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Abstract We combine forward stratigraphic models with a suite of uncertainty quantification and stochastic model calibration algorithms for the characterization of sedimentary successions in large scale systems. The analysis focuses on the information value provided by a probabilistic approach in the modelling of large-scale sedimentary basins. Stratigraphic forward models (SFMs) require a large number of input parameters usually affected by uncertainty. Thus, model calibration requires considerable time both in terms of human and computational resources, an issue currently limiting the applications of SFMs. Our work tackles this issue through the combination of sensitivity analysis, model reduction techniques and machine learning-based optimization algorithms. We first employ a two-step parameter screening procedure to identify relevant parameters and their assumed probability distributions. After selecting a restricted set of important parameters these are calibrated against available information, i.e., the depth of interpreted stratigraphic surfaces. Because of the large costs associated with SFM simulations, probability distributions of model parameters and outputs are obtained through a data driven reduced complexity model. Our study demonstrates the numerical approaches by considering a portion of the Porcupine Basin, Ireland. Results of the analysis are postprocessed to assess (i) the uncertainty and practical identifiability of model parameters given a set of observations, (ii) spatial distribution of lithologies. We analyse here the occurrences of sand bodies pinching against the continental slope, these systems likely resulting from gravity driven processes in deep sea environment.

Bark and ambrosia beetles are among the most ecologically and economically damaging introduced plant pests worldwide. Life history traits including polyphagy, haplodiploidy, inbreeding polygyny, and symbiosis with fungi contribute to their dispersal and impact. Species vary in their interactions with host trees, with many attacking stressed or recently dead trees, such as the globally distributed Euwallacea similis (Ferrari). Other species, like the Polyphagous Shot Hole Borer Euwallacea fornicatus (Eichhoff), can attack over 680 host plants and is causing considerable economic damage in several countries. Despite their notoriety, publicly accessible genomic resources for Euwallacea Hopkins species are scarce, hampering our understanding of their invasive capabilities as well as modern control measures, surveillance, and management. Using a combination of long and short read sequencing platforms, we assembled and annotated high quality (BUSCO > 98% complete) pseudo-chromosome-level genomes for these species. Comparative macrosynteny analysis identified an increased number of pseudo-chromosome scaffolds in the haplodiploid inbreeding species of Euwallacea compared to diploid outbred species, due to fission events. This suggests that life history traits can impact chromosome structure. Further, the genome of E. fornicatus had a higher relative proportion of repetitive elements, up to 17% more, than E. similis. Metagenomic assembly pipelines identified microbiota associated with both species including Fusarium fungal symbionts and a novel Wolbachia strain. These novel genomes of haplodiploid inbreeding species will contribute to the understanding of how life history traits are related to their evolution and to the management of these invasive pests., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

Introduction: Adaptive behavior, defined as a critical set of skills learned and performed throughout daily life to cope with society's age-appropriate expectations, is a central concept for people with disabilities in both clinical and research contexts. As AB is an essential component of daily functioning, assessment is necessary both for the diagnostic process and for intervention, as it enables scores to be compared with the developmental norm, identifies strengths and weaknesses of the persons and monitors the progress of interventions. AB assessment is common in children with developmental delays but less common in children with visual impairment (VI). The aim of this study was to evaluate the AB of young children with VI through a pilot study and descriptive data., Methods: The participants were recruited through an early childhood special needs education service specialized in VI in the French-speaking part of Switzerland. Overall, 10 families gave their consent for their child to be assessed using the Vineland Adaptative Behavior Scale-II (VABS-II) completed by their early childhood educator., Results: Globally, the results showed that participants were rated between the Adapted to Moderately High levels. The highest domains were in the areas of communication, daily living skills and socialization., Discussion: The results showed a trend that is superior to previous studies assessing the AB of a similar population. As a result, one obvious perspective would be to adapt the scale to ensure that the items assessed are more consistent with the specificities of their development and the intervention priorities, enabling them to achieve adaptive behavior and independence in carrying out activities of daily living.

