A transient in planta editing assay identifies specific binding of the splicing regulator PTB as a prerequisite for cassette exon inclusion.

The dynamic interaction of RNA-binding proteins (RBPs) with their target RNAs contributes to the diversity of ribonucleoprotein (RNP) complexes that are involved in a myriad of biological processes. Identifying the RNP components at high resolution and defining their interactions are key to understanding their regulation and function. Expressing fusions between an RBP of interest and an RNA editing enzyme can result in nucleobase changes in target RNAs, representing a recent addition to experimental approaches for profiling RBP/RNA interactions. Here, we have used the MS2 protein/RNA interaction to test four RNA editing proteins for their suitability to detect target RNAs of RBPs in planta. We have established a transient test system for fast and simple quantification of editing events and identified the hyperactive version of the catalytic domain of an adenosine deaminase (hADARcd) as the most suitable editing enzyme. Examining fusions between homologs of polypyrimidine tract binding proteins (PTBs) from Arabidopsis thaliana and hADARcd allowed determining target RNAs with high sensitivity and specificity. Moreover, almost complete editing of a splicing intermediate provided insight into the order of splicing reactions and PTB dependency of this particular splicing event. Addition of sequences for nuclear localisation of the fusion protein increased the editing efficiency, highlighting this approach's potential to identify RBP targets in a compartment-specific manner. Our studies have established the editing-based analysis of interactions between RBPs and their RNA targets in a fast and straightforward assay, offering a new system to study the intricate composition and functions of plant RNPs in vivo.

Combination of immune-checkpoint inhibitors and targeted therapies for melanoma therapy: The more, the better?

The approval of immune-checkpoint inhibitors (CPI) and mitogen activated protein kinase inhibitors (MAPKi) in recent years significantly improved the treatment management and survival of patients with advanced malignant melanoma. CPI aim to counter-act receptor-mediated inhibitory effects of tumor cells and immunomodulatory cell types on effector T cells, whereas MAPKi are intended to inhibit tumor cell survival. In agreement with these complementary modes of action preclinical data indicated that the combined application of CPI and MAPKi or their optimal sequencing might provide additional clinical benefit. In this review the rationale and preclinical evidence that support the combined application of MAPKi and CPI either in concurrent or consecutive regimens are presented. Further, we will discuss the results from clinical trials investigating the sequential or combined application of MAPKi and CPI for advanced melanoma patients and their implications for clinical practice. Finally, we outline mechanisms of MAPKi and CPI cross-resistance which limit the efficacy of currently available treatments, as well as combination regimens.

Atrial fibrosis heterogeneity is a risk for atrial fibrillation in pigs with ischaemic heart failure.

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia and is associated with considerable morbidity and mortality. Ischaemic heart failure (IHF) remains one of the most common causes of AF in clinical practice. However, ischaemia-mediated mechanisms leading to AF are still incompletely understood, and thus, current treatment approaches are limited. To improve our understanding of the pathophysiology, we studied a porcine IHF model. METHODS: In pigs, IHF was induced by balloon occlusion of the left anterior descending artery for 90 min. After 30 days of reperfusion, invasive haemodynamic measurements and electrophysiological studies were performed. Masson trichrome and immunofluorescence staining were conducted to assess interstitial fibrosis and myofibroblast activation in different heart regions. RESULTS: After 30 days of reperfusion, heart failure with significantly reduced ejection fraction (left anterior obique 30°, 34.78 ± 3.29% [IHF] vs. 62.03 ± 2.36% [control], p < .001; anterior-posterior 0°, 29.16 ± 3.61% vs. 59.54 ± 1.09%, p < .01) was observed. These pigs showed a significantly higher susceptibility to AF (33.90% [IHF] vs. 12.98% [control], p < .05). Histological assessment revealed aggravated fibrosis in atrial appendages but not in atrial free walls in IHF pigs (11.13 ± 1.44% vs. 5.99 ± .86%, p < .01 [LAA], 8.28 ± .56% vs. 6.01 ± .35%, p < .01 [RAA]), which was paralleled by enhanced myofibroblast activation (12.09 ± .65% vs. 9.00 ± .94%, p < .05 [LAA], 14.37 ± .60% vs. 10.30 ± 1.41%, p < .05 [RAA]). Correlation analysis indicated that not fibrosis per se but its cross-regional heterogeneous distribution across the left atrium was associated with AF susceptibility (r = .6344, p < .01). CONCLUSION: Our results suggest that left atrial cross-regional fibrosis difference rather than overall fibrosis level is associated with IHF-related AF susceptibility, presumably by establishing local conduction disturbances and heterogeneity.

