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The mTOR pathway is a key regulator of normal brain development. Here, the authors identify de novo mutations in RHEB, an mTOR activator protein, in patients with intellectual disability associated with megalencephaly and find a role for RHEB in regulating neuronal soma size and migration in vitro and in vivo.

Abstract Background Tuberous sclerosis complex (TSC) is a rare monogenic disorder characterized by benign tumors in multiple organs as well as a high prevalence of epilepsy, intellectual disability and autism. TSC is caused by inactivating mutations in the TSC1 or TSC2 genes. Heterozygocity induces hyperactivation of mTOR which can be inhibited by mTOR inhibitors, such as rapamycin, which have proven efficacy in the treatment of TSC-associated symptoms. The aim of the present study was (1) to identify molecular changes associated with social and cognitive deficits in the brain tissue of Tsc1 +/− mice and (2) to investigate the molecular effects of rapamycin treatment, which has been shown to ameliorate genotype-related behavioural deficits. Methods Molecular alterations in the frontal cortex and hippocampus of Tsc1 +/− and control mice, with or without rapamycin treatment, were investigated. A quantitative mass spectrometry-based shotgun proteomic approach (LC-MSE) was employed as an unbiased method to detect changes in protein levels. Changes identified in the initial profiling stage were validated using selected reaction monitoring (SRM). Protein Set Enrichment Analysis was employed to identify dysregulated pathways. Results LC-MSE analysis of Tsc1 +/− mice and controls (n = 30) identified 51 proteins changed in frontal cortex and 108 in the hippocampus. Bioinformatic analysis combined with targeted proteomic validation revealed several dysregulated molecular pathways. Using targeted assays, proteomic alterations in the hippocampus validated the pathways “myelination”, “dendrite,” and “oxidative stress”, an upregulation of ribosomal proteins and the mTOR kinase. LC-MSE analysis was also employed on Tsc1 +/− and wildtype mice (n = 34) treated with rapamycin or vehicle. Rapamycin treatment exerted a stronger proteomic effect in Tsc1 +/− mice with significant changes (mainly decreased expression) in 231 and 106 proteins, respectively. The cellular pathways “oxidative stress” and “apoptosis” were found to be affected in Tsc1 +/− mice and the cellular compartments “myelin sheet” and “neurofilaments” were affected by rapamycin treatment. Thirty-three proteins which were altered in Tsc1 +/− mice were normalized following rapamycin treatment, amongst them oxidative stress related proteins, myelin-specific and ribosomal proteins. Conclusions Molecular changes in the Tsc1 +/− mouse brain were more prominent in the hippocampus compared to the frontal cortex. Pathways linked to myelination and oxidative stress response were prominently affected and, at least in part, normalized following rapamycin treatment. The results could aid in the identification of novel drug targets for the treatment of cognitive, social and psychiatric symptoms in autism spectrum disorders. Similar pathways have also been implicated in other psychiatric and neurodegenerative disorders and could imply similar disease processes. Thus, the potential efficacy of mTOR inhibitors warrants further investigation not only for autism spectrum disorders but also for other neuropsychiatric and neurodegenerative diseases.

Abstract RASopathies, characterized by germline mutations in genes encoding proteins of the RAS-ERK signaling pathway, show overlapping phenotypes, which manifest themselves with a varying severity of intellectual disability. However, it is unclear to what extent they share the same downstream pathophysiology that underlies the cognitive deficits. Costello syndrome (CS) is a rare RASopathy caused by activating mutations in the HRAS gene. Here we investigated the mechanisms underlying the cognitive deficits of HRas G12V/G12V mice. HRas G12V/G12V mice showed robust upregulation of ERK signaling, neuronal hypertrophy, increased brain volume, spatial learning deficits, and impaired mGluR-dependent long-term depression (LTD). In contrast, long-term potentiation (LTP), which is affected in other RASopathy mouse models was unaffected. Treatment with lovastatin, a HMG-CoA-Reductase inhibitor which has been shown to rescue the behavioral phenotypes of mouse models of NF1 and Noonan syndrome, was unable to restore ERK signaling and the cognitive deficits of HRas G12V/G12V mice. Administration of a potent mitogen-activated protein kinase (MEK) inhibitor rescued the ERK upregulation and the mGluR-LTD deficit of HRas G12V/G12V mice, but failed to rescue the cognitive deficits. Taken together, this study indicates that the fundamental molecular and cellular mechanisms underlying the cognitive aspects of different RASopathies are remarkably distinct, and may require disease specific treatments.