Background: Nor1/NR4A3 is a member of the NR4A subfamily of nuclear receptors that play essential roles in regulating gene expression related to development, cell homeostasis and neurological functions. However, Nor1 is still considered an orphan receptor, as its natural ligand remains unclear for mediating transcriptional activation. Yet other activation signals may modulate Nor1 activity, although their precise role in the development and maintenance of the nervous system remains elusive., Methods: We used transcriptional reporter assays, gene expression profiling, protein turnover measurement, and cell growth assays to assess the functional relevance of Nor1 and SUMO-defective variants in neuronal cells. SUMO1 and SUMO2 conjugation to Nor1 were assessed by immunoprecipitation. Tubulin stability was determined by acetylation and polymerization assays, and live-cell fluorescent microscopy., Results: Here, we demonstrate that Nor1 undergoes SUMO1 conjugation at Lys-89 within a canonical ψKxE SUMOylation motif, contributing to the complex pattern of Nor1 SUMOylation, which also includes Lys-137. Disruption of Lys-89, thereby preventing SUMO1 conjugation, led to reduced Nor1 transcriptional competence and protein stability, as well as the downregulation of genes involved in cell growth and metabolism, such as ENO3, EN1, and CFLAR, and in microtubule cytoskeleton dynamics, including MAP2 and MAPT, which resulted in reduced survival of neuronal cells. Interestingly, Lys-89 SUMOylation was potentiated in response to nocodazole, a microtubule depolymerizing drug, although this was insufficient to rescue cells from microtubule disruption despite enhanced Nor1 gene expression. Instead, Lys-89 deSUMOylation reduced the expression of microtubule-severing genes like KATNA1, SPAST, and FIGN, and enhanced α-tubulin cellular levels, acetylation, and microfilament organization, promoting microtubule stability and resistance to nocodazole. These effects contrasted with Lys-137 SUMOylation, suggesting distinct regulatory mechanisms based on specific Nor1 input SUMOylation signals., Conclusions: Our study provides novel insights into Nor1 transcriptional signaling competence and identifies a hierarchical mechanism whereby selective Nor1 SUMOylation may govern neuronal cytoskeleton network dynamics and resistance against microtubule disturbances, a condition strongly associated with neurodegenerative diseases., (© 2024. The Author(s).)

Four invasive Mediterranean snails, i.e., Theba pisana (Müller, 1774), Cernuella virgata (da Costa, 1778), Cochlicella acuta (Müller, 1774) and Cochlicella barbara (Linnaeus, 1758) cost $170 million yearly to the grain industry in Australia. Their impact is mainly due to their estivation behavior: snails climb on cereal and legume stalks to rest during summer, which coincides with harvest, causing grain contamination issues in crops such as wheat, barley and canola. Diverse management methods have been developed to regulate snail populations, with limited success. Our study investigates the potential for a push-pull strategy to divert invasive snails from cultivated fields. A "push" part (i.e. using a repellent stimuli) was based on the use of a chemical deterrent repelling snails from the cultivated field, and a "pull" part (i.e. using an attractive stimuli) was based on offering attractive estivation supports for snails to aggregate outside the cultivated field. First, artificial estivation supports of different colors were tested under laboratory and field conditions and showed that red supports were the most attractive for these snails. Second, different substances were tested as potential snail deterrents (garlic, coffee, coffee grounds, copper). Garlic extracts were the most powerful snail deterrent and were shown to effectively protect an estivation support and food source from snails under laboratory conditions. These results, which were highly consistent for the four species, illustrate the potential of a push-pull strategy against invasive snails in Australia. It is the first attempt to develop a push-pull strategy relying on both visual and chemical stimuli to achieve results, as well as manipulating the estivation behavior of a pest., (© 2024. Crown.)

