The changing role of history in restoration ecology

In the face of rapid environmental and cultural change, orthodox concepts in restoration ecology such as historical fidelity are being challenged. Here we re-examine the diverse roles played by historical knowledge in restoration, and argue that these roles remain vitally important. As such, historical knowledge will be critical in shaping restoration ecology in the future. Perhaps the most crucial role in shifting from the present version of restoration ecology (“v1.0”) to a newer formulation (“v2.0”) is the value of historical knowledge in guiding scientific interpretation, recognizing key ecological legacies, and influencing the choices available to practitioners of ecosystem intervention under conditions of open-ended and rapid change

Terutroban, a Thromboxane/Prostaglandin Endoperoxide Receptor Antagonist, Increases Survival in Stroke-Prone Rats by Preventing Systemic Inflammation and Endothelial Dysfunction: Comparison with Aspirin and Rosuvastatin

ABSTRACT This study investigated the efficacy of terutroban, a specific thromboxane/prostaglandin endoperoxide receptor antagonist, on stroke incidence in spontaneously hypertensive strokeprone rats (SHRSP). The effects of terutroban were compared with those of aspirin, another antiplatelet agent, and rosuvastatin, known to exert end-organ protection in SHRSP. Saltloaded male SHRSP were treated orally once a day with vehicle, terutroban (30 mg/kg/day), aspirin (60 mg/kg/day), or rosuvastatin (10 mg/kg/day). Compared with vehicle, and regardless of any effect on blood pressure or serum thromboxane B 2 levels, terutroban significantly increased survival (p Ͻ 0.001) as a consequence of a delayed brain lesion occurrence monitored by magnetic resonance imaging (p Ͻ 0.001), and a delayed increase of proteinuria (p Ͻ 0.001). Terutroban decreased cerebral mRNA transcription of interleukin-1␤, transforming growth factor-␤, and monocyte chemoattractant protein-1 after 6 weeks of dietary treatment. Terutroban also prevented the accumulation of urinary acute-phase proteins at high molecular weight, identified as markers of systemic inflammation, and assessed longitudinally by one-dimensional electrophoresis. Terutroban also has protective effects on the vasculature as suggested by the preservation of endothelial function and endothelial nitric-oxide synthase expression in isolated carotid arteries. These effects are similar to those obtained with rosuvastatin, and superior to those of aspirin. Terutroban increases survival in SHRSP by reducing systemic inflammation as well as preserving endothelial function. These data support clinical development of terutroban in the prevention of cerebrovascular and cardiovascular complications of atherothrombosis. Several clinical and experimental studies Spontaneously hypertensive stroke-prone rats (SHRSP) develop hypertension and proteinuria and die after the onset Article, publication date, and citation information can be found a

Deleterious ZNRF3 germline variants cause neurodevelopmental disorders with mirror brain phenotypes via domain-specific effects on Wnt/β-catenin signaling

Zinc and RING finger 3 (ZNRF3) is a negative-feedback regulator of Wnt/β-catenin signaling, which plays an important role in human brain development. Although somatically frequently mutated in cancer, germline variants in ZNRF3 have not been established as causative for neurodevelopmental disorders (NDDs). We identified 12 individuals with ZNRF3 variants and various phenotypes via GeneMatcher/Decipher and evaluated genotype-phenotype correlation. We performed structural modeling and representative deleterious and control variants were assessed using in vitro transcriptional reporter assays with and without Wnt-ligand Wnt3a and/or Wnt-potentiator R-spondin (RSPO). Eight individuals harbored de novo missense variants and presented with NDD. We found missense variants associated with macrocephalic NDD to cluster in the RING ligase domain. Structural modeling predicted disruption of the ubiquitin ligase function likely compromising Wnt receptor turnover. Accordingly, the functional assays showed enhanced Wnt/β-catenin signaling for these variants in a dominant negative manner. Contrarily, an individual with microcephalic NDD harbored a missense variant in the RSPO-binding domain predicted to disrupt binding affinity to RSPO and showed attenuated Wnt/β-catenin signaling in the same assays. Additionally, four individuals harbored de novo truncating or de novo or inherited large in-frame deletion variants with non-NDD phenotypes, including heart, adrenal, or nephrotic problems. In contrast to NDD-associated missense variants, the effects on Wnt/β-catenin signaling were comparable between the truncating variant and the empty vector and between benign variants and the wild type. In summary, we provide evidence for mirror brain size phenotypes caused by distinct pathomechanisms in Wnt/β-catenin signaling through protein domain-specific deleterious ZNRF3 germline missense variants

