Partial reconstitution of cutaneous microvessels in long-term survivors after allogeneic bone marrow transplantation

BACKGROUND: Graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation (HSCT) and skin is involved in acute and chronic disease. Immune-mediated vessel attack and subsequent microvessel loss have been observed in skin of patients with chronic GVHD. OBJECTIVES: To test whether long-term survivors (LTS) after allogeneic HSCT without cutaneous GVHD show signs of persistent vascular remodeling. METHODS: Microvessels in skin biopsies were investigated in a cohort of 32 LTS with a median follow-up of 17 years (range 11-26). Five were currently classified as having chronic GVHD other than skin involvement. RESULTS: LTS showed no significant difference in median microvessel density and relative vessel size distribution pattern compared to healthy controls. Past experience of GVHD and current status of chronic GVHD other than skin involvement had no impact on vessel density. In contrast, recipients with chronic cutaneous GVHD of sclerotic type and patients with lichen sclerosus have significant microvessel loss in the upper dermis. CONCLUSION: The complex therapy of allogeneic HSCT had no sustained effect on the microvascular architecture of LTS when clinicopathological evidence of cutaneous GVHD is absent. Microvascular remodeling as observed during chronic GVHD recovers completely after resolution of chronic cutaneous GVHD

Spatial patterns of climate change across the Paleocene–Eocene Thermal Maximum

This study was supported by Heising–Simons Founda-tion Grants 2016-015 (to J.E.T.), 2016-011 (to M.L. and L.R.K.), 2016-013 (toA.R.), 2016-014 (to G.J.H.), and 2016-012 (to C.J.P.). R.D.M.W. and J.W.B.R. acknowledge funding from the European Research Council under the European Union’s Horizon 2020 Research and Innovation Program Grant 805246. This material is based on work supported by the National Center for Atmospheric Research (NCAR), which is a major facility sponsored by NSF Cooperative Agreement 1852977. Computing and data storage resources, including the Cheyenne supercomputer (https://arc.ucar.edu/knowledgebase/70549542), were provided by the Computational and Information Systems Laboratory at NCAR.The Paleocene–Eocene Thermal Maximum (PETM; 56 Ma) is one of our best geological analogs for understanding climate dynamics in a “greenhouse” world. However, proxy data representing the event are only available from select marine and terrestrial sedimentary sequences that are unevenly distributed across Earth’s surface, limiting our view of the spatial patterns of climate change. Here, we use paleoclimate data assimilation (DA) to combine climate model and proxy information and create a spatially complete reconstruction of the PETM and the climate state that precedes it (“PETM-DA”). Our data-constrained results support strong polar amplification, which in the absence of an extensive cryosphere, is related to temperature feedbacks and loss of seasonal snow on land. The response of the hydrological cycle to PETM warming consists of a narrowing of the Intertropical Convergence Zone, off-equatorial drying, and an intensification of seasonal monsoons and winter storm tracks. Many of these features are also seen in simulations of future climate change under increasing anthropogenic emissions. Since the PETM-DA yields a spatially complete estimate of surface air temperature, it yields a rigorous estimate of global mean temperature change (5.6 ∘C; 5.4 ∘C to 5.9 ∘C, 95% CI) that can be used to calculate equilibrium climate sensitivity (ECS). We find that PETM ECS was 6.5 ∘C (5.7 ∘C to 7.4 ∘C, 95% CI), which is much higher than the present-day range. This supports the view that climate sensitivity increases substantially when greenhouse gas concentrations are high.Publisher PDFPeer reviewe

Axolotl Nanog activity in mouse embryonic stem cells demonstrates that ground state pluripotency is conserved from urodele amphibians to mammals

Cells in the pluripotent ground state can give rise to somatic cells and germ cells, and the acquisition of pluripotency is dependent on the expression of Nanog. Pluripotency is conserved in the primitive ectoderm of embryos from mammals and urodele amphibians, and here we report the isolation of a Nanog ortholog from axolotls (axNanog). axNanog does not contain a tryptophan repeat domain and is expressed as a monomer in the axolotl animal cap. The monomeric form is sufficient to regulate pluripotency in mouse embryonic stem cells, but axNanog dimers are required to rescue LIF-independent self-renewal. Our results show that protein interactions mediated by Nanog dimerization promote proliferation. More importantly, they demonstrate that the mechanisms governing pluripotency are conserved from urodele amphibians to mammals. © 2010. Published by The Company of Biologists Ltd

Proposed initiative would study Earth's weathering engine

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94818/1/eost14765.pd

Identification of Mutant Genes and Introgressed Tiger Salamander DNA in the Laboratory Axolotl, \u3cem\u3eAmbystoma mexicanum\u3c/em\u3e

The molecular genetic toolkit of the Mexican axolotl, a classic model organism, has matured to the point where it is now possible to identify genes for mutant phenotypes. We used a positional cloning–candidate gene approach to identify molecular bases for two historic axolotl pigment phenotypes: white and albino. White (d/d) mutants have defects in pigment cell morphogenesis and differentiation, whereas albino (a/a) mutants lack melanin. We identified in white mutants a transcriptional defect in endothelin 3 (edn3), encoding a peptide factor that promotes pigment cell migration and differentiation in other vertebrates. Transgenic restoration of Edn3 expression rescued the homozygous white mutant phenotype. We mapped the albino locus to tyrosinase (tyr) and identified polymorphisms shared between the albino allele (tyra) and tyr alleles in a Minnesota population of tiger salamanders from which the albino trait was introgressed. tyra has a 142 bp deletion and similar engineered alleles recapitulated the albinophenotype. Finally, we show that historical introgression of tyrasignificantly altered genomic composition of the laboratory axolotl, yielding a distinct, hybrid strain of ambystomatid salamander. Our results demonstrate the feasibility of identifying genes for traits in the laboratory Mexican axolotl

