A paREDOX in the control of cholesterol biosynthesis: Does the NADPH sensor and E3 ubiquitin ligase MARCHF6 protect mammalian cells during oxidative stress by controlling sterol biosynthesis?

Sterols and the reductant nicotinamide adenine dinucleotide phosphate (NADPH), essential for eukaryotic life, arose because of, and as an adaptation to, rising levels of molecular oxygen (O2). Hence, the NADPH and O2-intensive process of sterol biosynthesis is inextricably linked to redox status. In mammals, cholesterol biosynthesis is exquisitely regulated post-translationally by multiple E3 ubiquitin ligases, with membrane associated Really Interesting New Gene (RING) C3HC4 finger 6 (MARCHF6) degrading at least six enzymes in the pathway. Intriguingly, all these MARCHF6-dependent enzymes require NADPH. Moreover, MARCHF6 is activated by NADPH, although what this means for control of cholesterol synthesis is unclear. Indeed, this presents a paradox for how NADPH regulates this vital pathway, since NADPH is a cofactor in cholesterol biosynthesis and yet, low levels of NADPH should spare cholesterol biosynthesis enzymes targeted by MARCHF6 by reducing its activity. We speculate MARCHF6 helps mammalian cells adapt to oxidative stress (signified by low NADPH levels) by reducing degradation of cholesterogenic enzymes, thereby maintaining synthesis of protective cholesterol.

Impact of changing climate on bryophyte contributions to terrestrial water, carbon, and nitrogen cycles.

Bryophytes, including the lineages of mosses, liverworts, and hornworts, are the second-largest photoautotroph group on Earth. Recent work across terrestrial ecosystems has highlighted how bryophytes retain and control water, fix substantial amounts of carbon (C), and contribute to nitrogen (N) cycles in forests (boreal, temperate, and tropical), tundra, peatlands, grasslands, and deserts. Understanding how changing climate affects bryophyte contributions to global cycles in different ecosystems is of primary importance. However, because of their small physical size, bryophytes have been largely ignored in research on water, C, and N cycles at global scales. Here, we review the literature on how bryophytes influence global biogeochemical cycles, and we highlight that while some aspects of global change represent critical tipping points for survival, bryophytes may also buffer many ecosystems from change due to their capacity for water, C, and N uptake and storage. However, as the thresholds of resistance of bryophytes to temperature and precipitation regime changes are mostly unknown, it is challenging to predict how long this buffering capacity will remain functional. Furthermore, as ecosystems shift their global distribution in response to changing climate, the size of different bryophyte-influenced biomes will change, resulting in shifts in the magnitude of bryophyte impacts on global ecosystem functions.

How will climate change and forest harvesting influence the habitat quality of two culturally salient species?

Boreal landscapes face increasing disturbances which can affect cultural keystone species, i.e. culturally salient species that shape in a major way the cultural identity of a people. Given their importance, the fate of such species should be assessed to be able to act to ensure their perennity. We assessed how climate change and forest harvesting will affect the habitat quality of Rhododendron groenlandicum and Vaccinium angustifolium, two cultural keystone species for many Indigenous peoples in eastern Canada. We used the forest landscape model LANDIS-II in combination with species distribution models to simulate the habitat quality of these two species on the territories of three Indigenous communities according to different climate change and forest harvesting scenarios. Climate-sensitive parameters included wildfire regimes as well as tree growth. Moderate climate change scenarios were associated with an increased proportion of R. groenlandicum and V. angustifolium in the landscape, the latter species also responding positively to severe climate change scenarios. Harvesting had a minimal effect, but slightly decreased the probability of presence of both species where it occurred. According to the modeling results, neither species is at risk under moderate climate change scenarios. However, under severe climate change, R. groenlandicum could decline as the proportion of deciduous trees would increase in the landscape. Climate change mitigation strategies, such as prescribed fires, may be necessary to limit this increase. This would prevent the decrease of R. groenlandicum, as well as contribute to preserve biodiversity and harvestable volumes.

A tale of 2 gasses, 1 regulator, and cholesterol homeostasis.

There is a burgeoning appreciation for the wide-ranging effects of carbon dioxide on transcriptional regulation and metabolism. Here, Bolshette and colleagues provide the first link between carbon dioxide and the master transcriptional regulator of cholesterol homeostasis.

