An Executive Functioning Perspective in Neurofibromatosis Type 1: From ADHD and Autism Spectrum Disorder to Research Domains

Purpose: Neurofibromatosis type 1 (NF1) is a rare monogenic disorder associated with executive function (EF) deficits and heightened risk for attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). The goal of this paper is to understand how EFs provide a common foundation to understand vulnerabilities for ADHD and ASD within NF1. Methods: A literature review and synthesis was conducted. Results: EF difficulties in working memory, inhibitory control, cognitive flexibility, and planning are evident in NF1, ADHD, and ASD. However, relatively little is known about the heterogeneity of EFs and ADHD and ASD outcomes in NF1. Assessment of ADHD and ASD in NF1 is based on behavioral symptoms without understanding neurobiological contributions. Recent efforts are promoting the use of dimensional and multidisciplinary methods to better understand normal and abnormal behavior, including integrating information from genetics to self-report measures. Conclusion: NF1 is a monogenic disease with well-developed molecular and phenotypic research as well as complementary animal models. NF1 presents an excellent opportunity to advance our understanding of the neurobiological impact of known pathogenic variation in normal and abnormal neural pathways implicated in human psychopathology. EFs are core features of NF1, ADHD, and ASD, and these neurodevelopmental outcomes are highly prevalent in NF1. We propose a multilevel approach for understanding EFs in patients with NF1.This is essential to advance targeted interventions for NF1 patients and to advance the exciting field of research in this condition

ADGRL3 (LPHN3) variants are associated with a refined phenotype of ADHD in the MTA study

Background ADHD is the most common neuropsychiatric condition affecting individuals of all ages. Long-term outcomes of affected individuals and association with severe comorbidities as SUD or conduct disorders are the main concern. Genetic associations have been extensively described. Multiple studies show that intronic variants harbored in the ADGRL3 (LPHN3) gene are associated with ADHD, especially associated with poor outcomes. Methods In this study, we evaluated this association in the Multimodal Treatment Study of children with ADHD (MTA), initiated as a 14-month randomized clinical trial of 579 children diagnosed with DSM-IV ADHD-Combined Type (ADHD-C), that transitioned to a 16-year prospective observational follow-up, and 289 classmates added at the 2-year assessment to serve as a local normative comparison group (LNCG). Diagnostic evaluations at entry were based on the Diagnostic Interview Schedule for Children-Parent (DISC-P), which was repeated at several points over the years. For an add-on genetic study, blood samples were collected from 232 in the MTA group and 139 in the LNCG. Results For the 205 MTA participants, 14.6% retained the DISC-P diagnosis of ADHD-C in adolescence. For 127 LNCG participants, 88.2% remained undiagnosed by the DISC-P. We genotyped 15 polymorphic SNP markers harbored in the ADGRL3 gene, and compared allele frequencies for the 30 cases with continued diagnosis of ADHD-C in adolescence to the other participants. Replication of the association of rs2345039 ADGRL3 variant was observed (P value = 0.004, FDR corrected = 0.03; Odds ratio = 2.25, upper CI 1.28–3.97). Conclusion The detection of susceptibility conferred by ADGRL3 variants in the extreme phenotype of continued diagnosis of ADHD-C from childhood to adolescence provides additional support that the association of ADGRL3 and ADHD is not spurious. Exploring genetic effects in longitudinal cohorts, in which refined, age-dependent phenotypes are documented, is crucial to understand the natural history of ADHD

Strength in numbers:combining multi-source remotely sensed data to model plant invasions in coastal dune ecosystems

International audienceA common feature of most theories of invasion ecology is that the extent and intensity of invasions is driven by a combination of drivers, which can be grouped into three main factors propagule pressure (P), abiotic drivers (A) and biotic interactions (B). However, teasing apart the relative contribution of P, A and B on Invasive Alien Species (IAS) distributions is typically hampered by a lack of data. We focused on Mediterranean coastal dunes as a model system to test the ability of a combination of multi-source Remote Sensing (RS) data to characterize the distribution of five IAS. Using generalized linear models, we explored and ranked correlates of P, A and B derived from high-resolution optical imagery and three-dimensional (3D) topographic models obtained from LiDAR, along two coastal systems in Central Italy (Lazio and Molise Regions). Predictors from all three factors contributed significantly to explaining the presence of IAS, but their relative importance varied among the two Regions, supporting previous studies suggesting that invasion is a context-dependent process. The use of RS data allowed us to characterize the distribution of IAS across broad, regional scales and to identify coastal sectors that are most likely to be invaded in the future. © 2019 by the authors

Collision of protostellar jets in the star-forming region IC 1396N: Analysis of knot proper motions

