectomy patients are discharged home the same day. One hypothesis is day-case cholecystectomy rates, defined as patients discharged the same day as their operation, may be improved by better assessment of patients using standard preoperative variables. Methods Data were extracted from a prospectively collected data set of cholecystectomy patients from 166 UK and Irish hospitals (CholeS). Cholecystectomies performed as elective procedures were divided into main (75%) and validation (25%) data sets. Preoperative predictors were identified, and a risk score of failed day case was devised using multivariate logistic regression. Receiver operating curve analysis was used to validate the score in the validation data set. Results Of the 7426 elective cholecystectomies performed, 49% of these were discharged home the same day. Same-day discharge following cholecystectomy was less likely with older patients (OR 0.18, 95% CI 0.15–0.23), higher ASA scores (OR 0.19, 95% CI 0.15–0.23), complicated cholelithiasis (OR 0.38, 95% CI 0.31 to 0.48), male gender (OR 0.66, 95% CI 0.58–0.74), previous acute gallstone-related admissions (OR 0.54, 95% CI 0.48–0.60) and preoperative endoscopic intervention (OR 0.40, 95% CI 0.34–0.47). The CAAD score was developed using these variables. When applied to the validation subgroup, a CAAD score of ≤5 was associated with 80.8% successful day-case cholecystectomy compared with 19.2% associated with a CAAD score >5 (p < 0.001). Conclusions The CAAD score which utilises data readily available from clinic letters and electronic sources can predict same-day discharges following cholecystectomy

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Gender effects on the post-facilitation performance of two dioecious Juniperus species

7 páginas, 2 figuras, 2 tablas.1. Plant facilitation usually changes to competition as plants age. In dioecious plants, females should be affected more negatively than males by stressful conditions because of the greater costs of female reproduction.2. We investigated the gender effects on the post-facilitation performance of adult plants of two dioecious Juniperus species from the high mountains of eastern Spain: J. sabina L. acts as a nurse plant for J. communis L. We compared physiological (water potential, carbon isotope discrimination and nitrogen concentration), vegetative (shoot growth) and reproductive (number of male flowers, and number of fruits and seeds) characters of associated and non-associated plants of both species, to test the hypothesis that this association represents a more stressful condition for females than for males because of the greater costs of female reproduction.3. Despite their close phylogenetic relatedness, both species showed a distinct performance pattern after the facilitation phase. Association with the nurse plant reduced the growth and reproductive capacity of both genders in J. communis, the facilitated species. In contrast, the association with J. communis did not affect the fitness of the nurse plant, J. sabina , although in accordance with our hypothesis a gender effect was found on several hysiological parameters. Thus J.sabina associated females had a more negative water potential and carbon isotope discrimination than the associated males, but there were no differences between genders when growing in isolation.4. The consequences of the post-facilitation interaction between the two long-lived woody Juniperus species are asymmetrical: harmful for the facilitated species, but harmless for the nurse.5. Gender had also asymmetrical consequences on some functional traits of the nurse – but not the facilitated – species.We sincerely thank all the people of Puebla de San Miguel who helped us with the field work. Carbon isotope analyses were run in the Laboratorio de Isótopos Estables(Universidad Autónoma de Madrid, Spain) and analyses of leaf nitrogen content in the Centro de Investigaciones sobre Desertificación (Valencia, Spain). This research was supported by projects FEDER 1FD97-0551, AGL2001-1061 and REN 2000-0163- P4-05 from the Ministerio de Ciencia y Tecnología. M.V. received grants from contracts of the Reincorporación de Doctores y Tecnólogos and Programa Ramón y Cajal del Ministerio de Ciencia y Tecnología during this study.Peer reviewe