Person: Alonso, Jose
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Alonso
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Jose
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Alonso, Jose
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Publication Structural basis for pure antagonism of integrin αVβ3 by a high affinity form of fibronectin(2014) van Agthoven, Johannes; Xiong, Jian-Ping; Alonso, Jose; Rui, Xianliang; Adair, Brian; Goodman, Simon L.; Arnaout, M.Integrins are important therapeutic targets. However, current RGD-based anti-integrin drugs are also partial agonists, inducing conformational changes that trigger potentially fatal immune reactions and paradoxical cell adhesion. Here we describe the first crystal structure of αVβ3 bound to a physiologic ligand: the 10th type III RGD-domain of wild-type fibronectin (wtFN10), or to a high affinity mutant (hFN10) that acts as a pure antagonist. Comparison of these structures revealed a central π - π interaction between Trp1496 in the RGD-containing loop of hFN10 and Tyr122 of the β3-subunit that blocked conformational changes triggered by wtFN10, and trapped hFN10-bound αVβ3 in an inactive conformation. Removing the Trp1496 or Tyr122 side-chains, or reorienting Trp1496 away from Tyr122, converted hFN10 into a partial agonist. The findings offer new insights on the mechanism of integrin activation and a basis for design of RGD-based pure antagonists.Publication Parental psychopathology and the risk of suicidal behavior in their offspring: results from the World Mental Health surveys(Springer Nature, 2010) Gureje, O; Oladeji, Bibilola; Hwang, Irving; Chiu, Wai; Kessler, Ronald; Sampson, Nancy; Alonso, Jose; Andrade, Luis; Beautrais, A; Borges, G; Bromet, E; Bruffaerts, R; de Girolamo, G; de Graaf, R; Gal, G; He, Y; Hu, C; Iwata, N; Karam, E G; Kovess-Masféty, V; Matschinger, H; Moldovan, M V; Posada-Villa, J; Sagar, R; Scocco, P; Seedat, S; Tomov, Toma; Nock, MatthewPrior research suggests that parental psychopathology predicts suicidal behavior among offspring; however, the more fine-grained associations between specific parental disorders and distinct stages of the pathway to suicide are not well-understood. We set out to test the hypothesis that parental disorders associated with negative mood would predict offspring suicide ideation, whereas disorders characterized by impulsive-aggression (e,g., antisocial personality) and anxiety/agitation (e.g., panic disorder) would predict which offspring act on their suicide ideation and make a suicide attempt. Data were collected during face-to-face interviews conducted on nationally representative samples (N=55,299; age 18+) from 21 countries around the world. We tested the associations between a range of parental disorders and the onset and persistence over time (i.e., time-since-most-recent-episode controlling for age-of-onset and time-since-onset) of subsequent suicidal behavior (suicide ideation, plans, and attempts) among offspring. Analyses tested bivariate and multivariate associations between each parental disorder and distinct forms of suicidal behavior. Results revealed that each parental disorder examined increased the risk of suicide ideation among offspring, parental generalized anxiety and depression emerged as the only predictors of the onset and persistence (respectively) of suicide plans among offspring with ideation, whereas parental anti-social personality and anxiety disorders emerged as the only predictors of the onset and persistence of suicide attempts among ideators. A dose-response relation between parental disorders and respondent risk of suicide ideation and attempt also was found. Parental death by suicide was a particularly strong predictor of persistence of suicide attempts among offspring. These associations remained significant after controlling for comorbidity of parental disorders and for the presence of mental disorders among offspring. These findings should inform future explorations of the mechanisms of inter-generational transmission of suicidal behavior.Publication Mental disorders among college students in the World Health Organization World Mental Health Surveys(Cambridge University Press (CUP), 2016) Auerbach, Randy; Alonso, Jose; Axinn, W. G.; Cuijpers, P.; Ebert, D. D.; Green, J. G.; Hwang, Irving; Kessler, Ronald; Liu, Howard; Mortier, Philippe; Nock, Matthew; Pinder-Amaker, Stephanie; Sampson, Nancy; Aguilar-Gaxiola, S.; Al-Hamzawi, A.; Andrade, L. H.; Benjet, C.; Caldas-de-Almeida, J. M.; Demyttenaere, K.; Florescu, S.; de Girolamo, G.; Gureje, O.; Haro, J. M.; Karam, E. G.; Kiejna, A.; Kovess-Masfety, V.; Lee, S.; McGrath, J. J.; O, S.; Pennell, B.-E.; Scott, K.; ten Have, M.; Torres, Y.; Zaslavsky, Alan; Zarkov, Z.; Bruffaerts, R.Background Although mental disorders are significant predictors of educational attainment throughout the entire educational career, most research on mental disorders among students has focused on the primary and secondary school years. Methods The World Health Organization World Mental Health Surveys were used to examine the associations of mental disorders with college entry and attrition by comparing college students (n = 1,572) and nonstudents in the same age range (18–22; n = 4,178), including nonstudents who recently left college without graduating (n = 702) based on surveys in 21 countries (4 low/lower-middle income, 5 upper middle-income, 1 lower-middle or upper-middle at the times of two different surveys, and 11 high income). Lifetime and 12-month prevalence and age-of-onset of DSM-IV anxiety, mood, behavioural and substance disorders were assessed with the Composite International Diagnostic Interview. Results One-fifth (20.3%) of college students had 12-month DSM-IV/CIDI disorders. 