Context. The bright-rimmed cloud IC 1396N is believed to host one of the few known cases where two bipolar CO outflows driven by young stellar objects collide. The CO outflows are traced by chains of knots of H2 emission, with enhanced emission at the position of the possible collision. Aims. The aim of this work is to use the proper motions of the H2 knots to confirm the collision scenario. Methods. A second-epoch H2 image was obtained, and the proper motions of the knots were determined with a time baseline of ∼11 yr. We also performed differential photometry on the images to check the flux variability of the knots. Results. For each outflow (N and S), we classified the knots as pre-collision or post-collision. The axes of the pre-collision knots, the position of the possible collision point, and the axes of the post-collision knots were estimated. The difference between the proper motion direction of the post-collision knots and the position angle from the collision point was also calculated. For some of the knots, we obtained the 3D velocity using the radial velocity derived from H2 spectra. Conclusions. The velocity pattern of the H2 knots in the area of interaction (post-collision knots) shows a deviation from that of the pre-collision knots, consistent with being a consequence of the interaction between the two outflows. This favours the interpretation of the IC 1396N outflows as a true collision between two protostellar jets instead of a projection effect

Neurofibromatosis Type 1 Implicates Ras Pathways in the Genetic Architecture of Neurodevelopmental Disorders

The genetic architecture of neurodevelopmental disorders is largely polygenic, non-specific, and pleiotropic. This complex genetic architecture makes the search for specific etiological mechanisms that contribute to neurodevelopmental risk more challenging. Monogenic disorders provide an opportunity to focus in on how well-articulated signaling pathways contribute to risk for neurodevelopmental outcomes. This paper will focus on neurofbromatosis type 1 (NF1), a rare monogenic disorder that is associated with varied neurodevelopmental outcomes. Specifically, this paper will provide a brief overview of NF1 and its phenotypic associations with autism spectrum disorder, attention-deficit/hyperactivity disorder, and specific learning disorders, describe how variation within the NF1 gene increases risk for neurodevelopmental disorders via altered Ras signaling, and provide future directions for NF1 research to help elucidate the genetic architecture of neurodevelopmental disorders in the general population

Genomics of clinal local adaptation in Pinus sylvestris under continuous environmental and spatial genetic setting

Understanding the consequences of local adaptation at the genomic diversity is a central goal in evolutionary genetics of natural populations. In species with large continuous geographical distributions the phenotypic signal of local adaptation is frequently clear, but the genetic basis often remains elusive. We examined the patterns of genetic diversity inPinus sylvestris, a keystone species in many Eurasian ecosystems with a huge distribution range and decades of forestry research showing that it is locally adapted to the vast range of environmental conditions. MakingP. sylvestrisan even more attractive subject of local adaptation study, population structure has been shown to be weak previously and in this study. However, little is known about the molecular genetic basis of adaptation, as the massive size of gymnosperm genomes has prevented large scale genomic surveys. We generated a both geographically and genomically extensive dataset using a targeted sequencing approach. By applying divergence-based and landscape genomics methods we identified several loci contributing to local adaptation, but only few with large allele frequency changes across latitude. We also discovered a very large (ca. 300 Mbp) putative inversion potentially under selection, which to our knowledge is the first such discovery in conifers. Our results call for more detailed analysis of structural variation in relation to genomic basis of local adaptation, emphasize the lack of large effect loci contributing to local adaptation in the coding regions and thus point out the need for more attention toward multi-locus analysis of polygenic adaptation

Budding yeast ATM/ATR control meiotic double-strand break (DSB) levels by down-regulating Rec114, an essential component of the DSB-machinery

An essential feature of meiosis is Spo11 catalysis of programmed DNA double strand breaks (DSBs). Evidence suggests that the number of DSBs generated per meiosis is genetically determined and that this ability to maintain a pre-determined DSB level, or "DSB homeostasis", might be a property of the meiotic program. Here, we present direct evidence that Rec114, an evolutionarily conserved essential component of the meiotic DSB-machinery, interacts with DSB hotspot DNA, and that Tel1 and Mec1, the budding yeast ATM and ATR, respectively, down-regulate Rec114 upon meiotic DSB formation through phosphorylation. Mimicking constitutive phosphorylation reduces the interaction between Rec114 and DSB hotspot DNA, resulting in a reduction and/or delay in DSB formation. Conversely, a non-phosphorylatable rec114 allele confers a genome-wide increase in both DSB levels and in the interaction between Rec114 and the DSB hotspot DNA. These observations strongly suggest that Tel1 and/or Mec1 phosphorylation of Rec114 following Spo11 catalysis down-regulates DSB formation by limiting the interaction between Rec114 and DSB hotspots. We also present evidence that Ndt80, a meiosis specific transcription factor, contributes to Rec114 degradation, consistent with its requirement for complete cessation of DSB formation. Loss of Rec114 foci from chromatin is associated with homolog synapsis but independent of Ndt80 or Tel1/Mec1 phosphorylation. Taken together, we present evidence for three independent ways of regulating Rec114 activity, which likely contribute to meiotic DSBs-homeostasis in maintaining genetically determined levels of breaks

Selective changes in human corneal sensation associated with herpes simplex virus keratitis