Using technology to encourage ward-culture change and provide individualised bladder care.

When discussing continence care in an acute hospital setting, it can be viewed as a negative subject that is a thinly veiled jab at overstretched nurses. This article takes a fresh and holistic look at continence care, identifying factors that could be causing poor care and how technology could support a change in care. This article includes suggestions on how the data collected could be used to deliver the person-centred care outcomes that may be lacking in some environments, something that one of the authors (DP) has experienced first hand. This article describes the results of a recent trial at Ysbyty Cwm Cynon (Canon Valley Hospital), NHS Wales, which looked at how continence care technology could support positive care outcomes.

Out of site, out of mind: Changes in feather moss phyllosphere microbiota in mine offsite boreal landscapes.

Plant-microbe interactions play a crucial role in maintaining biodiversity and ecological services in boreal forest biomes. Mining for minerals, and especially the emission of heavy metal-enriched dust from mine sites, is a potential threat to biodiversity in offsite landscapes. Understanding the impacts of mining on surrounding phyllosphere microbiota is especially lacking. To investigate this, we characterized bacterial and fungal communities in the phyllosphere of feather moss Pleurozium schreberi (Brid). Mitt in boreal landscapes near six gold mine sites at different stages of the mine lifecycle. We found that (1) both mining stage and ecosystem type are drivers of the phyllosphere microbial community structure in mine offsite landscapes; (2) Bacterial alpha diversity is more sensitive than fungal alpha diversity to mining stage, while beta diversity of both groups is impacted; (3) mixed and deciduous forests have a higher alpha diversity and a distinct microbial community structure when compared to coniferous and open canopy ecosystems; (4) the strongest effects are detectable within 0.2 km from operating mines. These results confirmed the presence of offsite effects of mine sites on the phyllosphere microbiota in boreal forests, as well as identified mining stage and ecosystem type as drivers of these effects. Furthermore, the footprint was quantified at 0.2 km, providing a reference distance within which mining companies and policy makers should pay more attention during ecological assessment and for the development of mitigation strategies. Further studies are needed to assess how these offsite effects of mines affect the functioning of boreal ecosystems.

Cholesterol synthesis enzyme SC4MOL is fine-tuned by sterols and targeted for degradation by the E3 ligase MARCHF6.

Cholesterol biosynthesis is a highly regulated pathway, with over 20 enzymes controlled at the transcriptional and posttranslational levels. While some enzymes remain stable, increased sterol levels can trigger degradation of several synthesis enzymes via the ubiquitin-proteasome system. Of note, we previously identified four cholesterol synthesis enzymes as substrates for one E3 ubiquitin ligase, membrane-associated RING-CH-type finger 6 (MARCHF6). Whether MARCHF6 targets the cholesterol synthesis pathway at other points is unknown. In addition, the posttranslational regulation of many cholesterol synthesis enzymes, including the C4-demethylation complex (sterol-C4-methyl oxidase-like, SC4MOL; NAD(P)-dependent steroid dehydrogenase-like, NSDHL; hydroxysteroid 17-beta dehydrogenase, HSD17B7), is largely uncharacterized. Using cultured mammalian cell lines (human-derived and Chinese hamster ovary cells), we show SC4MOL, the first acting enzyme of C4-demethylation, is a MARCHF6 substrate and is rapidly turned over and sensitive to sterols. Sterol depletion stabilizes SC4MOL protein levels, while sterol excess downregulates both transcript and protein levels. Furthermore, we found SC4MOL depletion by siRNA results in a significant decrease in total cell cholesterol. Thus, our work indicates SC4MOL is the most regulated enzyme in the C4-demethylation complex. Our results further implicate MARCHF6 as a crucial posttranslational regulator of cholesterol synthesis, with this E3 ubiquitin ligase controlling levels of at least five enzymes of the pathway.

Refining sugar's involvement in cholesterol synthesis.