Interference competition has the potential to alter avian assemblages at long-lasting arid zone waterholes, particularly in a warming world, as more potentially aggressive species frequent these sites to drink. We used camera traps and observational surveys to investigate interference competition between terrestrial avian species at six long-lasting waterholes across three sampling seasons (two summers and one winter) within the MacDonnell Ranges Bioregion in central Australia. The proportion of individuals drinking for each of four dietary classes (granivores, nectarivores, omnivores, and insectivores) was modelled in relation to their abundance in the immediate waterhole habitat, which informed the potential for competition in each season. We then used the temporal overlap estimators to quantify the degree of competition between species at waterholes with species grouped into families (Meliphagidae, Ptilonorhynchidae, Estrildidae, and Rhipiduridae). We found the proportion of individuals drinking at waterholes was greatest during hot and dry periods, suggesting the potential for interference competition is greatest during these times. This was particularly the case for nectarivores where, in hot and dry conditions, the proportion of drinking individuals increased significantly as their abundance also increased in the waterhole habitat. We predicted that subordinate species would alter their activity periods to avoid competitive interactions with meliphagids (honeyeaters), however, we found there was a high degree of temporal overlap between all families sampled across all seasons. These results suggest subordinate species are unlikely to be excluded from long-lasting waterholes by potentially aggressive species, such as honeyeaters. However, some species may face trade-offs between foraging and accessing waterholes to stay hydrated as they shift their activity to avoid the hottest parts of the day during the summer months. Under global warming, extended hot and dry periods will likely create conditions where balancing energy and hydration requirements becomes increasingly difficult and results in the loss of body condition., (© 2023 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Purpose: Dominant variants in the retinoic acid receptor beta (RARB) gene underlie a syndromic form of microphthalmia, known as MCOPS12, which is associated with other birth anomalies and global developmental delay with spasticity and/or dystonia. Here, we report 25 affected individuals with 17 novel pathogenic or likely pathogenic variants in RARB. This study aims to characterize the functional impact of these variants and describe the clinical spectrum of MCOPS12., Methods: We used in vitro transcriptional assays and in silico structural analysis to assess the functional relevance of RARB variants in affecting the normal response to retinoids., Results: We found that all RARB variants tested in our assays exhibited either a gain-of-function or a loss-of-function activity. Loss-of-function variants disrupted RARB function through a dominant-negative effect, possibly by disrupting ligand binding and/or coactivators' recruitment. By reviewing clinical data from 52 affected individuals, we found that disruption of RARB is associated with a more variable phenotype than initially suspected, with the absence in some individuals of cardinal features of MCOPS12, such as developmental eye anomaly or motor impairment., Conclusion: Our study indicates that pathogenic variants in RARB are functionally heterogeneous and associated with extensive clinical heterogeneity., Competing Interests: Conflict of Interest J.R.L. owns stock in 23andMe and is a paid consultant for Genome International. All other authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Exotic dung beetles have been introduced to Australia for over 50 years to mitigate issues caused by dung produced by livestock. This study aims at identifying fungi affecting a beetle colony and investigating their source. Fungal hyphae emerging from the cuticle of dead beetles were cultured and a multigene phylogeny showed that Beauveria bassiana and B. australis both infected these introduced beetles, likely acquired through local soil or dung. This is the first record of B. australis infecting family Scarabaeidae. This study highlights the importance of fungal outbreak management in insect rearing before release, and challenges associated with new pathogens., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Central response to insulin is suspected to be defective in Alzheimer's disease. As most insulin is secreted in the bloodstream by the pancreas, its capacity to regulate brain functions must, at least partly, be mediated through the cerebral vasculature. However, how insulin interacts with the blood-brain barrier and whether alterations of this interaction could contribute to Alzheimer's disease pathophysiology both remain poorly defined. Here, we show that human and murine cerebral insulin receptors (INSRs), particularly the long isoform INSRα-B, are concentrated in microvessels rather than in the parenchyma. Vascular concentrations of INSRα-B were lower in the parietal cortex of subjects diagnosed with Alzheimer's disease, positively correlating with cognitive scores, leading to a shift towards a higher INSRα-A/B ratio, consistent with cerebrovascular insulin resistance in the Alzheimer's disease brain. Vascular INSRα was inversely correlated with amyloid-β plaques and β-site APP cleaving enzyme 1, but positively correlated with insulin-degrading enzyme, neprilysin and P-glycoprotein. Using brain cerebral intracarotid perfusion, we found that the transport rate of insulin across the blood-brain barrier remained very low (<0.03 µl/g·s) and was not inhibited by an insulin receptor antagonist. However, intracarotid perfusion of insulin induced the phosphorylation of INSRβ that was restricted to microvessels. Such an activation of vascular insulin receptor was blunted in 3xTg-AD mice, suggesting that Alzheimer's disease neuropathology induces insulin resistance at the level of the blood-brain barrier. Overall, the present data in post-mortem Alzheimer's disease brains and an animal model of Alzheimer's disease indicate that defects in the insulin receptor localized at the blood-brain barrier strongly contribute to brain insulin resistance in Alzheimer's disease, in association with β-amyloid pathology., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Lay Abstract: What is already known about the topic? Quality of life refers to how people perceive aspects of their life such as physical health, material security, and interpersonal relationships. Studies have reported lower quality of life among autistic individuals than in the general population. What does this article contribute? This article contributes to a better understanding of quality of life and its measures from the point of view of autistic adults. By comparing two groups of French-speaking autistic adults from two different places (France and Québec-Canada), this research shows that the perception of quality of life and its determining factors differ for autistic adults living in each country. The Québec group reported a superior quality of life, and some quality of life predictors were different in each group. The social experience of autism-related stigmatization, however, was a powerful predictor of quality of life for all. Implications for practice, research, and policy To promote a higher quality of life for autistic people, it is important to consider the sociocultural context and implement awareness programs and public campaigns aimed at identifying and countering stigmatization processes.