Patterns of infant fecal metabolite concentrations and social behavioral development in toddlers.

BACKGROUND: Gut-derived metabolites, products of microbial and host co-metabolism, may inform mechanisms underlying children's neurodevelopment. We investigated whether infant fecal metabolites were related to toddler social behavior. METHODS: Stool samples collected from 6-week-olds (n = 86) and 1-year-olds (n = 209) in the New Hampshire Birth Cohort Study (NHBCS) were analyzed using nuclear magnetic resonance spectroscopy metabolomics. Autism-related behavior in 3-year-olds was assessed by caregivers using the Social Responsiveness Scale (SRS-2). To assess the association between metabolites and SRS-2 scores, we used a traditional single-metabolite approach, quantitative metabolite set enrichment (QEA), and self-organizing maps (SOMs). RESULTS: Using a single-metabolite approach and QEA, no individual fecal metabolite or metabolite set at either age was associated with SRS-2 scores. Using the SOM method, fecal metabolites of six-week-olds organized into four profiles, which were unrelated to SRS-2 scores. In 1-year-olds, one of twelve fecal metabolite profiles was associated with fewer autism-related behaviors, with SRS-2 scores 3.4 (95%CI: -7, 0.2) points lower than the referent group. This profile had higher concentrations of lactate and lower concentrations of short chain fatty acids than the reference. CONCLUSIONS: We uncovered metabolic profiles in infant stool associated with subsequent social behavior, highlighting one potential mechanism by which gut bacteria may influence neurobehavior. IMPACT: Differences in host and microbial metabolism may explain variability in neurobehavioral phenotypes, but prior studies do not have consistent results. We applied three statistical techniques to explore fecal metabolite differences related to social behavior, including self-organizing maps (SOMs), a novel machine learning algorithm. A 1-year-old fecal metabolite pattern characterized by high lactate and low short-chain fatty acid concentrations, identified using SOMs, was associated with social behavior less indicative of autism spectrum disorder. Our findings suggest that social behavior may be related to metabolite profiles and that future studies may uncover novel findings by applying the SOM algorithm.

Fish intake and mercury exposure in young children.

Fish consumption is one of the main sources of mercury (Hg) exposure, but few studies have examined Hg exposure from fish consumption among children. This study aimed to assess the frequency of fish intake and associations with Hg and other element concentrations among 700 three-year-old children from the New Hampshire Birth Cohort Study. Usual fish intake was derived from a validated food frequency questionnaire (Block Questionnaire for ages 2-7) and toenail element concentrations were determined using ICP-MS. Multiple linear regression analysis was used to assess the association between fish intake and toenail element concentrations. A mixture analysis, using Weighted quantile sum (WQS) regression, was used to estimate the relative contribution of fish consumption to element exposures. Twenty-three percent of children were reported to consume at least one fish meal/week on average during the previous 6 months. In adjusted linear regression models, children with any type of fish consumption versus no consumption had 108% (95% confidence interval (CI: 68%, 153%)) higher toenail Hg concentrations. To a lesser extent, children consuming "other fish (not fried) including tuna" and "fried fish or fish sticks" had 120% (95% CI: 82%, 164%), and 23% (95% CI: 2%, 51%) higher toenail concentrations, respectively, than those consuming no fish. Using WQS regression, Hg was the element most strongly related to fish consumption. Fish intake among young children was related to Hg exposure even at low levels of consumption. Future studies will need to determine the health consequences of this exposure.

Deciduous teeth from the New Hampshire birth cohort study: Early life environmental and dietary predictors of dentin elements.

