Miracle-dz/UniFAR-FTUs huggingface dataset:
Childhood Ataxia

Childhood ataxia is characterized by impaired balance and coordination primarily because of cerebellar dysfunction. Friedreich ataxia, a form of childhood ataxia, is the most common multisystem autosomal recessive disease. Most of these patients are homozygous for the GAA repeat expansion located on the first intron of the frataxin gene on chromosome 9. Mutations in the frataxin gene impair mitochondrial function, increase reactive oxygen species, and trigger redistribution of iron in the mitochondria and cytosol. Targeted therapies for Friedreich ataxia are undergoing testing. In addition, a centralized database, patient registry, and natural history study have been launched to support clinical trials in Friedreich ataxia. The 2011 Neurobiology of Disease in Children symposium, held in conjunction with the 40th annual Child Neurology Society meeting, aimed to (1) describe clinical features surrounding Friedreich ataxia, including cardiomyopathy and genetics; (2) discuss recent advances in the understanding of the pathogenesis of Friedreich ataxia and developments of clinical trials; (3) review new investigations of characteristic symptoms; and (4) establish clinical and biochemical overlaps in neurodegenerative diseases and possible directions for future basic, translational, and clinical studies.
Alleviation of Neonatal Sinovenous Compression to Enhance Cerebral Venous Blood Flow

Occipital bone compression of the superior sagittal sinus occurs in supine neonates. The authors previously showed that this compression is associated with neonatal cerebral sinovenous thrombosis, an important neonatal neurological condition, presumably via increased venous stasis. They hypothesized that a pillow alleviating occipital compression could improve cerebral venous flow. Neonates without cerebral sinovenous thrombosis requiring brain magnetic resonance imaging/venography were prospectively enrolled. Demographics, imaging indications, head position, and superior sagittal sinus compression were recorded. Flow velocities in the anterior and posterior superior sagittal sinus and sigmoid sinus before and after pillow placement were quantified using Doppler ultrasound. A total of 10 neonates (6 female, median postconceptional age 40.6 weeks) were enrolled. Flow velocities increased beyond the superior sagittal sinus compression point following pillow placement: 0.09 ± 0.04 m/sec to 0.15 ± 0.12 m/sec (P = .047) for posterior superior sagittal sinus; 0.10 ± 0.05 m/sec to 0.19 ± 0.15 m/sec (P = .005) for sigmoid sinus. Pillow decompression can improve neonatal cerebral venous flow, representing a potential noninvasive intervention for the prevention and treatment of neonatal cerebral sinovenous thrombosis.
Dendritic, Axonal, and Spinal Pathology of the Purkinje Cells and the Neurons of the Dentate Nucleus After Long-Term Phenytoin Administration

Phenytoin is a commonly prescribed anticonvulsant drug; however, there is evidence that long-term administration is related to cerebellar ataxia, cerebellar atrophy, loss of Purkinje cells, and hyperplasia of Bergman glia cells. The aim of the present study was to detect and describe any possible alterations of the Purkinje cells, and neurons of the dentate nucleus, as those can be seen with the use of silver impregnation techniques, such as Golgi and Nauta method. The study was performed on a 7-year-old boy who was under phenytoin treatment for more than 3.5 years and had clinical manifestations of cerebellar ataxia. Golgi silver impregnation technique revealed substantial loss of dendritic spines and tertiary dendritic branches, both on the Purkinje cells and the neurons of the dentate nucleus, whereas the Nauta method demonstrated swollen and degenerated axons of Purkinje cells.
Sexual Regional Dimorphism of Post-Adolescent and Middle Age Brain Maturation. A Multi-center 3T MRI Study

