Functional Comparison of Induced Pluripotent Stem Cell- and Blood-Derived GPIIbIIIa Deficient Platelets

Human induced pluripotent stem cells (hiPSCs) represent a versatile tool to model genetic diseases and are a potential source for cell transfusion therapies. However, it remains elusive to which extent patient-specific hiPSC-derived cells functionally resemble their native counterparts. Here, we generated a hiPSC model of the primary platelet disease Glanzmann thrombasthenia (GT), characterized by dysfunction of the integrin receptor GPIIbIIIa, and compared side-by-side healthy and diseased hiPSC-derived platelets with peripheral blood platelets. Both GT-hiPSC-derived platelets and their peripheral blood equivalents showed absence of membrane expression of GPIIbIIIa, a reduction of PAC-1 binding, surface spreading and adherence to fibrinogen. We demonstrated that GT-hiPSC-derived platelets recapitulate molecular and functional aspects of the disease and show comparable behavior to their native counterparts encouraging the further use of hiPSC-based disease models as well as the transition towards a clinical application

Global importance of large-diameter trees

Aim: To examine the contribution of large‐diameter trees to biomass, stand structure, and species richness across forest biomes. Location: Global. Time period: Early 21st century. Major taxa studied: Woody plants. Methods: We examined the contribution of large trees to forest density, richness and biomass using a global network of 48 large (from 2 to 60 ha) forest plots representing 5,601,473 stems across 9,298 species and 210 plant families. This contribution was assessed using three metrics: the largest 1% of trees ≥ 1 cm diameter at breast height (DBH), all trees ≥ 60 cm DBH, and those rank‐ordered largest trees that cumulatively comprise 50% of forest biomass. Results: Averaged across these 48 forest plots, the largest 1% of trees ≥ 1 cm DBH comprised 50% of aboveground live biomass, with hectare‐scale standard deviation of 26%. Trees ≥ 60 cm DBH comprised 41% of aboveground live tree biomass. The size of the largest trees correlated with total forest biomass (r2 = .62, p < .001). Large‐diameter trees in high biomass forests represented far fewer species relative to overall forest richness (r2 = .45, p < .001). Forests with more diverse large‐diameter tree communities were comprised of smaller trees (r2 = .33, p < .001). Lower large‐diameter richness was associated with large‐diameter trees being individuals of more common species (r2 = .17, p = .002). The concentration of biomass in the largest 1% of trees declined with increasing absolute latitude (r2 = .46, p < .001), as did forest density (r2 = .31, p < .001). Forest structural complexity increased with increasing absolute latitude (r2 = .26, p < .001). Main conclusions: Because large‐diameter trees constitute roughly half of the mature forest biomass worldwide, their dynamics and sensitivities to environmental change represent potentially large controls on global forest carbon cycling. We recommend managing forests for conservation of existing large‐diameter trees or those that can soon reach large diameters as a simple way to conserve and potentially enhance ecosystem services

Functional comparison of induced pluripotent stem cell- and blood-derived GPIIbIIIa deficient platelets.

Human induced pluripotent stem cells (hiPSCs) represent a versatile tool to model genetic diseases and are a potential source for cell transfusion therapies. However, it remains elusive to which extent patient-specific hiPSC-derived cells functionally resemble their native counterparts. Here, we generated a hiPSC model of the primary platelet disease Glanzmann thrombasthenia (GT), characterized by dysfunction of the integrin receptor GPIIbIIIa, and compared side-by-side healthy and diseased hiPSC-derived platelets with peripheral blood platelets. Both GT-hiPSC-derived platelets and their peripheral blood equivalents showed absence of membrane expression of GPIIbIIIa, a reduction of PAC-1 binding, surface spreading and adherence to fibrinogen. We demonstrated that GT-hiPSC-derived platelets recapitulate molecular and functional aspects of the disease and show comparable behavior to their native counterparts encouraging the further use of hiPSC-based disease models as well as the transition towards a clinical application

Flow cytometry of PAC-1 binding and integrin surface expression after platelet activation.

<p>(A) Cells were stained with PAC-1 (x-axis) and anti-CD42b (y-axis) antibodies in the absence (top) or presence (bottom) of ADP/TXA₂. (B) Flow cytometry of CD41 (GPIIb) and CD61 (GPIIIa) surface expression on hiPSC-derived and peripheral blood platelets in the presence of ADP/TXA₂. After activation with ADP/TXA₂, cells were stained with anti-CD42b, anti-CD41/CD61, anti-CD41 and anti-CD61 antibodies. The FSC/SSC log gate of peripheral platelets was applied and further gated for CD42b+ cells.</p

Generation and integrin surface expression of hiPSC-derived platelets from GT and CTR.