BACKGROUND: Sparse research exists on predictors of element concentrations measured in deciduous teeth. OBJECTIVE: To estimate associations between maternal/child characteristics, elements measured in home tap water during pregnancy and element concentrations in the dentin of shed deciduous teeth. METHODS: Our analysis included 152 pregnant person-infant dyads followed from the second trimester through the end of the first postnatal year from the New Hampshire Birth Cohort Study. During pregnancy and early infancy, we collected dietary and sociodemographic information via surveys, measured elements in home tap water, and later collected naturally exfoliated teeth from child participants. We measured longitudinal deposition of elements in dentin using LA-ICP-MS. Multivariable linear mixed models were used to estimate associations between predictors and dentin element concentrations. RESULTS: We measured 12 elements in dentin including those previously reported (Ba, Mn, Pb, Sr, Zn) and less frequently reported (Al, As, Cd, Cu, Hg, Li, and W). A doubling of Pb or Sr concentrations in water was associated with higher dentin Pb or Sr respectively in prenatally formed [9% (95%CI: 3%, 15%); 3% (1%, 6%)] and postnatally formed [10% (2%, 19%); 6% (2%, 10%)] dentin. Formula feeding from birth to 6 weeks or 6 weeks to 4 months was associated with higher element concentrations in postnatal dentin within the given time period as compared to exclusive human milk feeding: Sr: 6 weeks: 61% (36%, 90%) and 4 months: 85% (54%, 121%); Ba: 6 weeks: 35% (3.3%, 77%) and 4 months: 42% (10%, 83%); and Li: 6 weeks: 61% (33%, 95%) and 4 months: 58% (31%, 90%). SIGNIFICANCE: These findings offer insights into predictors of dentin elements and potential confounders in exposure-health outcome relationships during critical developmental periods.

Consented indicators for the evaluation of integrated strategies of community health promotion targeting children and adolescents: results of an eDelphi.

BACKGROUND: To date, there is no consensus on indicators for the evaluation of integrated community-based interventions for health promotion and prevention targeting children and adolescents. This study aims at consenting on a scoped set of indicators to evaluate integrated community-based interventions. METHODS: Out of 738 indicators derived from a literature search, we preselected 94 indicators allotted to 20 domains based on an internal quality appraisal and consensus process and conducted an eDelphi procedure to assess their relevance in view of experts. Experts were recruited in the field of public health, health sciences and communal health promotion in practice and were invited as participants in this eDelphi. During the eDelphi, 47 experts rated the relevance of 94 indicators in two rounds. Consensus was defined as agreement of 75% (or above). RESULTS: After round 1, 27 indicators among 11 consented subdomains reached a consensus on relevance. After round 2, a total of 36 indicators reached consensus on relevance in 9 subdomains (such as socioeconomic factors, health education, nutrition and physical activity, oral health, overall health status, specific health conditions, drug related behavior, exposure to drugs and violence, family factors). CONCLUSIONS: These identified indicators may provide a basis for evaluation concepts of integrated community-based interventions for children and adolescents to inform stakeholders about intervention impacts.

Use of cardiac cell cultures from salmonids to measure the cardiotoxic effect of environmental pollutants.

Environmental stressors such as micro- and nanosized plastic particles (MNPs) or crude oil have a detrimental effect on aquatic animals; however, the impact upon the cardiovascular system of fish remains relatively under-researched. This study presents a novel approach for investigating the effect of crude oil and MNPs on the cardiac system of fish. We used salmonid larvae and cardiac cell cultures derived from hearts of salmonid fish and exposed them to environmental stressors. Following exposure to plastic particles or crude oil, the larvae exhibited some variation in contraction rate. In contrast, significant alterations in the contraction rate were observed in all cardiac cell cultures. The greatest differences between the control and treatment groups were observed in cardiac cell cultures derived from older brown trout. Following 7 days of exposure to MNPs or crude oil in Atlantic salmon larval hearts or cardiac cell cultures, there were only minor responses noted in mRNA expression of the selected marker genes. These findings show the use of a novel in vitro technique contributing to the existing body of knowledge on the impact of MNPs and crude oil on the cardiovascular system of salmonids and the associated risk.