Sex-related differences are tied into neurodevelopmental and lifespan processes, beginning early in the perinatal and developmental phases and continue into adulthood. The present study was designed to investigate sexual dimorphism of changes in gray matter (GM) volume in post-adolescence, with a focus on early and middle-adulthood using a structural magnetic resonance imaging (MRI) dataset of healthy controls from the European Network on Psychosis, Affective disorders and Cognitive Trajectory (ENPACT). Three hundred and seventy three subjects underwent a 3.0 T MRI session across four European Centers. Age by sex effects on GM volumes were investigated using voxel-based morphometry (VBM) and the Automated Anatomical Labeling atlas regions (ROI). Females and males showed overlapping and non-overlapping patterns of GM volume changes during aging. Overlapping age-related changes emerged in bilateral frontal and temporal cortices, insula and thalamus. Both VBM and ROI analyses revealed non-overlapping changes in multiple regions, including cerebellum and vermis, bilateral mid frontal, mid occipital cortices, left inferior temporal and precentral gyri. These findings highlight the importance of accounting for sex differences in cross-sectional analyses, not only in the study of normative changes, but particularly in the context of psychiatric and neurologic disorders, wherein sex effects may be confounded with disease-related changes.
Human LilrB2 Is a β-Amyloid Receptor and Its Murine Homolog PirB Regulates Synaptic Plasticity in an Alzheimer’s Model

Amyloid Binding Partners Amyloid-β (Aβ) is critical to the pathology of Alzheimer's disease (AD), but its role in normal physiology remains unclear. Kim et al. (p. 1399; see the Perspective by Benilova and De Strooper) found that murine-paired immunoglobulin-like receptor B (PirB) and its human ortholog, leukocyte immunoglobulin-like receptor B2 (LilrB2) both bound to oligomerized Aβ. Early in mouse development, ocular dominance plasticity was affected by interactions between oligomeric Aβ and PirB. In hippocampal brain slices from a mouse model of AD, reductions in long-term potentiation induced by Aβ required PirB. Furthermore, the memory defects characteristic of a mouse model of AD were dependent on function of PirB. Many binding partners for Aβ have been identified, and so the extent to which these findings can be exploited therapeutically remains unclear. A potential β-amyloid receptor in neurons regulates ocular dominance in mouse brain development. [Also see Perspective by Benilova and De Strooper] Soluble β-amyloid (Aβ) oligomers impair synaptic plasticity and cause synaptic loss associated with Alzheimer’s disease (AD). We report that murine PirB (paired immunoglobulin-like receptor B) and its human ortholog LilrB2 (leukocyte immunoglobulin-like receptor B2), present in human brain, are receptors for Aβ oligomers, with nanomolar affinity. The first two extracellular immunoglobulin (Ig) domains of PirB and LilrB2 mediate this interaction, leading to enhanced cofilin signaling, also seen in human AD brains. In mice, the deleterious effect of Aβ oligomers on hippocampal long-term potentiation required PirB, and in a transgenic model of AD, PirB not only contributed to memory deficits present in adult mice, but also mediated loss of synaptic plasticity in juvenile visual cortex. These findings imply that LilrB2 contributes to human AD neuropathology and suggest therapeutic uses of blocking LilrB2 function.
Whole-brain white matter organization, intelligence, and educational attainment

General cognitive ability, sometimes referred to as intelligence, is associated with educational attainment throughout childhood. Most studies that have explored the neural correlates of intelligence in childhood focus on individual brain regions. This analytical approach is designed to identify restricted sets of voxels that overlap across participants. By contrast, we explored the relationship between white matter connectome organization, intelligence, and education. In both a sample of typically-developing children (N=63) and a sample of struggling learners (N=139), the white matter connectome efficiency was strongly associated with intelligence and educational attainment. Further, intelligence mediated the relationship between connectome efficiency and educational attainment. In contrast, a canonical voxel-wise analysis failed to identify any significant relationships. The results emphasize the importance of distributed brain network properties for cognitive or educational ability in childhood. Our findings are interpreted in the context of a developmental theory, which emphasizes the interaction between different subsystems over developmental time.
Sound Induces Change in Orientation Preference of V1 Neurons: Audio-Visual Cross-Influence