Terrestrial snails that live in hot and dry climates have developed strategies to cope with high summer temperatures. Several species estivate during the warmest months of the years by resting on vertical supports, typically in groups. Understanding how snails choose their estivation sites and aggregate may lead to the development of new management tools in areas where these snails are invasive. Here, we investigated the preferences of four snail species for vertical supports varying in widths and heights under laboratory and field conditions, and tested whether the presence of conspecifics or snails of other species affected these preferences. The results show that the snails strongly preferred wider supports in laboratory dual-choice tests, and one species ( Theba &nbsp; pisana ) showed a consistent preference for taller supports as well. These results were confirmed in the field, where more snails were found on wider and taller supports 24 h after being placed in test quadrats. The percentage of snails found in groups on a support was strongly density-dependent. The presence of conspecifics or their mucus did not affect the choices of the snails, nor did the presence of snails of other species or their mucus. Taken together, these results could lead to the development of attractive supports that could be used to mass-capture snails in the field.

Background: Vitamin A (VitA), via its active metabolite retinoic acid (RA), is critical for the maintenance of memory function with advancing age. Although its role in Alzheimer's disease (AD) is not well understood, data suggest that impaired brain VitA signaling is associated with the accumulation of β-amyloid peptides (Aβ), and could thus contribute to the onset of AD., Methods: We evaluated the protective action of a six-month-long dietary VitA-supplementation (20 IU/g), starting at 8 months of age, on the memory and the neuropathology of the 3xTg-AD mouse model of AD (n = 11-14/group; including 4-6 females and 7-8 males). We also measured protein levels of Retinoic Acid Receptor β (RARβ) and Retinoid X Receptor γ (RXRγ) in homogenates from the inferior parietal cortex of 60 participants of the Religious Orders study (ROS) divided in three groups: no cognitive impairment (NCI) (n = 20), mild cognitive impairment (MCI) (n = 20) and AD (n = 20)., Results: The VitA-enriched diet preserved spatial memory of 3xTg-AD mice in the Y maze. VitA-supplementation affected hippocampal RXR expression in an opposite way according to sex by tending to increase in males and decrease in females their mRNA expression. VitA-enriched diet also reduced the amount of hippocampal Aβ 40 and Aβ 42 , as well as the phosphorylation of tau protein at sites Ser396/Ser404 (PHF-1) in males. VitA-supplementation had no effect on tau phosphorylation in females but worsened their hippocampal Aβ load. However, the expression of Rxr-β in the hippocampus was negatively correlated with the amount of both soluble and insoluble Aβ in both males and females. Western immunoblotting in the human cortical samples of the ROS study did not reveal differences in RARβ levels. However, it evidenced a switch from a 60-kDa-RXRγ to a 55-kDa-RXRγ in AD, correlating with ante mortem cognitive decline and the accumulation of neuritic plaques in the brain cortex., Conclusion: Our data suggest that (i) an altered expression of RXRs receptors is a contributor to β-amyloid pathology in both humans and 3xTg-AD mice, (ii) a chronic exposure of 3xTg-AD mice to a VitA-enriched diet may be protective in males, but not in females., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Context: Intrauterine growth restriction (IUGR) is an immediate outcome of an adverse womb environment, exposing newborns to developing cardiometabolic disorders later in life., Objective: This study investigates the cardiac metabolic consequences and underlying mechanism of