[Participation in children's hospitals: approaches to participatory formats for paediatric patients]. / Teilhabe im Kinderkrankenhaus: Formate zur Verwirklichung des Rechts auf Partizipation von jungen Patientinnen und Patienten.

Based on the UN Convention on the Rights of the Child, children and young people have the right to participate in all matters and decisions that affect them. This applies in particular when they are patients in a children's hospital. In the international context, established formats for the participation of young patients regarding health issues already exist, for example "Children's Councils" or "Young Person's Advisory Groups". In Germany, such approaches are still mostly lacking. It thus remains important to develop suitable formats that enable meaningful and effective participation of young patients in the health system. These formats must be chosen in such a way that they can realistically be implemented in clinical settings as well as in pediatric research, and that they can be sustained in the long term. In order to strengthen the consideration of children's rights in the health system, the advancement of such participatory formats as well as their sustainable implementation and evaluation are desirable.

Associations of an industry-relevant metal mixture with verbal learning and memory in Italian adolescents: The modifying role of iron status.

BACKGROUND: Biomarker concentrations of metals are associated with neurodevelopment, and these associations may be modified by nutritional status (e.g., iron deficiency). No prior study on associations of metal mixtures with neurodevelopment has assessed effect modification by iron status. OBJECTIVES: We aimed to quantify associations of an industry-relevant metal mixture with verbal learning and memory among adolescents, and to investigate the modifying role of iron status on those associations. METHODS: We used cross-sectional data from 383 Italian adolescents (10-14 years) living in proximity to ferroalloy industry. Verbal learning and memory was assessed using the California Verbal Learning Test for Children (CVLT-C), and metals were quantified in hair (manganese, copper, chromium) or blood (lead) using inductively coupled plasma mass spectrometry. Serum ferritin, a proxy for iron status, was measured using immunoassays. Covariate-adjusted associations of the metal mixture with CVLT subtests were estimated using Bayesian Kernel Machine Regression, and modification of the mixture associations by ferritin was examined. RESULTS: Compared to the 50th percentile of the metal mixture, the 90th percentile was associated with a 0.12 standard deviation [SD] (95% CI = -0.27, 0.50), 0.16 SD (95% CI = -0.11, 0.44), and 0.11 SD (95% CI = -0.20, 0.43) increase in the number of words recalled for trial 5, long delay free, and long delay cued recall, respectively. For an increase from its 25th to 75th percentiles, copper was beneficially associated the recall trials when other metals were fixed at their 50th percentiles (for example, trial 5 recall: ß = 0.31, 95% CI = 0.14, 0.48). The association between copper and trial 5 recall was stronger at the 75th percentile of ferritin, compared to the 25th or 50th percentiles. CONCLUSIONS: In this metal mixture, copper was beneficially associated with neurodevelopment, which was more apparent at higher ferritin concentrations. These findings suggest that metal associations with neurodevelopment may depend on iron status, which has important public health implications.

In vitro modelling of the influence of alternative feeds (Hermetia illucens, Arthrospira platensis) on the resistance of different rainbow trout populations (Oncorhynchus mykiss) against the viral haemorrhagic septicaemia virus and Yersinia ruckeri.

Replacing fishmeal, a finite resource with high market demand, in the diet of carnivorous rainbow trout with proteins from alternative sources may be a challenge for these fish. Therefore, this study investigated whether replacing fishmeal with protein derived from Hermetia illucens or Arthrospira platensis could promote disease susceptibility in local trout populations with different growth performance. This was assessed in vitro by measuring susceptibility to infection with the viral haemorrhagic septicaemia virus (VHSV) or the bacterium Yersinia ruckeri. Analysis of fin tissue explants and primary cell cultures from scales from the three trout populations infected in vitro with VHSV and gill explants infected with Y. ruckeri showed no significant differences in virus replication or bacterial counts. Evaluation of the virucidal or bactericidal effect of skin mucus showed a significant reduction in viral load and bacterial count for all samples with mucus addition, but no significant difference was observed between the experimental groups. This study documents no apparent impairment of innate immune mechanisms in the skin and gills of trout after feeding a diet replacing fishmeal with Arthrospira or Hermetia proteins. This underlines the potential of these alternative protein sources for the further development of sustainable trout aquaculture.