83.1% of these cases had pre-matriculation onsets. Disorders with pre-matriculation onsets were more important than those with post-matriculation onsets in predicting subsequent college attrition, with substance disorders and, among women, major depression the most important such disorders. Only 16.4% of students with 12-month disorders received any 12-month healthcare treatment for their mental disorders. Conclusions Mental disorders are common among college students, have onsets that mostly occur prior to college entry, in the case of pre-matriculation disorders are associated with college attrition, and are typically untreated. Detection and effective treatment of these disorders early in the college career might reduce attrition and improve educational and psychosocial functioning.Publication Cross-national prevalence and risk factors for suicidal ideation, plans and attempts(Royal College of Psychiatrists, 2008) Nock, Matthew; Borges, G.; Bromet, E. J.; Alonso, Jose; Angermeyer, M.; Beautrais, A.; Bruffaerts, R.; Chiu, Wai; de Girolamo, G.; Gluzman, S.; de Graaf, R.; Gureje, O.; Haro, J. M.; Huang, Y.; Karam, E.; Kessler, Ronald; Lepine, J. P.; Levinson, D.; Medina-Mora, M. E.; Ono, Y.; Posada-Villa, J.; Williams, DavidBackground Suicide is a leading cause of death world-wide; however, the prevalence and risk factors for the immediate precursors to suicide: suicidal ideation, plans and attempts, are not well-known, especially in developing countries. Aims To report on the prevalence and risk factors for suicidal behaviors across 17 countries. Method 84,850 adults were interviewed regarding suicidal behaviors and socio-demographic and psychiatric risk factors. Results The cross-national lifetime prevalence (standard error) of suicidal ideation, plans, and attempts is 9.2% (0.1), 3.1% (0.1), and 2.7% (0.1). Across all countries, 60% of transitions from ideation to plan and attempt occur within the first year after ideation onset. Consistent cross-national risk factors included being: female, younger, less educated, unmarried, and having a mental disorder. Interestingly, the strongest diagnostic risk factors were mood disorders in developed countries but impulse-control disorders in developing countries. Conclusion Despite cross-national variability in prevalence, there is strong consistency in the characteristics of and risk factors for suicidal behaviors. These findings have significant implications for the prediction and prevention of suicidal behaviors.Publication Prophylactic orthosteric inhibition of leukocyte integrin CD11b/CD18 prevents long-term fibrotic kidney failure in cynomolgus monkeys(Nature Publishing Group, 2017) Dehnadi, Abbas; Benedict Cosimi, A.; Neal Smith, Rex; Li, Xiangen; Alonso, Jose; Means, Terry K.; Arnaout, M.Ischaemic acute kidney injury (AKI), an inflammatory disease process, often progresses to chronic kidney disease (CKD), with no available effective prophylaxis. This is in part due to lack of clinically relevant CKD models in non-human primates. Here we demonstrate that inhibition of the archetypal innate immune receptor CD11b/CD18 prevents progression of AKI to CKD in cynomolgus monkeys. Severe ischaemia-reperfusion injury of the right kidney, with subsequent periods of the left ureter ligation, causes irreversible right kidney failure 3, 6 or 9 months after AKI. Moreover, prophylactic inactivation of CD11b/CD18, using the orthosteric CD11b/CD18 inhibitor mAb107, improves microvascular perfusion and histopathology, reduces intrarenal pro-inflammatory mediators and salvages kidney function long term. These studies reveal an important early role of CD11b+ leukocytes in post-ischaemic kidney fibrosis and failure, and suggest a potential early therapeutic intervention to mitigate progression of ischaemic AKI to CKD in humans.Publication Crystal Structure of the Complete Integrin αVβ3 Ectodomain Plus an α/β Transmembrane Fragment(The Rockefeller University Press, 2009) Mahalingham, Bhuvaneshwari; Borrelli, Laura Ann; Rysiok, Thomas; Müller-Pompalla, Dirk; Goodman, Simon L.; Xiong, Jian-Ping; Alonso, Jose; Rui, Xianliang; Anand, Saurabh; Hyman, Bradley; Arnaout, M.We determined the crystal structure of 1TM-αVβ3, which represents the complete unconstrained ectodomain plus short C-terminal transmembrane stretches of the αV and β3 subunits. 1TM-αVβ3 is more compact and less active in solution when compared with ΔTM-αVβ3, which lacks the short C-terminal stretches. The structure reveals a bent conformation and defines the α–β interface between IE2 (EGF-like 2) and the thigh domains. Modifying this interface by site-directed mutagenesis leads to robust integrin activation. Fluorescent lifetime imaging microscopy of inactive full-length αVβ3 on live cells yields a donor–membrane acceptor distance, which is consistent with the bent conformation and does not change in the activated integrin. These data are the first direct demonstration of conformational coupling of the integrin leg and head domains, identify the IE2–thigh interface as a critical steric barrier in integrin activation, and suggest that inside-out activation in intact cells may involve conformational changes other than the postulated switch to a genu-linear state.Publication A microfluidic renal proximal tubule with active reabsorptive function(Public Library of Science, 2017) Vedula, Else M.; Alonso, Jose; Arnaout, M.; Charest, Joseph L.In the kidney, the renal proximal tubule (PT) reabsorbs solutes into the peritubular capillaries through active transport. Here, we replicate this reabsorptive function in vitro by engineering a microfluidic PT. The microfluidic PT architecture comprises a porous membrane with user-defined submicron surface topography separating two microchannels representing a PT filtrate lumen and a peritubular capillary lumen. Human PT epithelial cells and microvascular endothelial cells in respective microchannels created a PT-like reabsorptive barrier. Co-culturing epithelial and endothelial cells in the microfluidic architecture enhanced viability, metabolic activity, and compactness of the epithelial layer. The resulting tissue expressed tight junctions, kidney-specific morphology, and polarized expression of kidney markers. The microfluidic PT actively performed sodium-coupled glucose transport, which could be modulated by administration of a sodium-transport inhibiting drug. The microfluidic PT reproduces human physiology at the cellular and tissue levels, and measurable tissue function which can quantify kidney pharmaceutical efficacy and toxicity.