Glucose metabolism and cholesterol synthesis are often regarded in isolation. Increasing evidence not only links these pathways but also suggests glucose catabolism regulates cholesterol synthesis. Uptake of glucose increases cholesterol production. However, the precise mechanism by which this occurs is not fully understood and is likely to involve many aspects of cellular pathways participating in energy sensing, cholesterol regulation, and synthesis. Here, we review some interesting links between cholesterol synthesis and glucose metabolism. Given glucose breakdown produces energy (both via glycolysis and its products through oxidative phosphorylation), and considering cholesterol synthesis is an energetically demanding process, it would seem logical that glucose metabolism impacts cholesterol synthesis. The energy sensing kinase AMPK carefully monitors energy supply to induce or suppress cholesterol synthesis as needed. Akt, activated by the insulin signalling cascade, regulates key transcription factors involved in lipid metabolism. The insulin signalling pathway also activates machinery involved in the deubiquitination of a key cholesterol synthesis enzyme. Moreover, glucose metabolites, acetyl-CoA, and GlcNAc are substrates for protein acetylation and N-glycosylation, respectively, and can stabilise proteins involved in cholesterol synthesis. As glucose and cholesterol dysregulation are both associated with numerous diseases, understanding the mechanisms of how glucose metabolism and cholesterol synthesis intersect may offer new avenues for therapeutics that make use of these findings.

The Non Catalytic Protein ERG28 has a Functional Role in Cholesterol Synthesis and is Coregulated Transcriptionally.

The enzymatic pathway of cholesterol biosynthesis has been well characterized. However, there remain several potential interacting proteins that may play ancillary roles in the regulation of cholesterol production. Here, we identified ERG28 (chromosome 14 open reading frame 1 [C14orf1]), a homologue of the yeast protein Erg28p, as a player in mammalian cholesterol synthesis. ERG28 is conserved from yeast to humans but has been largely overlooked in mammals. Using quantitative RT-PCR, luciferase assays, and publicly available chromatin immunoprecipitation sequencing data, we found that transcription of this gene is driven by the transcription factor SREBP-2, akin to most cholesterol synthesis enzymes, as well as identifying sterol-responsive elements and cofactor binding sites in its proximal promoter. Based on a split luciferase system, ERG28 interacted with itself and two enzymes of cholesterol synthesis (NSDHL and SC4MOL). Huh7 ERG28-KO cell lines were generated, revealing reduced total cholesterol levels in sterol-depleted environments. In addition, radiolabeled metabolic flux assays showed a 60-75% reduction in the rate of cholesterol synthesis in the KO versus wild-type cells, which could be rescued by expression of ectopic ERG28. Unexpectedly, KO of ERG28 also impaired the activation of SREBP-2 under sterol-replete conditions, by a yet-to-be defined mechanism. These results indicate that ERG28 is clearly involved in cholesterol synthesis, although the precise role this noncatalytic protein plays in this complex metabolic pathway remains to be fully elucidated. A deeper understanding of ERG28, and other ancillary proteins of cholesterol synthesis, may help inform therapeutic strategies for diseases associated with aberrant cholesterol metabolism.

Dominance of coniferous and broadleaved trees drives bacterial associations with boreal feather mosses.

The composition of ecologically important moss-associated bacterial communities seems to be mainly driven by host species but may also be shaped by environmental conditions related with tree dominance. The moss phyllosphere has been studied in coniferous forests while broadleaf forests remain understudied. To determine if host species or environmental conditions defined by tree dominance drives the bacterial diversity in the moss phyllosphere, we used 16S rRNA gene amplicon sequencing to quantify changes in bacterial communities as a function of host species (Pleurozium schreberi and Ptilium crista-castrensis) and forest type (coniferous black spruce versus deciduous broadleaf trembling aspen) in eastern Canada. The overall composition of moss phyllosphere was defined by the interaction of both factors, though most of the bacterial phyla were determined by a strong effect of forest type. Bacterial α-diversity was highest in spruce forests, while there was greater turnover (ß-diversity) and higher γ-diversity in aspen forests. Unexpectedly, Cyanobacteria were much more relatively abundant in aspen than in spruce forests, with the cyanobacteria family Nostocaceae differing the most between forest types. Our results advance the understanding of moss-associated microbial communities among coniferous and broadleaf deciduous forests, which are important with the increasing changes in tree dominance in the boreal system.

Small but visible: Predicting rare bryophyte distribution and richness patterns using remote sensing-based ensembles of small models.