Heterodimerization of Chemoreceptors TAS1R3 and mGlu2 in Human Blood Leukocytes.

The expression of canonical chemosensory receptors of the tongue, such as the heteromeric sweet taste (TAS1R2/TAS1R3) and umami taste (TAS1R1/TAS1R3) receptors, has been demonstrated in many extra-oral cells and tissues. Gene expression studies have revealed transcripts for all TAS1 and metabotropic glutamate (mGlu) receptors in different types of immune cells, where they are involved, for example, in the chemotaxis of human neutrophils and the protection of T cells from activation-induced cell death. Like other class-C G protein-coupling receptors (GPCRs), TAS1Rs and mGlu receptors form heteromers within their families. Since mGlu receptors and TAS1R1/TAS1R3 share the same ligand, monosodium glutamate (MSG), we hypothesized their hitherto unknown heteromerization across receptor families in leukocytes. Here we show, by means of immunocytochemistry and co-IP/Western analysis, that across class-C GPCR families, mGlu2 and TAS1R3 co-localize and heterodimerize in blood leukocytes. Expressing the recombinant receptors in HEK-293 cells, we validated their heterodimerization by bioluminescence resonance energy transfer. We demonstrate MSG-induced, mGlu2/TAS1R3 heteromer-dependent gain-of-function and pertussis toxin-sensitive signaling in luminescence assays. Notably, we show that mGlu2/TAS1R3 is necessary and sufficient for MSG-induced facilitation of N-formyl-methionyl-leucyl-phenylalanine-stimulated IL-8 secretion in neutrophils, using receptor-specific antagonists. In summary, our results demonstrate mGlu2/TAS1R3 heterodimerization in leukocytes, suggesting cellular function-tailored chemoreceptor combinations to modulate cellular immune responses.

Conserved C-terminal motifs in odorant receptors instruct their cell surface expression and cAMP signaling.

The highly individual plasma membrane expression and cAMP signaling of odorant receptors have hampered their ligand assignment and functional characterization in test cell systems. Chaperones have been identified to support the cell surface expression of only a portion of odorant receptors, with mechanisms remaining unclear. The presence of amino acid motifs that might be responsible for odorant receptors' individual intracellular retention or cell surface expression, and thus, for cAMP signaling, is under debate: so far, no such protein motifs have been suggested. Here, we demonstrate the existence of highly conserved C-terminal amino acid motifs, which discriminate at least between class-I and class-II odorant receptors, with their numbers of motifs increasing during evolution, by comparing C-terminal protein sequences from 4808 receptors across eight species. Truncation experiments and mutation analysis of C-terminal motifs, largely overlapping with helix 8, revealed single amino acids and their combinations to have differential impact on the cell surface expression and on stimulus-dependent cAMP signaling of odorant receptors in NxG 108CC15 cells. Our results demonstrate class-specific and individual C-terminal motif equipment of odorant receptors, which instruct their functional expression in a test cell system, and in situ may regulate their individual cell surface expression and intracellular cAMP signaling.

Immunological insights into the resistance of Nile tilapia strains to an infection with tilapia lake virus.

The emergence of viral diseases affecting fish and causing very high mortality can lead to the disruption of aquaculture production. Recently, this occurred in Nile tilapia aquaculture where a disease caused by a systemic infection with a novel virus named tilapia lake virus (TiLV) caused havoc in cultured populations. With mortality surpassing 90% in young tilapia, the disease caused by TiLV has become a serious challenge for global tilapia aquaculture. In order to partly mitigate the losses, we explored the natural resistance to TiLV-induced disease in three genetic strains of tilapia which were kept at the University of Göttingen, Germany. We used two strains originating from Nilotic regions (Lake Mansala (MAN) and Lake Turkana (ELM)) and one from an unknown location (DRE). We were able to show that the virus is capable of overcoming the natural resistance of tilapia when injected, providing inaccurate mortality results that might complicate finding the resistant strains. Using the cohabitation infection model, we found an ELM strain that did not develop any clinical signs of the infection, which resulted in nearly 100% survival rate. The other two strains (DRE and MAN) showed severe clinical signs and much lower survival rates of 29.3% in the DRE strain and 6.7% in the MAN strain. The disease resistance of tilapia from the ELM strain was correlated with lower viral loads both at the mucosa and internal tissues. Our results suggest that the lower viral load could be caused by a higher magnitude of a mx1-based antiviral response in the initial phase of infection. The lower pro-inflammatory responses also found in the resistant strain might additionally contribute to its protection from developing pathological changes related to the disease. In conclusion, our results suggest the possibility of using TiLV-resistant strains as an ad hoc, cost-effective solution to the TiLV challenge. However, as the fish from the disease-resistant strain still retained significant virus loads in liver and brain and thus could become persistent virus carriers, they should be used within an integrative approach also combining biosecurity, diagnostics and vaccination measures.\.

