Identifying Key Drivers in the Pathogenesis of Martorell Hypertensive Ischaemic Leg Ulcer: A Comparative Analysis with Chronic Venous Leg Ulcer.

Martorell hypertensive ischaemic leg ulcer (Martorell HYTILU) is a rare but significant cause of distal leg ulcers. Although hypertension and diabetes are known factors in its development, the precise pathogenesis of Martorell HYTILU remains elusive. To reach a better understanding of Martorell HYTILU, transcriptomic analysis was conducted through RNA sequencing and immunohistochemical comparison of Martorell HYTILU (n = 17) with chronic venous ulcers (n = 4) and healthy skin (n = 4). Gene expression analysis showed a marked activation of immune-related pathways in both Martorell HYTILU and chronic venous ulcers compared with healthy skin. Notably, neutrophil activity was substantially higher in Martorell HYTILU. While pathway analysis revealed a mild downregulation of several immune pathways in Martorell HYTILU compared with chronic venous ulcers, keratinization, cornification, and epidermis development were significantly upregulated in Martorell HYTILU. Additionally, STAC2, a gene encoding for a protein promoting the expression of the calcium channel Cav1.1, was significantly upregulated in Martorell HYTILU and was detected perivascularly in situ (Martorell HYTILU n = 24; chronic venous ulcers n = 9, healthy skin n = 11). The high expression of STAC2 in Martorell HYTILU suggests that increased calcium influx plays an important role in the pathogenesis of the disease. Consequently, calcium channel antagonists could be a promising treatment avenue for Martorell HYTILU.

A very mild phenotype in six individuals of a three-generation family with the novel HRAS variant c.176C > G p.(Ala59Gly): Emergence of a new HRAS-related RASopathy distinct from Costello syndrome.

Costello syndrome is a clinically recognizable, severe neurodevelopmental disorder caused by heterozygous activating variants in HRAS. The vast majority of affected patients share recurring variants affecting HRAS codons 12 and 13 and a relatively uniform phenotype. Here, we report the unique and attenuated phenotype of six individuals of an extended family affected by the HRAS variant c.176C>T p.(Ala59Gly), which, to our knowledge, has never been reported as a germline variant in patients so far. HRAS Alanine 59 has been previously functionally investigated as an oncogenic hotspot and the p.Ala59Gly substitution was shown to impair intrinsic GTP hydrolysis. All six individuals we report share a phenotype of ectodermal anomalies and mild features suggestive of a RASopathy, reminiscent of patients with Noonan syndrome-like disorder with loose anagen hair. All six are of normal intelligence, none have a history of failure to thrive or malignancy, and they have no known cardiac or neurologic pathologies. Our report adds to the previous reports of patients with rare variants affecting amino acids located in the SWITCH II/G3 region of HRAS and suggests a consistent, attenuated phenotype distinct from classical Costello syndrome. We propose the definition of a new distinct HRAS-related RASopathy for patients carrying HRAS variants affecting codons 58, 59, 60.

Can we detect a nonlinear response to temperature in European plant phenology?

Over a large temperature range, the statistical association between spring phenology and temperature is often regarded and treated as a linear function. There are suggestions that a sigmoidal relationship with definite upper and lower limits to leaf unfolding and flowering onset dates might be more realistic. We utilised European plant phenological records provided by the European phenology database PEP725 and gridded monthly mean temperature data for 1951-2012 calculated from the ENSEMBLES data set E-OBS (version 7.0). We analysed 568,456 observations of ten spring flowering or leafing phenophases derived from 3657 stations in 22 European countries in order to detect possible nonlinear responses to temperature. Linear response rates averaged for all stations ranged between -7.7 (flowering of hazel) and -2.7 days °C-1 (leaf unfolding of beech and oak). A lower sensitivity at the cooler end of the temperature range was detected for most phenophases. However, a similar lower sensitivity at the warmer end was not that evident. For only ∼14 % of the station time series (where a comparison between linear and nonlinear model was possible), nonlinear models described the relationship significantly better than linear models. Although in most cases simple linear models might be still sufficient to predict future changes, this linear relationship between phenology and temperature might not be appropriate when incorporating phenological data of very cold (and possibly very warm) environments. For these cases, extrapolations on the basis of linear models would introduce uncertainty in expected ecosystem changes.

From observations to experiments in phenology research: investigating climate change impacts on trees and shrubs using dormant twigs.