energy expenditure in developing fetuses under conditions of IUGR., Methods: Using an animal model of IUGR characterized by uteroplacental vascular insufficiency, mitochondrial function, gene profiling, lipidomic analysis, and transcriptional assay were determined in fetal cardiac tissue and cardiomyocytes., Results: IUGR fetuses exhibited an upregulation of key genes associated with fatty acid breakdown and β-oxidation (Acadvl, Acadl, Acaa2), and mitochondrial carnitine shuttle (Cpt1a, Cpt2), instigating a metabolic gene reprogramming in the heart. Induction of Ech1, Acox1, Acox3, Acsl1, and Pex11a indicated a coordinated interplay with peroxisomal β-oxidation and biogenesis mainly observed in females, suggesting sexual dimorphism in peroxisomal activation. Concurring with the sex-related changes, mitochondrial respiration rates were stronger in IUGR female fetal cardiomyocytes, accounting for enhanced adenosine 5'-triphosphate production. Mitochondrial biogenesis was induced in fetal hearts with elevated expression of Ppargc1a transcript specifically in IUGR females. Lipidomic analysis identified the accumulation of arachidonic, eicosapentaenoic, and docosapentaenoic polyunsaturated long-chain fatty acids (LCFAs) in IUGR fetal hearts, which leads to nuclear receptor peroxisome proliferator-activated receptor α (PPARα) transcriptional activation in cardiomyocytes. Also, the enrichment of H3K27ac chromatin marks to PPARα-responsive metabolic genes in IUGR fetal hearts outlines an epigenetic control in the early metabolic energy switch., Conclusion: This study describes a premature and sex-related remodeling of cardiac metabolism in response to an unfavorable intrauterine environment, with specific LCFAs that may serve as predictive effectors leading to IUGR., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Neuron-derived orphan receptor 1, NR4A3 (Nor1)/NR4A3 is an orphan nuclear receptor involved in the transcriptional control of developmental and neurological functions. Oxidative stress-induced conditions are primarily associated with neurological defects in humans, yet the impact on Nor1-mediated transcription of neuronal genes remains with unknown mechanism. Here, we demonstrate that Nor1 is a non-conventional target of SUMO2/3 conjugation at Lys-137 contained in an atypic ψKxSP motif referred to as the pSuM. Nor1 pSuM SUMOylation differs from the canonical process with the obligate phosphorylation of Ser-139 by Ras signaling to create the required negatively charged interface for SUMOylation. Additional phosphorylation at sites flanking the pSuM is also mediated by the coordinated action of protein kinase casein kinase 2 to function as a small ubiquitin-like modifier enhancer, regulating Nor1-mediated transcription and proteasomal degradation. Nor1 responsive genes involved in cell proliferation and metabolism, such as activating transcription factor 3, cyclin D1, CASP8 and FADD-like apoptosis regulator, and enolase 3 were upregulated in response to pSuM disruption in mouse HT-22 hippocampal neuronal cells and human neuroblastoma SH-SY5Y cells. We also identified critical antioxidant genes, such as catalase, superoxide dismutase 1, and microsomal glutathione S-transferase 2, as responsive targets of Nor1 under pSuM regulation. Nor1 SUMOylation impaired gene transcription through less effective Nor1 chromatin binding and reduced enrichment of histone H3K27ac marks to gene promoters. These effects resulted in decreased neuronal cell growth, increased apoptosis, and reduced survival to oxidative stress damage, underlying the role of pSuM-modified Nor1 in redox homeostasis. Our findings uncover a hierarchical post-translational mechanism that dictates Nor1 non-canonical SUMOylation, disrupting Nor1 transcriptional competence, and neuroprotective redox sensitivity., (© 2021 Federation of American Societies for Experimental Biology.)