Associations of a metal mixture with iron status in U.S. adolescents: Evidence from the National Health and Nutrition Examination Survey.

Iron is needed for normal development in adolescence. Exposure to individual environmental metals (e.g., lead) has been associated with altered iron status in adolescence, but little is known about the cumulative associations of multiple metals with Fe status. We used data from the 2017-2018 National Health and Nutrition Examination Survey (NHANES) to examine associations between a metal mixture (lead, manganese, cadmium, selenium) and iron status in 588 U.S. adolescents (12-17 years). We estimated cumulative and interactive associations of the metal mixture with five iron status metrics using Bayesian Kernel Machine Regression (BKMR). Higher concentrations of manganese and cadmium were associated with lower log-transformed ferritin concentrations. Interactions were observed between manganese, cadmium, and lead for ferritin and the transferrin receptor, where iron status tended to be worse at higher concentrations of all metals. These results may reflect competition between environmental metals and iron for cellular uptake. Mixed metal exposures may alter normal iron function, which has implications for adolescent development.

Association of the alga Cladogonium sp. with a multifactorial disease outbreak in dwarf shrimp (Neocaridina davidi).

This study outlines a multifactorial disease outbreak in a population of the freshwater shrimp Neocaridina davidi, with the focus on a rarely described parasitic alga. Within this multifactorial disease outbreak, low but consistent mortality was observed. During microscopic examination, an infection of the shrimp with bacterial and fungal-like agents was diagnosed. Furthermore, the green alga Cladogonium sp. was found in pleopodal regions. The alga compromised the body surface of the shrimp, and its rhizoids penetrated the chitin shell and reached into the subcutaneous tissue. This might be a first indication of a parasitic lifestyle. In addition to a morphological description, sequencing data are presented which allow the taxonomic classification of the organism within the order Trentepohliales.

Impact of a reduced water salinity on the composition of Vibrio spp. in recirculating aquaculture systems for Pacific white shrimp (Litopenaeus vannamei) and its possible risks for shrimp health and food safety.

Tropical shrimp, like Litopenaeus vannamei, in land-based recirculating aquaculture systems (RAS) are often kept at low water salinities to reduce costs for artificial sea salt and the amount of salty wastewater. Although these shrimp are tolerant against low salinities, innate immunity suppression and changes in the microbial composition in the water can occur. As especially Vibrio spp. are relevant for shrimp health, alterations in the species composition of the Vibrio community were analysed in water from six RAS, run at 15‰ or 30‰. Additionally, pathogenicity factors including pirA/B, VPI, toxR, toxS, vhh, vfh, tdh, trh, flagellin genes and T6SS1/2 of V. parahaemolyticus were analysed. The Vibrio composition differed significantly depending on water salinity. In RAS at 15‰, higher numbers of the potentially pathogenic species V. parahaemolyticus, V. owensii and V. campbellii were detected, and especially in V. parahaemolyticus, various pathogenicity factors were present. A reduced salinity may therefore pose a higher risk of disease outbreaks in shrimp RAS. Because some of the detected pathogenicity factors are relevant for human health, this might also affect food safety. In order to produce healthy shrimp as a safe food for human consumption, maintaining high water salinities seems to be recommendable.

Oncogenic NRAS Accelerates Rhabdomyosarcoma Formation When Occurring within a Specific Time Frame during Tumor Development in Mice.