PURPOSE. To determine corneal sensitivity to selective mechanical, chemical, and thermal (heat and cold) stimulation in patients with a history of herpes simplex virus (HSV) keratitis. METHODS. Corneal sensitivity to different modalities of stimulus was determined in both eyes of 16 patients with unilateral HSV keratitis diagnosed 1 to 12 months before the study. On slit lamp examination, 13 HSV-affected eyes showed corneal scarring or opacities, and three had no signs of previous keratitis. Corneal sensitivity was determined with the Belmonte gas esthesiometer. Mechanical, chemical, heat, and cold stimuli were applied on the central cornea. Eyes from 10 healthy subjects served as controls. RESULTS. In all control and contralateral eyes, selective mechanical, chemical, heat, and cold stimulation evoked sensations of subjective intensity proportional to the magnitude of the applied stimulus. In one HSV patient, the affected cornea was unresponsive to all types of stimuli, four lost only corneal sensitivity to mechanical stimulation, and three lost only sensitivity to heat. Mechanical (P Ͻ 0.005) and heat (P Ͻ 0.05) thresholds were raised in HSV eyes, whereas thresholds for CO 2 were not modified. Also, HSV subjects identified poorly the intensity of mechanical, chemical, and heat stimuli, whereas sensitivity to cold stimulation was unaffected. CONCLUSIONS. In eyes that had had HSV keratitis, corneal sensitivity to mechanical forces and heat was significantly impaired, suggesting that axonal damage and/or altered expression of membrane ion channels involved in transduction and membrane excitability affects primarily the mechano-and polymodal nociceptor terminals. Corneal cold-sensitive terminals remain largely unaffected. (Invest Ophthalmol Vis Sci. 2010; 51:4516 -4522) DOI:10.1167/iovs.10-5225 C orneal infection by herpes simplex virus (HSV) is a common condition that usually develops as an acute or chronic corneal inflammation. 1 The disease is most often due to reactivation of a latent infection of trigeminal sensory neurons innervating the cornea and possibly also of corneal epithelial cells by the neurotropic HSV (HSV1, HSV2, or both). 2,3 As a result, the patient develops an epithelial keratitis. This condition is in many cases recurrent, mainly after HSV-1 infection, 2,5-7 HSV infection often affects also the corneal stroma, inducing a herpes stromal keratitis (HSK). Occasionally, HSV reaches the corneal endothelium, causing endothelial cell loss and permanent corneal swelling. Recurrent episodes may eventually lead to corneal scarring, opacities, and irregular astigmatism. Herpes simplex infection is a common cause of corneal sensory loss, 8 although less severe than in keratitis caused by reactivation of varicella-zoster virus. 10 Sensations evoked at the ocular surface result from the activation of several functional classes of primary sensory neurons located in the trigeminal ganglion (TG), the peripheral axons of which innervate the anterior segment of the eye. 11-13 Polymodal nociceptors, the most abundant receptor type in the cornea, respond to noxious or near-noxious mechanical and thermal stimuli, to exogenous irritants, and to inflammatory agents, predominantly mediating burning pain. Mechanonociceptors are activated only by noxious mechanical forces and possibly elicit mainly pricking pain, whereas cold thermoreceptors respond to small temperature reductions of the corneal surface and evoke cooling and perhaps dryness sensations referred to the eye. 14 -16 Unpleasant and painful ocular sensations arising in HSV keratitis patients may be due to an altered neural activity in infected TG corneal sensory neurons. METHODS Patients Sixteen patients (nine women and seven men; age 40.4 Ϯ 3.7 years, range 16 -66) with a history of unilateral HSV keratitis during the year From th

A search for spectral hysteresis and energy-dependent time lags from X-ray and TeV gamma-ray observations of Mrk 421

Blazars are variable emitters across all wavelengths over a wide range of timescales, from months down to minutes. It is therefore essential to observe blazars simultaneously at different wavelengths, especially in the X-ray and gamma-ray bands, where the broadband spectral energy distributions usually peak. In this work, we report on three "target-of-opportunity" (ToO) observations of Mrk 421, one of the brightest TeV blazars, triggered by a strong flaring event at TeV energies in 2014. These observations feature long, continuous, and simultaneous exposures with XMM-Newton (covering X-ray and optical/ultraviolet bands) and VERITAS (covering TeV gamma-ray band), along with contemporaneous observations from other gamma-ray facilities (MAGIC and Fermi-LAT) and a number of radio and optical facilities. Although neither rapid flares nor significant X-ray/TeV correlation are detected, these observations reveal subtle changes in the X-ray spectrum of the source over the course of a few days. We search the simultaneous X-ray and TeV data for spectral hysteresis patterns and time delays, which could provide insight into the emission mechanisms and the source properties (e.g. the radius of the emitting region, the strength of the magnetic field, and related timescales). The observed broadband spectra are consistent with a one-zone synchrotron self-Compton model. We find that the power spectral density distribution at $\gtrsim 4\times 10^{-4}$ Hz from the X-ray data can be described by a power-law model with an index value between 1.2 and 1.8, and do not find evidence for a steepening of the power spectral index (often associated with a characteristic length scale) compared to the previously reported values at lower frequencies.Comment: 45 pages, 15 figure