Toward a New Normal: Trauma, Diversity, and the New Orleans Urban Long-Term Research Area Exploratory (ULTRA-Ex) Project

Though it is widely held that social-ecological diversity is critical for resilience and the recovery of post-trauma urban systems, there is disagreement over issues of causes and impacts. In this paper, we present analysis and findings of the impact of trauma on patterns of social-ecological diversity in New Orleans in the years following the Hurricane Katrina disaster (August-September 2005). We first provide an overview of conceptualizations of trauma and urban ecosystem resilience, and discuss programmatic research questions and objectives. We then examine city-wide land use / land cover change, showing that flood trauma reduced landscape-level ecological diversity across New Orleans. By reconstructing archival biotic surveys of indicator organisms, we also show that many ecological communities within New Orleans experienced an acute decline, followed by recovery over time. Census-based analyses indicate that ethno-racial diversity also increased over time. Unlike pre-Katrina conditions, ethno-racial and landscape-level ecological diversity were negatively correlated after the disaster as a consequence of contrasting responses to flooding. Our analyses and findings highlight the complexity and challenges of conceptualizing, operationalizing, and measuring social-ecological diversity and related processes of resilience

Reconsidering the New Normal: Trauma, Vulnerability & Resilience in Post-Katrina New Orleans

Traumatic anthropogenic or natural disasters can redefine the ecological and social diversity of cities, with "new normal" conditions often emerging in post-trauma urban landscapes. The objective of our ULTRA project is to examine how the pace and trajectory of recovery in post-Katrina New Orleans reflect ecological and social diversity. Specifically, we are examining potential parallels and interactions between ecological and social diversity within and among neighborhoods, and across the New Orleans metropolitan area. We are doing so by (1) organizing and coordinating a network of scholars and practitioners to exchange experience and knowledge and thereby advance understanding of connections between diversity and recovery in post-trauma urban ecosystems; (2) assembling a central data archive on the structure and diversity of ecological communities of New Orleans, which involves conducting an inventory of the post-Katrina urban forest; (4) and conducting a GIS-based spatial analysis of pre- and post-trauma landscape and social metrics derived from satellite imagery and the 2000 and 2010 federal census, analyzed for diversification and compared to stabilization metrics. This citywide study is being supplemented with three fine-grained studies in the neighborhoods of the Lower Ninth Ward, Hollygrove, and Pontchartrain Park. Qualitative data collected in these neighborhoods provides insight into the relationships between trauma and ecological and social diversity, and identify variation in the timing, pace, and trajectory of neighborhood recovery. In the future, we will expand our efforts to consider how diversity reflects the availability and valuation of ecosystem services in post-trauma urban landscapes. Our intent is to develop New Orleans as a natural laboratory for the study of ecological and community resiliency

Evidence for the Early Evolutionary Loss of the M20D Auxin Amidohydrolase Family from Mosses and Horizontal Gene Transfer from Soil Bacteria of Cryptic Hydrolase Orthologues to Physcomitrella patens

Inactive auxin conjugates are accumulated in plants and hydrolyzed to recover phytohormone action. A family of metallopeptidase orthologues has been conserved in Plantae to help regulate auxin homeostatic levels during growth and development. This hydrolase family was recently traced back to liverwort, the most ancient extant land plant lineage. Liverwort’s auxin hydrolase has little activity against auxin conjugate substrates and does not appear to actively regulate auxin. This finding, along with data that shows moss can synthesize auxin conjugates, led to examining another bryophyte lineage, Physcomitrella patens. We have identified and isolated three M20D hydrolase paralogues from moss. The isolated enzymes strongly recognize and cleave a variety of auxin conjugates, including those of indole butyric and indole propionic acids. These P. patens hydrolases not only appear to be “cryptic”, but they are likely to have derived from soil bacteria through Horizontal Gene Transfer. Additionally, support is presented that the plant-type M20D peptidase family may have been universally lost from mosses after divergence from the common ancestor with liverwort

CXCL10 Can Inhibit Endothelial Cell Proliferation Independently of CXCR3

CXCL10 (or Interferon-inducible protein of 10 kDa, IP-10) is an interferon-inducible chemokine with potent chemotactic activity on activated effector T cells and other leukocytes expressing its high affinity G protein-coupled receptor CXCR3. CXCL10 is also active on other cell types, including endothelial cells and fibroblasts. The mechanisms through which CXCL10 mediates its effects on non-leukocytes is not fully understood. In this study, we focus on the anti-proliferative effect of CXCL10 on endothelial cells, and demonstrate that CXCL10 can inhibit endothelial cell proliferation in vitro independently of CXCR3. Four main findings support this conclusion. First, primary mouse endothelial cells isolated from CXCR3-deficient mice were inhibited by CXCL10 as efficiently as wildtype endothelial cells. We also note that the proposed alternative splice form CXCR3-B, which is thought to mediate CXCL10's angiostatic activity, does not exist in mice based on published mouse CXCR3 genomic sequences as an in-frame stop codon would terminate the proposed CXCR3-B splice variant in mice. Second, we demonstrate that human umbilical vein endothelial cells and human lung microvascular endothelial cells that were inhibited by CXL10 did not express CXCR3 by FACS analysis. Third, two different neutralizing CXCR3 antibodies did not inhibit the anti-proliferative effect of CXCL10. Finally, fourth, utilizing a panel of CXCL10 mutants, we show that the ability to inhibit endothelial cell proliferation correlates with CXCL10's glycosaminoglycan binding affinity and not with its CXCR3 binding and signaling. Thus, using a very defined system, we show that CXCL10 can inhibit endothelial cell proliferation through a CXCR3-independent mechanism