In the Ptch+/- mouse model for embryonal rhabdomyosarcoma (ERMS), we recently showed that oncogenic (onc) H-, K- or NRAS mutations do not influence tumor growth when induced at the advanced, full-blown tumor stage. However, when induced at the invisible ERMS precursor stage at 4 weeks of age, tumor development was enforced upon oncHRAS and oncKRAS but not by oncNRAS, which instead initiated tumor differentiation. These data indicate that oncRAS-associated processes differ from each other in dependency on the isoform and their occurrence during tumor development. Here, we investigated the outcome of oncNRAS induction at an earlier ERMS precursor stage at 2 weeks of age. In this setting, oncNRAS accelerates tumor growth because it significantly shortens the ERMS-free survival and increases the ERMS incidence. However, it does not seem to alter the differentiation of the tumors. It is also not involved in tumor initiation. Together, these data show that oncNRAS mutations can accelerate tumor growth when targeting immature ERMS precursors within a specific time window, in which the precursors are permissive to the mutation and show that oncNRAS-associated processes differ from each other in dependency on their occurrence during tumor development.

Social cognition in an adult epilepsy patient with developmental amnesia.

Reports on social cognition in patients with developmental amnesia resulting from bilateral hippocampal lesions are rare, although the link between social cognition and temporal lobe structures is well established. We present the case of a 23-year-old male epilepsy patient, BM, with developmental amnesia due to perinatal cerebral hypoxia. The patient was examined with neuroimaging and neuropsychological methods and compared to IQ-matched patients with epilepsy to control for effects of epilepsy. In addition, we used a test battery that evaluates emotion recognition and theory of mind to study his social cognition abilities. Structural high-resolution magnetic resonance imaging showed bilateral hippocampal atrophy. The comparison to controls showed that, in addition to the well-documented memory disorders in developmental amnesia, BM showed remarkable deficits in 9 out of 17 social cognitive tasks assessing emotion recognition and theory of mind. In contrast, BM's performance on tasks of executive functions was largely preserved. The relevance of deficits in social cognition for patients with developmental amnesia is discussed.

Safety of the paramedian supracerebellar-transtentorial approach for selective amygdalohippocampectomy.

OBJECTIVE: The goal of this study was to assess the reproducibility and safety of the recently introduced paramedian supracerebellar-transtentorial (PST) approach for selective amygdalohippocampectomy (SA). METHODS: The authors performed a retrospective analysis of prospectively collected data originating from their surgical register of patients undergoing SA via a PST approach for lesional medial temporal lobe epilepsy. All patients received thorough pre- and postoperative clinical (neurological, neuropsychological, psychiatric) and instrumental (ictal and long-term EEG, invasive EEG if needed, MRI) workup. Surgery-induced complications were assessed at discharge and at every follow-up thereafter and were classified according to Clavien-Dindo grade (CDG). Epilepsy outcome was defined according to Engel classification. Data were reported according to common descriptive statistical methods. RESULTS: Between May 2015 and May 2018, 17 patients underwent SA via a PST approach at the authors' institution (hippocampal sclerosis in 13 cases, WHO grade II glioma in 2 cases, and reactive gliosis in 2 cases). The median postoperative follow-up was 7 months (mean 9 months, range 3-19 months). There was no surgery-related mortality and no complication (CDG ≥ 2) in the whole series. Transitory CDG 1 surgical complications occurred in 4 patients and had resolved in all of them by the first postoperative follow-up. One patient showed a deterioration of neuropsychological performance with new slight mnestic deficits. No patient experienced a clinically relevant postoperative visual field defect. No morbidity due to semisitting position was recorded. At last follow-up 13/17 (76.4%) patients were in Engel class I (9/17 [52.9%] were in class IA). CONCLUSIONS: The PST approach is a reproducible and safe surgical route for SA. The achievable complication rate is in line with the best results in the literature. Visual function outcome particularly benefits from this highly selective, neocortex-sparing approach. A larger patient sample and longer follow-up will show in the future if the seizure control rate and neuropsychological outcome also compare better than those achieved with current common surgical techniques.