High potential for weathering and climate effects of non-vascular vegetation in the Late Ordovician

It has been hypothesized that predecessors of today’s bryophytes significantly increased global chemical weathering in the Late Ordovician, thus reducing atmospheric CO2 concentration and contributing to climate cooling and an interval of glaciations. Studies that try to quantify the enhancement of weathering by non-vascular vegetation, however, are usually limited to small areas and low numbers of species, which hampers extrapolating to the global scale and to past climatic conditions. Here we present a spatially explicit modelling approach to simulate global weathering by non-vascular vegetation in the Late Ordovician. We estimate a potential global weathering flux of 2.8 (km3 rock) yr−1, defined here as volume of primary minerals affected by chemical transformation. This is around three times larger than today’s global chemical weathering flux. Moreover, we find that simulated weathering is highly sensitive to atmospheric CO2 concentration. This implies a strong negative feedback between weathering by non-vascular vegetation and Ordovician climate

Earliest Triassic microbialites in the South China Block and other areas; controls on their growth and distribution

Earliest Triassic microbialites (ETMs) and inorganic carbonate crystal fans formed after the end-Permian mass extinction (ca. 251.4 Ma) within the basal Triassic Hindeodus parvus conodont zone. ETMs are distinguished from rarer, and more regional, subsequent Triassic microbialites. Large differences in ETMs between northern and southern areas of the South China block suggest geographic provinces, and ETMs are most abundant throughout the equatorial Tethys Ocean with further geographic variation. ETMs occur in shallow-marine shelves in a superanoxic stratified ocean and form the only widespread Phanerozoic microbialites with structures similar to those of the Cambro-Ordovician, and briefly after the latest Ordovician, Late Silurian and Late Devonian extinctions. ETMs disappeared long before the mid-Triassic biotic recovery, but it is not clear why, if they are interpreted as disaster taxa. In general, ETM occurrence suggests that microbially mediated calcification occurred where upwelled carbonate-rich anoxic waters mixed with warm aerated surface waters, forming regional dysoxia, so that extreme carbonate supersaturation and dysoxic conditions were both required for their growth. Long-term oceanic and atmospheric changes may have contributed to a trigger for ETM formation. In equatorial western Pangea, the earliest microbialites are late Early Triassic, but it is possible that ETMs could exist in western Pangea, if well-preserved earliest Triassic facies are discovered in future work

Late inception of a resiliently oxygenated upper ocean

This is the author accepted manuscript. The final version is available from American Association for the Advancement of Science via the DOI in this record Rising oceanic and atmospheric oxygen levels through time have been crucial to enhanced habitability of surface Earth environments. Few redox proxies can track secular variations in dissolved oxygen concentrations around threshold levels for metazoan survival in the upper ocean. We present an extensive compilation of iodine-to-calcium ratios (I/Ca) in marine carbonates. Our record supports a major rise in the partial pressure of oxygen in the atmosphere at ~400 million years (Ma) ago and reveals a step change in the oxygenation of the upper ocean to relatively sustainable near-modern conditions at ~200 Ma ago. An Earth system model demonstrates that a shift in organic matter remineralization to greater depths, which may have been due to increasing size and biomineralization of eukaryotic plankton, likely drove the I/Ca signals at ~200 Ma ago.NER

The Geological Record of Ocean Acidification

Ocean acidification may have severe consequences for marine ecosystems; however, assessing its future impact is difficult because laboratory experiments and field observations are limited by their reduced ecologic complexity and sample period, respectively. In contrast, the geological record contains long-term evidence for a variety of global environmental perturbations, including ocean acidification plus their associated biotic responses. We review events exhibiting evidence for elevated atmospheric CO2, global warming, and ocean acidification over the past ~300 million years of Earth's history, some with contemporaneous extinction or evolutionary turnover among marine calcifiers. Although similarities exist, no past event perfectly parallels future projections in terms of disrupting the balance of ocean carbonate chemistry—a consequence of the unprecedented rapidity of CO2 release currently taking place

Follow-up of phase I trial of adalimumab and rosiglitazone in FSGS: III. Report of the FONT study group

Abstract Background Patients with resistant primary focal segmental glomerulosclerosis (FSGS) are at high risk of progression to chronic kidney disease stage V. Antifibrotic agents may slow or halt this process. We present outcomes of follow-up after a Phase I trial of adalimumab and rosiglitazone, antifibrotic drugs tested in the Novel Therapies in Resistant FSGS (FONT) study. Methods 21 patients -- 12 males and 9 females, age 16.0 ± 7.5 yr, and estimated GFR (GFRe) 121 ± 56 mL/min/1.73 m2 -- received adalimumab (n = 10), 24 mg/m2 every 14 days or rosiglitazone (n = 11), 3 mg/m2 per day for 16 weeks. The change in GFRe per month prior to entry and after completion of the Phase I trial was compared. Results 19 patients completed the 16-week FONT treatment phase. The observation period pre-FONT was 18.3 ± 10.2 months and 16.1 ± 5.7 months after the study. A similar percentage of patients, 71% and 56%, in the rosiglitazone and adalimumab cohorts, respectively, had stabilization in GFRe, defined as a reduced negative slope of the line plotting GFRe versus time without requiring renal replacement therapy after completion of the FONT treatment period (P = 0.63). Conclusion Nearly 50% of patients with resistant FSGS who receive novel antifibrotic agents may have a legacy effect with delayed deterioration in kidney function after completion of therapy. Based on this proof-of-concept preliminary study, we recommend long-term follow-up of patients enrolled in clinical trials to ascertain a more comprehensive assessment of the efficacy of experimental treatments