Mathematical model reveals role of nucleotide signaling in airway surface liquid homeostasis and its dysregulation in cystic fibrosis

The intrapulmonary airways conduct air to the alveoli and are defended from inhaled pathogens by a highly regulated protective system of mucus, cilia, and liquid. In healthy lungs, a well-hydrated mucus layer is cleared by cilia from airway surfaces. In cystic fibrosis (CF), airway surfaces are dehydrated, leading to a failure of cilia-mediated mucus clearance and accumulation of pathogen-infected mucus. In this study, we created a mathematical model of airway surface liquid regulation in normal and CF cells and used the model to investigate a potential therapy to rehydrate CF airways and restore proper mucus clearance

Scaling smallholder tree cover restoration across the tropics

Restoring tree cover in tropical countries has the potential to benefit millions of smallholders through improvements in income and environmental services. However, despite their dominant landholding shares in many countries, smallholders' role in restoration has not been addressed in prior global or pan-tropical restoration studies. We fill this lacuna by using global spatial data on trees and people, national indicators of enabling conditions, and micro-level expert information. We find that by 2050, low-cost restoration is feasible within 280, 200, and 60 million hectares of tropical croplands, pasturelands, and degraded forestlands, respectively. Such restoration could affect 210 million people in croplands, 59 million people in pasturelands and 22 million people in degraded forestlands. This predominance of low-cost restoration opportunity in populated agricultural lands has not been revealed by prior analyses of tree cover restoration potential. In countries with low-cost tropical restoration potential, smallholdings comprise a significant proportion of agricultural lands in Asia (∼76 %) and Africa (∼60 %) but not the Americas (∼3%). Thus, while the Americas account for approximately half of 21st century tropical deforestation, smallholder-based reforestation may play a larger role in efforts to reverse recent forest loss in Asia and Africa than in the Americas. Furthermore, our analyses show that countries with low-cost restoration potential largely lack policy commitments or smallholder supportive institutional and market conditions. Discussions among practitioners and researchers suggest that four principles - partnering with farmers and prioritizing their preferences, reducing uncertainty, strengthening markets, and mobilizing innovative financing - can help scale smallholder-driven restoration in the face of these challenges

Biophysical Model of Ion Transport across Human Respiratory Epithelia Allows Quantification of Ion Permeabilities

Lung health and normal mucus clearance depend on adequate hydration of airway surfaces. Because transepithelial osmotic gradients drive water flows, sufficient hydration of the airway surface liquid depends on a balance between ion secretion and absorption by respiratory epithelia. In vitro experiments using cultures of primary human nasal epithelia and human bronchial epithelia have established many of the biophysical processes involved in airway surface liquid homeostasis. Most experimental studies, however, have focused on the apical membrane, despite the fact that ion transport across respiratory epithelia involves both cellular and paracellular pathways. In fact, the ion permeabilities of the basolateral membrane and paracellular pathway remain largely unknown. Here we use a biophysical model for water and ion transport to quantify ion permeabilities of all pathways (apical, basolateral, paracellular) in human nasal epithelia cultures using experimental (Ussing Chamber and microelectrode) data reported in the literature. We derive analytical formulas for the steady-state short-circuit current and membrane potential, which are for polarized epithelia the equivalent of the Goldman-Hodgkin-Katz equation for single isolated cells. These relations allow parameter estimation to be performed efficiently. By providing a method to quantify all the ion permeabilities of respiratory epithelia, the model may aid us in understanding the physiology that regulates normal airway surface hydration

Integrable N=2 Supersymmetric Field Theories

Some additional references are included on the last 3 pages.Comment: 14 pages, OUTP-92-12

Natural climate solutions for the United States

Limiting climate warming t

An Assessment of the Representation of Ecosystems in Global Protected Areas Using New Maps of World Climate Regions and World Ecosystems