In the cortex, demarcated unimodal sensory regions often respond to unforeseen sensory stimuli and exhibit plasticity. The goal of the current investigation was to test evoked responses of primary visual cortex (V1) neurons when an adapting auditory stimulus is applied in isolation. Using extracellular recordings in anesthetized cats, we demonstrate that, unlike the prevailing observation of only slight modulations in the firing rates of the neurons, sound imposition in isolation entirely shifted the peaks of orientation tuning curves of neurons in both supra- and infragranular layers of V1. Our results suggest that neurons specific to either layer dynamically integrate features of sound and modify the organization of the orientation map of V1. Intriguingly, these experiments present novel findings that the mere presentation of a prolonged auditory stimulus may drastically recalibrate the tuning properties of the visual neurons and highlight the phenomenal neuroplasticity of V1 neurons.
Primate Transcript and Protein Expression Levels Evolve Under Compensatory Selection Pressures

Don't Ape Protein Variation Changes in DNA and messenger RNA (mRNA) expression levels have been used to estimate evolutionary changes between species. However protein expression levels may better reflect selection on divergent and constrained phenotypes. Khan et al. (p. 1100, published online 17 October; see the Perspective by Vogel) measured the differences among and within species between mRNA expression and protein levels in humans, chimpanzees, and rhesus macaques, identifying protein transcripts that seem to be under lineage-specific constraint between humans and chimpanzees. In humans, chimpanzees, and macaques, protein expression levels evolve under stronger evolutionary constraint than messenger RNA levels. [Also see Perspective by Vogel] Changes in gene regulation have likely played an important role in the evolution of primates. Differences in messenger RNA (mRNA) expression levels across primates have often been documented; however, it is not yet known to what extent measurements of divergence in mRNA levels reflect divergence in protein expression levels, which are probably more important in determining phenotypic differences. We used high-resolution, quantitative mass spectrometry to collect protein expression measurements from human, chimpanzee, and rhesus macaque lymphoblastoid cell lines and compared them to transcript expression data from the same samples. We found dozens of genes with significant expression differences between species at the mRNA level yet little or no difference in protein expression. Overall, our data suggest that protein expression levels evolve under stronger evolutionary constraint than mRNA levels.
Molecular Mechanism for Plant Steroid Receptor Activation by Somatic Embryogenesis Co-Receptor Kinases

Steroid Receptor Signaling Plant brassinosteroids signal to diverse pathways in plant physiology. These steroid hormones are perceived at the cell surface, where they bind to the receptor BRASSINOSTEROID INSENSITIVE 1 (BRI1). Santiago et al. (p. 889, published online 8 August) now show that somatic embryogenesis receptor kinase 1 (SERK1) complexes with BRI1. Together, these receptor kinases form the steroid binding site, with the hormone acting as a “molecular glue” that stabilizes the interaction. Hormone-induced heteromerization of BRI1 with SERK1 leads to the activation of the cytoplasmic signaling cascade, triggering plant growth and differentiation. Crystal structures reveal why the brassinosteroid receptor kinase requires another kinase helper protein for activation. Brassinosteroids, which control plant growth and development, are sensed by the leucine-rich repeat (LRR) domain of the membrane receptor kinase BRASSINOSTEROID INSENSITIVE 1 (BRI1), but it is unknown how steroid binding at the cell surface activates the cytoplasmic kinase domain of the receptor. A family of somatic embryogenesis receptor kinases (SERKs) has been genetically implicated in mediating early brassinosteroid signaling events. We found a direct and steroid-dependent interaction between the BRI1 and SERK1 LRR domains by analysis of their complex crystal structure at 3.3 angstrom resolution. We show that the SERK1 LRR domain is involved in steroid sensing and, through receptor–co-receptor heteromerization, in the activation of the BRI1 signaling pathway. Our work reveals how known missense mutations in BRI1 and in SERKs modulate brassinosteroid signaling and the targeting mechanism of BRI1 receptor antagonists.
Intracranial Arteriopathy in Tuberous Sclerosis Complex

Arterial aneurysms, mostly aortic and intracranial, have been occasionally reported in patients with tuberous sclerosis complex. Brain magnetic resonance imaging reports of 404 patients with definite and 16 patients with either probable or possible tuberous sclerosis complex were revised for intracranial aneurysms. Among these patients, brain images of 220 patients with definite and 16 with probable or possible tuberous sclerosis complex were reviewed. Intracranial aneurysms were reported in 3 of 404 patients with a definite diagnosis (0.74%) (general population: 0.35%), including 2 children. A fourth intracranial aneurysm was found in a patient with probable tuberous sclerosis complex, who did not have tubers or subependymal nodules but had clinical manifestations related to neural crest derivatives, including lymphangioleiomyomatosis and extrarenal angiomyolipomas. The authors hypothesize that neural crest dysfunction can have a major role in intracranial arteriopathy in tuberous sclerosis complex, as smooth muscle cells in the forebrain vessels are of neural crest origin.
Evolving diverse populations of Prisoner’s Dilemma strategies