In Canadian boreal forests, bryophytes represent an essential component of biodiversity and play a significant role in ecosystem functioning. Despite their ecological importance and sensitivity to disturbances, bryophytes are overlooked in conservation strategies due to knowledge gaps on their distribution, which is known as the Wallacean shortfall. Rare species deserve priority attention in conservation as they are at a high risk of extinction. This study aims to elaborate predictive models of rare bryophyte species in Canadian boreal forests using remote sensing-derived predictors in an Ensemble of Small Models (ESMs) framework. We hypothesize that high ESMs-based prediction accuracy can be achieved for rare bryophyte species despite their low number of occurrences. We also assess if there is a spatial correspondence between rare and overall bryophyte richness patterns. The study area is located in western Quebec and covers 72,292 km2. We selected 52 bryophyte species with <30 occurrences from a presence-only database (214 species, 389 plots in total). ESMs were built from Random Forest and Maxent techniques using remote sensing-derived predictors related to topography and vegetation. Lee's L statistic was used to assess and map the spatial relationship between rare and overall bryophyte richness patterns. ESMs yielded poor to excellent prediction accuracy (AUC > 0.5) for 73% of the modeled species, with AUC values > 0.8 for 19 species, which confirmed our hypothesis. In fact, ESMs provided better predictions for the rarest bryophytes. Likewise, our study revealed a spatial concordance between rare and overall bryophyte richness patterns in different regions of the study area, which have important implications for conservation planning. This study demonstrates the potential of remote sensing for assessing and making predictions on inconspicuous and rare species across the landscape and lays the basis for the eventual inclusion of bryophytes into sustainable development planning.

Trends and gaps in the use of citizen science derived data as input for species distribution models: A quantitative review.

Citizen science (CS) currently refers to the participation of non-scientist volunteers in any discipline of conventional scientific research. Over the last two decades, nature-based CS has flourished due to innovative technology, novel devices, and widespread digital platforms used to collect and classify species occurrence data. For scientists, CS offers a low-cost approach of collecting species occurrence information at large spatial scales that otherwise would be prohibitively expensive. We examined the trends and gaps linked to the use of CS as a source of data for species distribution models (SDMs), in order to propose guidelines and highlight solutions. We conducted a quantitative literature review of 207 peer-reviewed articles to measure how the representation of different taxa, regions, and data types have changed in SDM publications since the 2010s. Our review shows that the number of papers using CS for SDMs has increased at approximately double the rate of the overall number of SDM papers. However, disparities in taxonomic and geographic coverage remain in studies using CS. Western Europe and North America were the regions with the most coverage (73%). Papers on birds (49%) and mammals (19.3%) outnumbered other taxa. Among invertebrates, flying insects including Lepidoptera, Odonata and Hymenoptera received the most attention. Discrepancies between research interest and availability of data were as especially important for amphibians, reptiles and fishes. Compared to studies on animal taxa, papers on plants using CS data remain rare. Although the aims and scope of papers are diverse, species conservation remained the central theme of SDM using CS data. We present examples of the use of CS and highlight recommendations to motivate further research, such as combining multiple data sources and promoting local and traditional knowledge. We hope our findings will strengthen citizen-researchers partnerships to better inform SDMs, especially for less-studied taxa and regions. Researchers stand to benefit from the large quantity of data available from CS sources to improve global predictions of species distributions.

Soil data for mapping paludification in black spruce forests of eastern Canada.

Soil data and soil mapping are indispensable tools in sustainable forest management. In northern boreal ecosystems, paludification is defined as the accumulation of partially decomposed organic matter over saturated mineral soils, a process that reduces tree regeneration and forest growth. Given this negative effect on forest productivity, spatial prediction of paludification in black spruce stands is important in forest management. This paper provides a description of the soil database to predict organic layer thickness (OLT) as a proxy of paludification in northeastern Canada. The database contains 13,944 OLT measurements (in cm) and their respective GPS coordinates. We collected OLT measurements from georeferenced ground plots and transects from several previous projects. Despite the variety of sources, the sampling design for each dataset was similar, consisting of manual measurements of OLT with a hand probe. OLT measurements were variable across the study area, with a mean ± standard deviation of 21 ± 24 cm (ranging from a minimum of 0 cm to a maximum of 150 cm), and the distribution tended toward positive skewing, with a large number of low OLT values and fewer high OLT values. The dataset has been used to perform OLT mapping at 30-m resolution and predict the risk of paludification in northeastern Canada (Mansuy et al., 2018) [1]. The spatially explicit and continuous database is also available to support national and international efforts in digital soil mapping.