The brown marmorated stink bug Halyomorpha halys (Stål) (Hemiptera: Pentatomidae) is native to Northeast Asia, but has become a serious invasive species in North America and Europe, causing major damage to crops. While it has not established itself in Australia, it has been intercepted at the border several times, indicating that future incursions and establishment are a case of when, not if. Biological control is one of the few control options for this species and will be important for managing H. halys should it become established in Australia. Prioritizing species that could be used as biological control agents would ensure Australia is prepared. This study summarizes the literature on natural enemies of H. halys in its native and invaded ranges and prioritizes potential biological control agents of H. halys that could be used in Australia. Two egg parasitoid species were identified: Trissolcus japonicus (Ashmead) and Trissolcus mitsukurii (Ashmead) (Hymenoptera: Scelionidae). Future efforts to develop biological control should focus on T. mitsukurii , as it is already present in Australia. However, little is known about this species and further work is required to: (1) assess its potential effectiveness in parasitizing H. halys , (2) determine its current distribution and (3) host range in Australia.

The brown marmorated stink bug, Halyomorpha halys (Stål) (Hemiptera: Pentatomidae), is native to northeast Asia. It was accidentally introduced to Europe and North America, where it has become a key pest, feeding on many important crops. Previous eco-climatic niche modelling indicates that H. halys could expand its distribution vastly, and numerous border interceptions of this pest in many countries, including Australia and New Zealand, indicate that it would be prudent to prepare for its eventual arrival. Similar niche modelling was used to assess the potential distribution of Trissolcus japonicus (Ashmead) (Hymenoptera: Scelionidae), the key parasitoid of H. halys in China. Trissolcus mitsukurii (Ashmead) is one of the main parasitoids of H. halys in Japan. It is known to have existed in Australia since the early 20th century and was also specifically introduced to Australia in the 1960s, and it has now also invaded Italy. We used CLIMEX to model the climatic niche of T. mitsukurii to estimate its global potential distribution. We found that T. mitsukurii should be able to significantly expand its range globally, and that there is a significant degree of overlap in the projected ranges of T. mitsukurii , T. japonicus and H. halys . From a biological control perspective, this implies that the two Trissolcus species may be able to help mitigate the potential impacts of H. halys .

Background: Alzheimer's disease (AD) is a multifactorial disease, implying that multi-target treatments may be necessary to effectively cure AD. Tetrahydrobiopterin (BH4) is an enzymatic cofactor required for the synthesis of monoamines and nitric oxide that also exerts antioxidant and anti-inflammatory effects. Despite its crucial role in the CNS, the potential of BH4 as a treatment in AD has never been scrutinized., Objective: Here, we investigated whether BH4 peripheral administration improves cognitive symptoms and AD neuropathology in the triple-transgenic mouse model of AD (3xTg-AD), a model of age-related tau and amyloid-β (Aβ) neuropathologies associated with behavior impairment., Methods: Non-transgenic (NonTg) and 3xTg-AD mice were subjected to a control diet (5% fat - CD) or to a high-fat diet (35% fat - HFD) from 6 to 13 months to exacerbate metabolic disorders. Then, mice received either BH4 (15 mg/kg/day, i.p.) or vehicle for ten consecutive days., Results: This sub-chronic administration of BH4 rescued memory impairment in 13-month-old 3xTg-AD mice, as determined using the novel object recognition test. Moreover, the HFD-induced glucose intolerance was completely reversed by the BH4 treatment in 3xTg-AD mice. However, the HFD or BH4 treatment had no significant impact on Aβ and tau neuropathologies., Conclusion: Overall, our data suggest a potential benefit from BH4 administration against AD cognitive and metabolic deficits accentuated by HFD consumption in 3xTg-AD mice, without altering classical neuropathology. Therefore, BH4 should be considered as a candidate for drug repurposing, at least in subtypes of cognitively impaired patients experiencing metabolic disorders.

Uncovering the biological role of nuclear receptor peroxisome proliferator-activated receptors (PPARs) has greatly advanced our knowledge of the transcriptional control of glucose and energy metabolism. As such, pharmacological activation of PPARγ has emerged as an efficient approach for treating metabolic disorders with the current use of thiazolidinediones to improve insulin resistance in diabetic patients. The recent identification of growth hormone releasing peptides (GHRP) as potent inducers of PPARγ through activation of the scavenger receptor CD36 has defined a novel alternative to regulate essential aspects of lipid and energy metabolism. Recent advances on the emerging role of CD36 and GHRP hexarelin in regulating PPARγ downstream actions with benefits on atherosclerosis, hepatic cholesterol biosynthesis and fat mitochondrial biogenesis are summarized here. The response of PPARγ coactivator PGC-1 is also discussed in these effects. The identification of the GHRP-CD36-PPARγ pathway in controlling various tissue metabolic functions provides an interesting option for metabolic disorders.