Species-specific consequences of an E40K missense mutation in superoxide dismutase 1 (SOD1)

A glutamic acid to lysine (E40K) residue substitution in superoxide dismutase 1 (SOD1) is associated with canine degenerative myelopathy: the only naturally occurring large animal model of amyotrophic lateral sclerosis (ALS). The E40 residue is highly conserved across mammals, except the horse, which naturally carries the (dog mutant) K40 residue. Here we hypothesized that in vitro expression of mutant dog SOD1 would recapitulate features of human ALS (ie, SOD1 protein aggregation, reduced cell viability, perturbations in mitochondrial morphology and membrane potential, reduced ATP production, and increased superoxide ion levels); further, we hypothesized that an equivalent equine SOD1 variant would share similar perturbations in vitro, thereby explain horses’ susceptibility to certain neurodegenerative diseases. As in human ALS, expression of mutant dog SOD1 was associated with statistically significant increased aggregate formation, raised superoxide levels (ROS), and altered mitochondrial morphology (increased branching (form factor)), when compared to wild‐type dog SOD1‐expressing cells. Similar deficits were not detected in cells expressing the equivalent horse SOD1 variant. Our data helps explain the ALS‐associated cellular phenotype of dogs expressing the mutant SOD1 protein and reveals that species‐specific sequence conservation does not necessarily predict pathogenicity. The work improves understanding of the etiopathogenesis of canine degenerative myelopathy

Mitochondrial ATP synthase: architecture, function and pathology

Human mitochondrial (mt) ATP synthase, or complex V consists of two functional domains: F1, situated in the mitochondrial matrix, and Fo, located in the inner mitochondrial membrane. Complex V uses the energy created by the proton electrochemical gradient to phosphorylate ADP to ATP. This review covers the architecture, function and assembly of complex V. The role of complex V di-and oligomerization and its relation with mitochondrial morphology is discussed. Finally, pathology related to complex V deficiency and current therapeutic strategies are highlighted. Despite the huge progress in this research field over the past decades, questions remain to be answered regarding the structure of subunits, the function of the rotary nanomotor at a molecular level, and the human complex V assembly process. The elucidation of more nuclear genetic defects will guide physio(patho)logical studies, paving the way for future therapeutic interventions

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension

Clinical-grade Detection of Microsatellite Instability in Colorectal Tumors by Deep Learning

Background and Aims: Microsatellite instability (MSI) and mismatch-repair deficiency (dMMR) in colorectal tumors are used to select treatment for patients. Deep learning can detect MSI and dMMR in tumor samples on routine histology slides faster and cheaper than molecular assays. But clinical application of this technology requires high performance and multisite validation, which have not yet been performed. Methods: We collected hematoxylin and eosin-stained slides, and findings from molecular analyses for MSI and dMMR, from 8836 colorectal tumors (of all stages) included in the MSIDETECT consortium study, from Germany, the Netherlands, the United Kingdom, and the United States. Specimens with dMMR were identified by immunohistochemistry analyses of tissue microarrays for loss of MLH1, MSH2, MSH6, and/or PMS2. Specimens with MSI were identified by genetic analyses. We trained a deep-learning detector to identify samples with MSI from these slides; performance was assessed by cross-validation (n=6406 specimens) and validated in an external cohort (n=771 specimens). Prespecified endpoints were area under the receiver operating characteristic (AUROC) curve and area under the precision-recall curve (AUPRC). Results: The deep-learning detector identified specimens with dMMR or MSI with a mean AUROC curve of 0.92 (lower bound 0.91, upper bound 0.93) and an AUPRC of 0.63 (range, 0.59–0.65), or 67% specificity and 95% sensitivity, in the cross-validation development cohort. In the validation cohort, the classifier identified samples with dMMR with an AUROC curve of 0.95 (range, 0.92–0.96) without image-preprocessing and an AUROC curve of 0.96 (range, 0.93–0.98) after color normalization. Conclusions: We developed a deep-learning system that detects colorectal cancer specimens with dMMR or MSI using hematoxylin and eosin-stained slides; it detected tissues with dMMR with an AUROC of 0.96 in a large, international validation cohort. This system might be used for high-throughput, low-cost evaluation of colorectal tissue specimens