BACKGROUND AND AIMS: Climate change is advancing the leaf-out times of many plant species and mostly extending the growing season in temperate ecosystems. Laboratory experiments using twig cuttings from woody plant species present an affordable, easily replicated approach to investigate the relative importance of factors such as winter chilling, photoperiod, spring warming and frost tolerance on the leafing-out times of plant communities. This Viewpoint article demonstrates how the results of these experiments deepen our understanding beyond what is possible via analyses of remote sensing and field observation data, and can be used to improve climate change forecasts of shifts in phenology, ecosystem processes and ecological interactions. SCOPE: The twig method involves cutting dormant twigs from trees, shrubs and vines on a single date or at intervals over the course of the winter and early spring, placing them in containers of water in controlled environments, and regularly recording leaf-out, flowering or other phenomena. Prior to or following leaf-out or flowering, twigs may be assigned to treatment groups for experiments involving temperature, photoperiod, frost, humidity and more. Recent studies using these methods have shown that winter chilling requirements and spring warming strongly affect leaf-out and flowering times of temperate trees and shrubs, whereas photoperiod requirements are less important than previously thought for most species. Invasive plant species have weaker winter chilling requirements than native species in temperate ecosystems, and species that leaf-out early in the season have greater frost tolerance than later leafing species. CONCLUSIONS: This methodology could be extended to investigate additional drivers of leaf-out phenology, leaf senescence in the autumn, and other phenomena, and could be a useful tool for education and outreach. Additional ecosystems, such as boreal, southern hemisphere and sub-tropical forests, could also be investigated using dormant twigs to determine the drivers of leaf-out times and how these ecosystems will be affected by climate change.

Chilling outweighs photoperiod in preventing precocious spring development.

It is well known that increased spring temperatures cause earlier onset dates of leaf unfolding and flowering. However, a temperature increase in winter may be associated with delayed development when species' chilling requirements are not fulfilled. Furthermore, photosensitivity is supposed to interfere with temperature triggers. To date, neither the relative importance nor possible interactions of these three factors have been elucidated. In this study, we present a multispecies climate chamber experiment to test the effects of chilling and photoperiod on the spring phenology of 36 woody species. Several hypotheses regarding their variation with species traits (successional strategy, floristic status, climate of their native range) were tested. Long photoperiods advanced budburst for one-third of the studied species, but magnitudes of these effects were generally minor. In contrast to prior hypotheses, photosensitive responses were not restricted to climax or oceanic species. Increased chilling length advanced budburst for almost all species; its effect greatly exceeding that of photoperiod. Moreover, we suggest that photosensitivity and chilling effects have to be rigorously disentangled, as the response to photoperiod was restricted to individuals that had not been fully chilled. The results indicate that temperature requirements and successional strategy are linked, with climax species having higher chilling and forcing requirements than pioneer species. Temperature requirements of invasive species closely matched those of native species, suggesting that high phenological concordance is a prerequisite for successful establishment. Lack of chilling not only led to a considerable delay in budburst but also caused substantial changes in the chronological order of species' budburst. The results reveal that increased winter temperatures might impact forest ecosystems more than formerly assumed. Species with lower chilling requirements, such as pioneer or invasive species, might profit from warming winters, if late spring frost events would in parallel occur earlier.

The genetic landscape and clinical implication of pediatric Moyamoya angiopathy in an international cohort.

Pediatric Moyamoya Angiopathy (MMA) is a progressive intracranial occlusive arteriopathy that represents a leading cause of transient ischemic attacks and strokes in childhood. Despite this, up to now no large, exclusively pediatric MMA cohort has been subjected to systematic genetic investigation. In this study, we performed molecular karyotyping, exome sequencing and automated structural assessment of missense variants on a series of 88 pediatric MMA patients and correlated genetic, angiographic and clinical (stroke burden) findings. The two largest subgroups in our cohort consisted of RNF213 and neurofibromatosis type 1 (NF1) patients. While deleterious RNF213 variants were associated with a severe MMA clinical course with early symptom onset, frequent posterior cerebral artery involvement and higher stroke rates in multiple territories, NF1 patients had a similar infarct burden compared to non-NF1 individuals and were often diagnosed incidentally during routine MRIs. Additionally, we found that MMA-associated RNF213 variants have lower predicted functional impact compared to those associated with aortic disease. We also raise the question of MMA as a feature of recurrent as well as rare chromosomal imbalances and further support the possible association of MMA with STAT3 deficiency. In conclusion, we provide a comprehensive characterization at the genetic and clinical level of a large exclusively pediatric MMA population. Due to the clinical differences found across genetic subgroups, we propose genetic testing for risk stratification as part of the routine assessment of pediatric MMA patients.