Global trait-environment relationships of plant communities.

Plant functional traits directly affect ecosystem functions. At the species level, trait combinations depend on trade-offs representing different ecological strategies, but at the community level trait combinations are expected to be decoupled from these trade-offs because different strategies can facilitate co-existence within communities. A key question is to what extent community-level trait composition is globally filtered and how well it is related to global versus local environmental drivers. Here, we perform a global, plot-level analysis of trait-environment relationships, using a database with more than 1.1 million vegetation plots and 26,632 plant species with trait information. Although we found a strong filtering of 17 functional traits, similar climate and soil conditions support communities differing greatly in mean trait values. The two main community trait axes that capture half of the global trait variation (plant stature and resource acquisitiveness) reflect the trade-offs at the species level but are weakly associated with climate and soil conditions at the global scale. Similarly, within-plot trait variation does not vary systematically with macro-environment. Our results indicate that, at fine spatial grain, macro-environmental drivers are much less important for functional trait composition than has been assumed from floristic analyses restricted to co-occurrence in large grid cells. Instead, trait combinations seem to be predominantly filtered by local-scale factors such as disturbance, fine-scale soil conditions, niche partitioning and biotic interactions.

Resting cranial and upper cervical muscle activity is increased in patients with migraine.

OBJECTIVE: To compare comprehensive measures of scalp-recorded muscle activity in migraineurs and controls. METHOD: We used whole-of-head high-density scalp electrical recordings, independent component analysis (ICA) and spectral slope of the derived components, to define muscle (electromyogram-containing) components. After projecting muscle components back to scalp, we quantified scalp spectral power in the frequency range, 52-98 Hz, reflecting muscle activation. We compared healthy subjects (n = 65) and migraineurs during a non-headache period (n = 26). We also examined effects due to migraine severity, gender, scalp-region and task (eyes-closed and eyes-open). We could not examine the effect of pre-ictal versus inter-ictal versus post-ictal as this information was not available in the pre-existing dataset. RESULTS: There was more power due to muscle activity (mean ±â€¯SEM) in migraineurs than controls (respectively, -13.61 ±â€¯0.44 dB versus -14.73 ±â€¯0.24 dB, p = 0.028). Linear regression showed no relationship between headache frequency and muscle activity in any combination of region and task. There was more power during eyes-open than eyes-closed (respectively, -13.42 ±â€¯0.34 dB versus -14.92 ±â€¯0.34 dB, p = 0.002). CONCLUSIONS: There is an increase in cranial and upper cervical muscle activity in non-ictal migraineurs versus controls. This raises questions of the role of muscle in migraine, and the possible differentiation of non-ictal phases. SIGNIFICANCE: This provides preliminary evidence to date of possible cranial muscle involvement in migraine.

On the diversity and richness of understory bryophytes at Nectandra Cloud Forest Reserve, Costa Rica.

BACKGROUND: A survey of the understory bryophytes in the Nectandra Cloud Forest Preserve yielded 1083 specimens distributed among 55 families, represented by 74 genera of mosses, 75 genera of liverworts and 3 of hornworts. We studied and analyzed the bryophytic distribution on six types of substrates: 1) corticolous, 2) epiphyllous, 3) saxicolous, 4) terricolous, 5) aquatic and 6) lignicolous. The richness and composition of bryophyte genera are compared to those of other previous bryophyte surveys from 4 other sites with different oceanic exposures, climatic and geographic conditions in Costa Rica. NEW INFORMATION: This is a report of the first extensive general survey of bryophytes at the Nectandra Reserve, a premontane cloud forest located on the Atlantic slope of Costa Rica, an area much less studied compared to the Monteverde cloud forest on the Pacific slope.

Self-Management and Health Care Use in an Adolescent and Young Adult Medicaid Population With Differing Chronic Illnesses.