It is common for evolved populations of Iterated prisonerpsilas dilemma to become homogenous with most of the strategies either identical or similar to each other. As fitness is usually based on play with other members of the population, this favors the evolution of strategies which score well when playing themselves or close mutants of themselves. Also, populations tend to change considerably over time. New strategies arise and take over. A population consisting entirely of a highly cooperative strategy like tit-for-tat can become a population consisting entirely of a highly uncooperative strategy like always-defect. This study uses an experimental setup which incorporates geography in an attempt to evolve a diversity of coexisting strategies. The resulting populations are analyzed using prisonerpsilas dilemma fingerprints and found to be both diverse and ldquostablerdquo in the sense that they remain highly cooperative over time.
UDAE: Universal Data Access Engine for Sensor Networks

We present the design and implementation of UDAE, a universal data access engine for wireless sensor networks. The UDAE allows developers to access data both locally and over the network from a variety of sources, such as sensors, communications links and platform components in a unified manner. It is also fully extensible, allowing data sources and users to be added flexibly at run-time. This enables capabilities for cross-component optimization and run-time configuration. In order to validate our proposed system, we have implemented UDAE for two operating systems (Contiki and TinyOS). While the TinyOS implementation has been done as native code, the Contiki implementation is based on a reconfigurable component-oriented middleware enabling developers to fully benefit from the flexibility offered by the UDAE. Both of these implementations have been made publicly available under an open source license. A detailed performance evaluation carried out with these implementations shows that the overhead induced by the adoption of UDAE in terms of memory, processing requirements and energy consumption is very small and the additional latencies induced by the framework negligible. We also discuss various different application scenarios for UDAE in some detail, particularly cross-component optimization and run-time configuration. Furthermore, a practical case study of cross-component optimization selected from the TinyOS domain is addressed.
TGF-β1 Genotype in Pediatric Migraine Patients

There is no information about the role of transforming growth factor–beta 1 (TGF-β1) in the pathogenesis of pediatric migraine. This study included 100 consecutive children and adolescents in whom migraine was diagnosed and 88 healthy children and adolescents. The isolated genomic DNA was used as a template for TGFβ-1 (–800G/A, –509C/T, 869T/C [codon 10] and 915G/C [codon 25]) genotyping. The allelic frequency of 509C/T was significantly different between control and migraine without aura patients (P = .04). Codon 10 C/T genotypic and C10 C allelic frequency of TGF-β1 polymorphisms were significantly higher in migraine and migraine without aura patients versus healthy controls (P = .00; P = .00). To our knowledge, this is the first report dealing with the relationship between TGF-β1 genotype and migraine in the pediatric age group. Further studies related to this subject are needed, along with a search for new therapeutic agents with anti-inflammatory properties.
Identifying important features for intrusion detection using support vector machines and neural networks

Intrusion detection is a critical component of secure information systems. This paper addresses the issue of identifying important input features in building an intrusion detection system (IDS). Since elimination of the insignificant and/or useless inputs leads to a simplification of the problem, faster and more accurate detection may result. Feature ranking and selection, therefore, is an important issue in intrusion detection. We apply the technique of deleting one feature at a time to perform experiments on SVMs and neural networks to rank the importance of input features for the DARPA collected intrusion data. Important features for each of the 5 classes of intrusion patterns in the DARPA data are identified. It is shown that SVM-based and neural network based IDSs using a reduced number of features can deliver enhanced or comparable performance. An IDS for class-specific detection based on five SVMs is proposed.
Spectrum of Neurodevelopmental Disabilities