Farnesoid X receptor (FXR) is a ligand-activated nuclear receptor that plays a central role in regulating genes involved in bile acid homeostasis, and fat and glucose metabolism. Here, we demonstrate a post-translational interplay between FXR phosphorylation, SUMOylation, and ubiquitination that directs the receptor into an activation-degradation pathway in hepatocytes. We identify a non-canonical SUMOylation motif termed pSuM that conjugates SUMO2 at Lys-325 of FXR under the direct control of casein kinase 2 (CK2), which provides the required negative charge for Ubc9 and PIAS1 to perform SUMOylation, by phosphorylating Ser-327. Lys-325 SUMOylation is indispensable to the promotion of efficient ligand activation and transcriptional coactivation of FXR. Constitutive pSuM activation using a phospho-mimic Ser-327 mutant or catalytic CK2 expression strongly induces SUMO2 conjugation, which directs FXR ubiquitination and proteasome-dependent degradation. We also determine that such SUMOylation-dependent ubiquitination of FXR is mediated by the E3 ubiquitin ligase RNF4, which is required to achieve maximal induction of FXR and optimal up- or downregulation of responsive genes involved in bile acid homeostasis and liver regeneration. Our findings identify a highly regulated atypical SUMO conjugation motif that serves to coordinate FXR transcriptional competence, thereby expanding the intricate dynamics of the SUMOylation process used by incoming signals to govern metabolic gene regulation., (© The Author (2017). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.)

For young children with autism spectrum disorders, one of the choice interventions is Early Intensive Behavioral Intervention. Over the past ten years, its effectiveness has been abundantly evaluated based on various parameters, including the intensity and duration of the intervention. Despite major advances in effectiveness evaluation, data concerning the implementation of the intervention are often described briefly, and the active ingredients of the intervention are but rarely linked to the documented effects., Objectives: This study aims at reviewing with a systematic method, the studies pertaining to EIBI provided to children with autism spectrum disorders over the past ten years (2005-2015) and at documenting the program implementation components described in the studies, based on Dane and Schneider's (1998) model in accordance with PRISMA guidelines., Results: The results show that, although the variables related to intervention dosage and protocol are relatively well described, the authors do not always consider them in the effects analysis. Furthermore, the majority of the studies did not report information on intervention participation, differentiation or quality., Conclusions: Data concerning the implementation of the intervention are partially described in the articles retained. In this regard, a better description of the intervention provided and a more systematic evaluation of its implementation seem necessary to detect the subtle differences in the effects of the intervention., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Controlling the transcriptional program is essential to maintain the identity and the biological functions of a cell. The Mediator and Cohesin complexes have been established as central cofactors controlling the transcriptional program in normal cells. However, the distribution, recruitment and importance of these complexes in cancer cells have not been fully investigated. Here we show that FOXA and master transcription factors are part of the core transcriptional regulatory circuitry of cancer cells and are essential to recruit M ediator and Cohesin. Indeed, Mediator and Cohesin occupied the enhancer and promoter regions of actively transcribed genes and maintained the proliferation and colony forming potential. Through integration of publically available ChIP-Seq datasets, we predicted the core transcriptional regulatory circuitry of each cancer cell. Unexpectedly, for all cells investigated, the pioneer transcription factors FOXA1 and/or FOXA2 were identified in addition to cell-specific master transcription factors. Loss of both types of transcription factors phenocopied the loss of Mediator and Cohesin. Lastly, the master and pioneer transcription factors were essential to recruit Mediator and Cohesin to regulatory regions of actively transcribed genes. Our study proposes that maintenance of the cancer cell state is dependent on recruitment of Mediator and Cohesin through FOXA and master transcription factors.