Abstract High‐diversity mixtures of perennial tallgrass prairie vegetation could be useful biomass feedstocks for marginal farmland in the Midwestern United States. These agroenergy crops can help meet cellulosic agrofuel targets while also enhancing other ecosystem services on the landscape. One proposed advantage of high‐diversity prairie biomass feedstocks is that they should become nutrient limited at a slower rate than monoculture feedstocks. In this study, we examine rates of soil nutrient depletion and the physiology and performance of a focal species (switchgrass, Panicum virgatum L.) in four prairie agroenergy feedstocks with different species composition and diversity. The feedstocks in this study were a 1‐species switchgrass monoculture, a 5‐species mixture of C4 grasses, a 16‐species mixture of C3 and C4 grasses, forbs, and legumes, and a 32‐species mixture of C3 and C4 grasses, forbs, legumes, and sedges. To assess feedstock effects on soil, we measured changes in soil N/P/K over a five‐year period. We also performed a greenhouse study, in which we grew switchgrass plants in field soil conditioned by each feedstock. To assess feedstock effects on plant function, we measured four physiological traits (photosynthetic rate, chlorophyll concentration, leaf florescence, leaf N concentration) on switchgrass plants within each feedstock in the field. In the soil analysis, we found that the 5‐species feedstock displayed higher rates of soil N/P/K depletion than other feedstocks. In the greenhouse analysis, we found that switchgrass plants grown in soil conditioned by the 5‐species feedstock were smaller than plants grown in soil conditioned by other feedstocks. In the physiological analysis, we found that switchgrass plants in the 5‐species feedstock had lower leaf N, photosynthesis, chlorophyll concentration, and higher florescence than switchgrass plants growing in other feedstocks. Collectively, our results show that prairie agroenergy feedstocks with different species composition and diversity have different rates of soil nutrient depletion, which influences the physiology and performance of plants within the feedstock. These differences would ultimately impact the ecosystem services (e.g., biomass production, need for fertilizer) that these prairie agroenergy feedstocks provide.

The urachus is a vestigial structure of the allantois and cloaca. It involutes as fetal development progresses to become a fibrous cord, which courses between the umbilicus and bladder dome within the retropubic space. Infection occasionally occurs in patients with congenital patent urachus. Here, we report a patient with infection of a previously closed urachal tract presenting as an abdominal mass. This has rarely been described in the literature. Current knowledge on imaging findings to the diagnosis is discussed.

BackgroundAs depression has a recurrent course, relapse and recurrence prevention is essential.AimsIn our randomised controlled trial (registered with the Nederlands trial register, identifier: NTR1907), we found that adding preventive cognitive therapy (PCT) to maintenance antidepressants (PCT+AD) yielded substantial protective effects versus antidepressants only in individuals with recurrent depression. Antidepressants were not superior to PCT while tapering antidepressants (PCT/−AD). To inform decision-makers on treatment allocation, we present the corresponding cost-effectiveness, cost-utility and budget impact.MethodData were analysed (n = 289) using a societal perspective with 24-months of follow-up, with depression-free days and quality-adjusted life years (QALYs) as health outcomes. Incremental cost-effectiveness ratios were calculated and cost-effectiveness planes and cost-effectiveness acceptability curves were derived to provide information about cost-effectiveness. The budget impact was examined with a health economic simulation model.ResultsMean total costs over 24 months were €6814, €10 264 and €13 282 for AD+PCT, antidepressants only and PCT/−AD, respectively. Compared with antidepressants only, PCT+AD resulted in significant improvements in depression-free days but not QALYs. Health gains did not significantly favour antidepressants only versus PCT/−AD. High probabilities were found that PCT+AD versus antidepressants only and antidepressants only versus PCT/−AD were dominant with low willingness-to-pay thresholds. The budget impact analysis showed decreased societal costs for PCT+AD versus antidepressants only and for antidepressants only versus PCT/−AD.ConclusionsAdding PCT to antidepressants is cost-effective over 24 months and PCT with guided tapering of antidepressants in long-term users might result in extra costs. Future studies examining costs and effects of antidepressants versus psychological interventions over a longer period may identify a break-even point where PCT/−AD will become cost-effective.Declaration of interestC.L.H.B. is co-editor of PLOS One and receives no honorarium for this role. She is also co-developer of the Dutch multidisciplinary clinical guideline for anxiety and depression, for which she receives no remuneration. She is a member of the scientific advisory board of the National Insure Institute, for which she receives an honorarium, although this role has no direct relation to this study. C.L.H.B. has presented keynote addresses at conferences, such as the European Psychiatry Association and the European Conference Association, for which she sometimes receives an honorarium. She has presented clinical training workshops, some including a fee. She receives royalties from her books and co-edited books and she developed preventive cognitive therapy on the basis of the cognitive model of A. T. Beck. W.A.N. has received grants from the Netherlands Organisation for Health Research and Development and the European Union and honoraria and speakers' fees from Lundbeck and Aristo Pharma, and has served as a consultant for Daleco Pharma.

The U.S. Department of Agriculture’s Conservation Reserve Program (CRP) is one of the largest private lands conservation programs in the United States, establishing perennial vegetation on environmentally sensitive lands formerly in agricultural production. Over its 35 year existence, the CRP has evolved to include diverse conservation practices (CPs) while concomitantly meeting its core goals of reducing soil erosion, improving water quality, and providing wildlife habitat. Ongoing threats to grasslands and decreased CRP acreage highlighted the need for a national evaluation of the effectiveness in providing the program’s intended benefits. To address this need, we conducted edge-of-field surveys of erosional features, vegetation, and soil cover on 1 786 fields across 10 CPs and 14 central and western states from 2016 to 2018. We grouped practices into three types (grassland, wetland, and wildlife) and states into six regions for analysis. Across practice types, ⩾99% of fields had no evidence of rills, gullies, or pedestaling from erosion, and 91% of fields had 50% and native forb presence occurred most frequently in wildlife practices, with region being the strongest driver of differences. Federally listed noxious grass and forb species occurred on 23% and 61% of fields, respectively, but tended to constitute a small portion of cover in the field. Estimates from edge-of-field surveys and in-field validation sampling were strongly correlated, demonstrating the utility of the edge-of-field surveys. Our results provide the first national-level assessment of CRP establishment in three decades, confirming that enrolled wildlife and wetland practices often have diverse perennial vegetation cover and very few erosional features.