INTRODUCTION: Few studies of adults question the validity of the claim that self-management reduces the use of health care services and, as a result, health care costs. The aim of our study was to determine the relationship between self-management and health care use in a population of adolescent and young adult recipients of North Carolina Medicaid with chronic health conditions, who received care in either the pediatric or adult clinic. Our secondary objective was to characterize the patterns of health care use among this same population. METHODS: One hundred and fifty adolescents or young adults aged 14 to 29 were recruited for this study. Participants completed a demographics questionnaire and the self-management subdomain of the University of North Carolina TRxANSITION Scale. Information on each participant's emergency department and inpatient use was obtained by using the North Carolina Medicaid Provider Portal. RESULTS: This cohort had a high level of emergency health care use; average lifetime use was 3.18 (standard deviation [SD], 5.58) emergency department visits, 2.02 (SD, 3.42) inpatient visits, and 12.5 (SD, 23.9 ) days as an inpatient. Age group (pediatric or adult), diagnosis, race/ethnicity, and sex were controlled for in all analyses. Results indicate that patients with a high rate of disease self-management had more emergency department visits and hospitalizations and a longer length of stay in the hospital than did those with a low rate. CONCLUSION: In a group of North Carolina Medicaid recipients with chronic conditions, better self-management is associated with more health care use. This is likely the result of many factors, including more interactions with health care professionals, greater ability to recognize the need for emergency medical attention, and the use of the emergency department for primary health care.

Self-Management and Transition Readiness Assessment: Concurrent, Predictive and Discriminant Validation of the STARx Questionnaire.

INTRODUCTION: The STARx Questionnaire was designed with patient and provider input, to measure self-management and transition skills in adolescents and young adults (AYA) with chronic health conditions. With proven reliability and an empirically-based factor structure, the self-report STARx Questionnaire requires further validation to demonstrate its clinical and research utility. In this study we examine the concurrent, predictive, and discriminant validity of the STARx Questionnaire. METHODS: To examine concurrent validity, the STARx Questionnaire was compared to two other published transition readiness tools. Predictive validity was examined using linear regressions between the STARx Total Score and literacy, medication adherence, quality of life, and health services use. Discriminant validity was examined by comparing the performance of three chronic illness conditions on the STARx Total Score and associated subscales. RESULTS: The STARx Questionnaire and its subscales positively correlated with the scores for both transition readiness tools reflecting strong concurrent validity. The STARx Questionnaire also correlated positively with the literacy, self-efficacy, and adherence measures indicating strong predictive validity; however, it did not correlate with either quality of life or health care utilization. The performance of AYA across three different clinical conditions was not significant, indicating the clinical utility of this HCT tool for a variety of chronic health conditions. CONCLUSION: The strong validity of the STARx Questionnaire, in tandem with its strong reliability, indicated adequate psychometric properties for this generic self-report measure. These strong psychometric properties should contribute to the STARx being a viable measure of health care transition for both research and clinical purposes.

The relationship of health care transition readiness to disease-related characteristics, psychosocial factors, and health care outcomes: preliminary findings in adolescents with chronic kidney disease.

PURPOSE: The current study utilized the Disability-Stress-Coping Model to conceptualize how disease-related risk factors (disease severity, age of diagnosis, and disease burden) and psychosocial resilience factors (coping efficacy, family cohesion, and quality of life) influence health care transition (HCT) readiness when controlling for age and disease severity [1]. Additionally, the impact of low HCT readiness on emergency room visits and medication adherence was examined. METHODS: The sample was comprised of 41 adolescents with chronic kidney disease (CKD) who ranged in age from 13 to 18 years (Mean=15.7). Multiple regression analyses were conducted. RESULTS: None of the disease-related factors were associated with HCT readiness. Of the psychosocial factors, only family cohesion was a significant predictor and accounted for 10% unique variance. Transition readiness was significantly related to both the number of self-reported emergency room visits and medication adherence such that high readiness was related to fewer visits to the emergency room and better medication adherence; these variables accounted for 6.4% and 14.9% of the unique variance respectively. CONCLUSION: These findings suggest that disease-related risk factors may be less critical to predicting transition readiness than resilience factors such as family cohesion. Additionally, when adolescents have low transition readiness they are likely to experience significant negative health outcomes.