Retinoic acid (RA) signaling plays a key role in the development and function of several systems in mammals. We previously discovered that the de novo mutations c.1159C>T (p.Arg387Cys) and c.1159C>A (p.Arg387Ser) in the RA Receptor Beta (RARB) gene cause microphthalmia and diaphragmatic hernia. However, the natural history of affected subjects beyond the prenatal or neonatal period was unknown. Here, we describe nine additional subjects with microphthalmia who have de novo mutations in RARB, including the previously described p.Arg387Cys as well as the novel c.887G>C (p.Gly296Ala) and c.638T>C (p.Leu213Pro). Moreover, we review the information on four previously reported cases. All subjects who survived the neonatal period (n = 10) displayed severe global developmental delay with progressive motor impairment due to spasticity and/or dystonia (with or without chorea). The majority of subjects also showed Chiari type I malformation and severe feeding difficulties. We previously found that p.Arg387Cys and p.Arg387Ser induce a gain-of-function. We show here that the p.Gly296Ala and p.Leu213Pro RARB mutations further promote the RA ligand-induced transcriptional activity by twofold to threefold over the wild-type receptor, also indicating a gain-of-function mechanism. These observations suggest that precise regulation of RA signaling is required for brain development and/or function in humans., (© 2016 WILEY PERIODICALS, INC.)

Introduction: Cutaneous arterio-venous malformations (AVM) are high-flow vascular malformations made up of a direct link between arteries and veins without intermediary capillary space. 'Distal limb's AVM', which mean involving hands or feet, are rare and their functional prognosis is often poor. Little is known about their early clinical symptoms. The objectives of this study were to identify early clinical symptoms of distal limb's cutaneous AVMs and to determine their long-term clinical outcome., Methods: A retrospective study was carried out including adult patients who had distal limb's AVM, who were followed up between January 2000 and November 2013 in two regional tertiary care centres. The information was collected from patients' clinical records and completed by a structured telephone questionnaire., Results: Nineteen patients were included in the study: four (21%) with foot AVM and 15 (79%) with hand AVM. The first clinical symptoms were as follows: swelling (47%), pain (47%), one or several venous dilatations (37%) and rarely abnormal skin colour, hyperthermia and pulsating sensation. The median diagnosis delay was 9 years after the onset of first manifestations. Amongst the 17 patients who underwent a treatment, 53% had embolotherapy session(s), 12% surgery and 35% had both. After an average follow-up of 57.6 months, 31% of the 13 patients contacted who were receiving treatment were in complete remission; 31% had partial remission; 15% had relapse after initial improvement and 23% had treatment failure. Overall, 74% of patients had a serious development of the AVM: 37% had digital or hand amputation, and 42% remained symptomatic and/or unstable., Conclusion: This study suggests that initial manifestations of distal limb's AVMs are discreet and non-specific, leading to a diagnosis delay of about 10 years, with poor prognosis. Doctors should evoke the diagnosis earlier, when these symptoms are shown: pain and/or swelling, sometimes with a large vein., (© 2015 European Academy of Dermatology and Venereology.)

Coagulase-negative staphylococci (CNS) have traditionally been considered minor mastitis pathogens and are the bacteria most frequently isolated from intramammary infection. Previously, our laboratory demonstrated that a majority of CNS isolated from Canadian milk were able to form biofilm and this was strongly and positively associated with days in milk. Biofilms offer protection against antibiotics and disinfectants, and the presence of CNS biofilms near the end of the lactation cycle could have an impact on the prevention and recurrence of CNS infections in the next lactation cycle. The objective of this study was to investigate the effect of biofilm formation on efficacy of commonly used antibiotics and disinfectants against CNS. The minimal inhibitory concentration (MIC) and minimal biofilm eradication concentration (MBEC) of several CNS isolates were determined using microdilution method and the MBEC device, respectively. Biofilm cells were more resistant to a penicillin G/novobiocin combination and to ceftiofur than their planktonic counterparts and the increase in resistance ranged from 4× to 2048×. For the disinfectants, we determined the minimum contact time required for different teat disinfectants to eradicated planktonic cells and biofilms. The chlorhexidine-based teat disinfectants eradicated planktonic cells and biofilms within 30s. For iodine-based teat disinfectants, it took 2-10× longer to eradicate the biofilms than planktonic cells. In conclusion, CNS biofilms were less susceptible to antibiotics; however, chlorhexidine-based teat disinfectants were still effective against CNS biofilms. This reinforces the use of post-milking teat disinfectants as a preventive measure of intramammary infections., (Copyright © 2014 Elsevier B.V. All rights reserved.)