The spectrum of neurodevelopmental disabilities was studied in a cohort of patients in Hungary. A search for etiologies and assessment of the degree of intellectual disability were carried out. The study included 241 (131 boys) patients. Disability occurred without any prenatal, perinatal, and/or neonatal adverse events in 167 patients. They were classified into the following subgroups: genetic syndromes with recognized etiology, global developmental delay/intellectual disability in association with dysmorphic features but unknown etiology, global developmental delay/intellectual disability without dysmorphic features and recognized etiology, brain malformations, inborn errors of metabolism, leukoencephalopathies, epileptic syndromes, developmental language impairment, and neuromuscular disorders. Adverse events occurred in 74 children classified into subgroups such as cerebral palsy after delivery preterm or at term, and disabilities without cerebral palsy. The etiology was identified in 66.4%, and genetic diagnosis was found in 19.5%. Classification of neurodevelopmental disorders contribute to etiological diagnosis, proper rehabilitation, and genetic counseling.
Phosphoinositide 3-Kinase δ Gene Mutation Predisposes to Respiratory Infection and Airway Damage

Answers from Exomes Exome sequencing, which targets only the protein-coding regions of the genome, has the potential to identify the underlying genetic causes of rare inherited diseases. Angulo et al. (p. 866, published online 17 October; see Perspective by Conley and Fruman) performed exome sequencing of individuals from seven unrelated families with severe, recurrent respiratory infections. The patients carried the same mutation in the gene coding for the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ). The mutation caused aberrant activation of this kinase, which plays a key role in immune cell signaling. Drugs inhibiting PI3Kδ are already in clinical trials for other disorders. Gene sequencing of unrelated patients with recurrent airway infections identifies a common underlying mutation. [Also see Perspective by Conley and Fruman] Genetic mutations cause primary immunodeficiencies (PIDs) that predispose to infections. Here, we describe activated PI3K-δ syndrome (APDS), a PID associated with a dominant gain-of-function mutation in which lysine replaced glutamic acid at residue 1021 (E1021K) in the p110δ protein, the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ), encoded by the PIK3CD gene. We found E1021K in 17 patients from seven unrelated families, but not among 3346 healthy subjects. APDS was characterized by recurrent respiratory infections, progressive airway damage, lymphopenia, increased circulating transitional B cells, increased immunoglobulin M, and reduced immunoglobulin G2 levels in serum and impaired vaccine responses. The E1021K mutation enhanced membrane association and kinase activity of p110δ. Patient-derived lymphocytes had increased levels of phosphatidylinositol 3,4,5-trisphosphate and phosphorylated AKT protein and were prone to activation-induced cell death. Selective p110δ inhibitors IC87114 and GS-1101 reduced the activity of the mutant enzyme in vitro, which suggested a therapeutic approach for patients with APDS.
Mosaic Copy Number Variation in Human Neurons

Not All Neurons Are Alike As life proceeds, many cells acquire individualized mutations. In the immune system, genome rearrangements generate useful antibody diversity. McConnell et al. (p. 632; see the Perspective by Macosko and McCarroll) now show that human neurons also diversify. Neurons taken from postmortem human frontal cortex tissue and neurons derived from induced pluripotent stem cell differentiation in vitro showed surprising diversity in individual cell genomes. Up to 41% of the frontal cortex neurons had copy number variations—no two alike—with deletions more common than duplications. Single-cell genomics reveals that individual adult human neurons acquire diverse individual genomes. [Also see Perspective by Macosko and McCarroll] We used single-cell genomic approaches to map DNA copy number variation (CNV) in neurons obtained from human induced pluripotent stem cell (hiPSC) lines and postmortem human brains. We identified aneuploid neurons, as well as numerous subchromosomal CNVs in euploid neurons. Neurotypic hiPSC-derived neurons had larger CNVs than fibroblasts, and several large deletions were found in hiPSC-derived neurons but not in matched neural progenitor cells. Single-cell sequencing of endogenous human frontal cortex neurons revealed that 13 to 41% of neurons have at least one megabase-scale de novo CNV, that deletions are twice as common as duplications, and that a subset of neurons have highly aberrant genomes marked by multiple alterations. Our results show that mosaic CNV is abundant in human neurons.