Vitalism and the Resistance to Experimentation on Life in the Eighteenth Century

There is a familiar opposition between a ‘Scientific Revolution’ ethos and practice of experimentation, including experimentation on life, and a ‘vitalist’ reaction to this outlook. The former is often allied with different forms of mechanism – if all of Nature obeys mechanical laws, including living bodies, ‘iatromechanism’ should encounter no obstructions in investigating the particularities of animal-machines – or with more chimiatric theories of life and matter, as in the ‘Oxford Physiologists’. The latter reaction also comes in different, perhaps irreducibly heterogeneous forms, ranging from metaphysical and ethical objections to the destruction of life, as in Margaret Cavendish, to more epistemological objections against the usage of instruments, the ‘anatomical’ outlook and experimentation, e.g. in Locke and Sydenham. But I will mainly focus on a third anti-interventionist argument, which I call ‘vitalist’ since it is often articulated in the writings of the so-called Montpellier Vitalists, including their medical articles for the Encyclopédie. The vitalist argument against experimentation on life is subtly different from the metaphysical, ethical and epistemological arguments, although at times it may borrow from any of them. It expresses a Hippocratic sensibility – understood as an artifact of early modernity, not as some atemporal trait of medical thought – in which Life resists the experimenter, or conversely, for the experimenter to grasp something about Life, it will have to be without torturing or radically intervening in it. I suggest that this view does not have to imply that Nature is something mysterious or sacred; nor does the vitalist have to attack experimentation on life in the name of some ‘vital force’ – which makes it less surprising to find a vivisectionist like Claude Bernard sounding so close to the vitalists

Deleterious ZNRF3 germline variants cause neurodevelopmental disorders with mirror brain phenotypes via domain-specific effects on Wnt/β-catenin signaling

Zinc and RING finger 3 (ZNRF3) is a negative-feedback regulator of Wnt/β-catenin signaling, which plays an important role in human brain development. Although somatically frequently mutated in cancer, germline variants in ZNRF3 have not been established as causative for neurodevelopmental disorders (NDDs). We identified 12 individuals with ZNRF3 variants and various phenotypes via GeneMatcher/Decipher and evaluated genotype-phenotype correlation. We performed structural modeling and representative deleterious and control variants were assessed using in vitro transcriptional reporter assays with and without Wnt-ligand Wnt3a and/or Wnt-potentiator R-spondin (RSPO). Eight individuals harbored de novo missense variants and presented with NDD. We found missense variants associated with macrocephalic NDD to cluster in the RING ligase domain. Structural modeling predicted disruption of the ubiquitin ligase function likely compromising Wnt receptor turnover. Accordingly, the functional assays showed enhanced Wnt/β-catenin signaling for these variants in a dominant negative manner. Contrarily, an individual with microcephalic NDD harbored a missense variant in the RSPO-binding domain predicted to disrupt binding affinity to RSPO and showed attenuated Wnt/β-catenin signaling in the same assays. Additionally, four individuals harbored de novo truncating or de novo or inherited large in-frame deletion variants with non-NDD phenotypes, including heart, adrenal, or nephrotic problems. In contrast to NDD-associated missense variants, the effects on Wnt/β-catenin signaling were comparable between the truncating variant and the empty vector and between benign variants and the wild type. In summary, we provide evidence for mirror brain size phenotypes caused by distinct pathomechanisms in Wnt/β-catenin signaling through protein domain-specific deleterious ZNRF3 germline missense variants