Representation of ecosystems in protected area networks and conservation strategies is a core principle of global conservation priority setting approaches and a commitment in Aichi Target 11 of the Convention on Biological Diversity. The 2030 Sustainable Development Goals (SDGs) explicitly call for the conservation of terrestrial, freshwater, and marine ecosystems. Accurate ecosystem distribution maps are required to assess representation of ecosystems in protected areas, but standardized, high spatial resolution, and globally comprehensive ecosystem maps have heretofore been lacking. While macroscale global ecoregions maps have been used in global conservation priority setting exercises, they do not identify distinct localized ecosystems at the occurrence (patch) level, and instead describe large ecologically meaningful areas within which additional conservation planning and management are necessary. We describe a new set of maps of globally consistent climate regions and ecosystems at a much finer spatial resolution (250 m) than existing ecological regionalizations. We then describe a global gap analysis of the representation of these ecosystems in protected areas. The new map of terrestrial World Ecosystems was derived from the objective development and integration of 1) global temperature domains, 2) global moisture domains, 3) global landforms, and 4) 2015 global vegetation and land use. These new terrestrial World Ecosystems do not include either freshwater or marine ecosystems, but analog products for the freshwater and marine domains are in development. A total of 431 World Ecosystems were identified, and of these a total of 278 units were natural or semi-natural vegetation/environment combinations, including different kinds of forestlands, shrublands, grasslands, bare areas, and ice/snow regions. The remaining classes were different kinds of croplands and settlements. Of the 278 natural and semi-natural classes, 9 were not represented in global protected areas with a strict biodiversity conservation management objective (IUCN management categories I-IV), and an additional 206 were less than 8.5% protected (half way to the 17% Aichi Target 11 goal). Forty four classes were between 8.5% and 17% protected (more than half way towards the Aichi 17% target), and only 19 classes exceeded the 17% Aichi target. However, when all protected areas (IUCN management categories I-VI plus protected areas with no IUCN designation) were included in a separate global gap analysis, representation of ecosystems increases substantially, with a third of the ecosystems exceeding the 17% Aichi target, and another third between 8.5% and 17%. The overall protection (representation) of global ecosystems in protected areas is considerably less when assessed using only strictly conserved protected areas, and more if all protected areas are included in the analysis. Protected area effectiveness should be included in further evaluations of global ecosystem protection. The ecosystems with the highest representation in protected areas were often bare or sparsely vegetated and found in inhospitable environments (e.g. cold mountains, deserts), and the eight most protected ecosystems were all snow and ice ecosystems. In addition to the global gap analysis of World Ecosystems in protected areas, we report on the representation results for the ecosystems in each biogeographic realm (Neotropical, Nearctic, Afrotropical, Palearctic, Indomalayan, Australasian, and Oceania)

Mathematical Model of Nucleotide Regulation on Airway Epithelia: IMPLICATIONS FOR AIRWAY HOMEOSTASIS

In the airways, adenine nucleotides support a complex signaling network mediating host defenses. Released by the epithelium into the airway surface liquid (ASL) layer, they regulate mucus clearance through P2 (ATP) receptors, and following surface metabolism through P1 (adenosine; Ado) receptors. The complexity of ASL nucleotide regulation provides an ideal subject for biochemical network modeling. A mathematical model was developed to integrate nucleotide release, the ectoenzymes supporting the dephosphorylation of ATP into Ado, Ado deamination into inosine (Ino), and nucleoside uptake. The model also includes ecto-adenylate kinase activity and feed-forward inhibition of Ado production by ATP and ADP. The parameters were optimized by fitting the model to experimental data for the steady-state and transient concentration profiles generated by adding ATP to polarized primary cultures of human bronchial epithelial (HBE) cells. The model captures major aspects of ATP and Ado regulation, including their >4-fold increase in concentration induced by mechanical stress mimicking normal breathing. The model also confirmed the independence of steady-state nucleotide concentrations on the ASL volume, an important regulator of airway clearance. An interactive approach between simulations and assays revealed that feed-forward inhibition is mediated by selective inhibition of ecto-5′-nucleotidase. Importantly, the model identifies ecto-adenylate kinase as a key regulator of ASL ATP and proposes novel strategies for the treatment of airway diseases characterized by impaired nucleotide-mediated clearance. These new insights into the biochemical processes supporting ASL nucleotide regulation illustrate the potential of this mathematical model for fundamental and clinical research

Increased water vapour lifetime due to global warming

Water vapour in the atmosphere is the source of a major climate feedback mechanism and potential increases in the availability of water vapour could have important consequences for mean and extreme precipitation. Future precipitation changes further depend on how the hydrological cycle responds to drivers of climate change, such as greenhouse gases and aerosols. Currently, neither the total anthropogenic influence on the hydrological cycle, nor those from individual drivers, are constrained sufficiently to make solid projections. We investigate how integrated water vapour (IWV) responds to different drivers of climate change. Results from 11 global climate models have been used, based on simulations where CO2, methane, solar irradiance, black carbon (BC), and sulphate have been perturbed separately. While the global-mean IWV is usually assumed to increase by ~7% per degree K surface temperature change, we find that the feedback response of IWV differs somewhat between drivers. Fast responses, which include the initial radiative effect and rapid adjustments to an external forcing, amplify these differences. The resulting net changes in IWV range from 6.4±0.9%/K for sulphate to 9.8±2%/K for BC. We further calculate the relationship between global changes in IWV and precipitation, which can be characterized by quantifying changes in atmospheric water vapour lifetime. Global climate models simulate a substantial increase in the lifetime, from 8.2±0.5 to 9.9±0.7 days between 1986-2005 and 2081-2100 under a high emission scenario, and we discuss to what extent the water vapour lifetime provides additional information compared to analysis of IWV and precipitation separately. We conclude that water vapour lifetime changes are an important indicator of changes in precipitation patterns and that BC is particularly efficient in prolonging the distance between evaporation and precipitation

In vivo imaging of extracellular matrix remodeling by tumor-associated fibroblasts.

Here we integrated multiphoton laser scanning microscopy and the registration of second harmonic generation images of collagen fibers to overcome difficulties in tracking stromal cell-matrix interactions for several days in live mice. We show that the matrix-modifying hormone relaxin increased tumor-associated fibroblast (TAF) interaction with collagen fibers by stimulating beta1-integrin activity, which is necessary for fiber remodeling by matrix metalloproteinases