<p>(A) Immunofluorescence (top) and flow cytometry (bottom) of hiPSC-derived and peripheral blood platelets. The cells were stained with anti-CD42b (red / y-axis), anti-CD41/CD61 (green / x-axis) antibodies and DAPI (blue). (B) Flow cytometry of CD41 (GPIIb) and CD61 (GPIIIb) surface expression on hiPSC-derived and peripheral blood platelets. The cells were stained with anti-CD42b, anti-CD41/CD61, anti-CD41 and anti-CD61 antibodies. The FSC/SSC log gate of peripheral platelets was applied and further gated for CD42b+ cells. All scale bars represent 10 μm. Representative images for each sample.</p

Surface spreading, adhesion and cytoskeleton rearrangement of peripheral blood and hiPSC-derived platelets.

<p>(A) Platelets spreading on fibrinogen-coated wells were imaged with DICM in the presence of ADP/TXA₂ at the indicated time points. For complete movie sequence see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115978#pone.0115978.s012" target="_blank">S1</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115978#pone.0115978.s015" target="_blank">S4</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115978#pone.0115978.s016" target="_blank">S5</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115978#pone.0115978.s018" target="_blank">S7</a> Movies. (B) Quantification of fibrinogen binding of MKs and platelets. The percentages of attached cells are shown as scatter columns with horizontal bars representing the mean. In the hiPSC-derived groups, red and black symbols indicate results from the two hiPSC clones. A total mean of 1991±262.6 cells per sample was counted before washing. P-values from unpaired t-tests; peripheral blood platelets from GT (n = 10) and CTR (n = 10); hiPSC-derived platelets from GT (n = 5) and CTR (n = 6). (C) Rhodamine-conjugated phalloidin was used to stain actin filaments after permeabilization of platelets spreading on fibrinogen. All cells shown stained positive for CD42b and negative for DAPI. All scale bars represent 10 μm. Representative images for each sample.</p

Zygosity Differences in Height and Body Mass Index of Twins From Infancy to Old Age: A Study of the CODATwins Project

A trend toward greater body size in dizygotic (DZ) than in monozygotic (MZ) twins has been suggested by some but not all studies, and this difference may also vary by age. We analyzed zygosity differences in mean values and variances of height and body mass index (BMI) among male and female twins from infancy to old age. Data were derived from an international database of 54 twin cohorts participating in the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins), and included 842,951 height and BMI measurements from twins aged 1 to 102 years. The results showed that DZ twins were consistently taller than MZ twins, with differences of up to 2.0 cm in childhood and adolescence and up to 0.9 cm in adulthood. Similarly, a greater mean BMI of up to 0.3 kg/m2 in childhood and adolescence and up to 0.2 kg/m2 in adulthood was observed in DZ twins, although the pattern was less consistent. DZ twins presented up to 1.7% greater height and 1.9% greater BMI than MZ twins; these percentage differences were largest in middle and late childhood and decreased with age in both sexes. The variance of height was similar in MZ and DZ twins at most ages. In contrast, the variance of BMI was significantly higher in DZ than in MZ twins, particularly in childhood. In conclusion, DZ twins were generally taller and had greater BMI than MZ twins, but the differences decreased with age in both sexes

Correspondence. Human Proteinpedia enables sharing of human protein data

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ForestGEO: understanding forest diversity and dynamics through a global observatory network

ForestGEO is a network of scientists and long-term forest dynamics plots (FDPs) spanning the Earth's major forest types. ForestGEO's mission is to advance understanding of the diversity and dynamics of forests and to strengthen global capacity for forest science research. ForestGEO is unique among forest plot networks in its large-scale plot dimensions, censusing of all stems ≥1 cm in diameter, inclusion of tropical, temperate and boreal forests, and investigation of additional biotic (e.g., arthropods) and abiotic (e.g., soils) drivers, which together provide a holistic view of forest functioning. The 71 FDPs in 27 countries include approximately 7.33 million living trees and about 12,000 species, representing 20% of the world's known tree diversity. With >1300 published papers, ForestGEO researchers have made significant contributions in two fundamental areas: species coexistence and diversity, and ecosystem functioning. Specifically, defining the major biotic and abiotic controls on the distribution and coexistence of species and functional types and on variation in species' demography has led to improved understanding of how the multiple dimensions of forest diversity are structured across space and time and how this diversity relates to the processes controlling the role of forests in the Earth system. Nevertheless, knowledge gaps remain that impede our ability to predict how forest diversity and function will respond to climate change and other stressors. Meeting these global research challenges requires major advances in standardizing taxonomy of tropical species, resolving the main drivers of forest dynamics, and integrating plot-based ground and remote sensing observations to scale up estimates of forest diversity and function, coupled with improved predictive models. However, they cannot be met without greater financial commitment to sustain the long-term research of ForestGEO and other forest plot networks, greatly expanded scientific capacity across the world's forested nations, and increased collaboration and integration among research networks and disciplines addressing forest science