Element-resolved x-ray ferrimagnetic and ferromagnetic resonance spectroscopy

We report on the measurement of element-specific magnetic resonance spectra at gigahertz frequencies using x-ray magnetic circular dichroism (XMCD). We investigate the ferrimagnetic precession of Gd and Fe ions in Gd-substituted Yttrium Iron Garnet, showing that the resonant field and linewidth of Gd precisely coincide with Fe up to the nonlinear regime of parametric excitations. The opposite sign of the Gd x-ray magnetic resonance signal with respect to Fe is consistent with dynamic antiferromagnetic alignment of the two ionic species. Further, we investigate a bilayer metal film, Ni$_{80}$Fe$_{20}$(5 nm)/Ni(50 nm), where the coupled resonance modes of Ni and Ni$_{80}$Fe$_{20}$ are separately resolved, revealing shifts in the resonance fields of individual layers but no mutual driving effects. Energy-dependent dynamic XMCD measurements are introduced, combining x-ray absorption and magnetic resonance spectroscopies.Comment: 16 pages, 8 figure

Eu0.5_{0.5}Sr1.5_{1.5}MnO4_4: a three-dimensional XY spin glass

The frequency, temperature, and dc-bias dependence of the ac-susceptibility of a high quality single crystal of the Eu$_{0.5}$Sr$_{1.5}$MnO$_4$ layered manganite is investigated. Eu$_{0.5}$Sr$_{1.5}$MnO$_4$ behaves like a XY spin glass with a strong basal anisotropy. Dynamical and static scalings reveal a three-dimensional phase transition near $T_g$ = 18 K, and yield critical exponent values between those of Heisenberg- and Ising-like systems, albeit slightly closer to the Ising case. Interestingly, as in the latter system, the here observed rejuvenation effects are rather weak. The origin and nature of the low temperature XY spin glass state is discussed.Comment: REVTeX 4 style; 5 pages, 4 figure

Transcriptomic signatures of neuronal differentiation and their association with risk genes for autism spectrum and related neuropsychiatric disorders.

Genes for autism spectrum disorders (ASDs) are also implicated in fragile X syndrome (FXS), intellectual disabilities (ID) or schizophrenia (SCZ), and converge on neuronal function and differentiation. The SH-SY5Y neuroblastoma cell line, the most widely used system to study neurodevelopment, is currently discussed for its applicability to model cortical development. We implemented an optimal neuronal differentiation protocol of this system and evaluated neurodevelopment at the transcriptomic level using the CoNTeXT framework, a machine-learning algorithm based on human post-mortem brain data estimating developmental stage and regional identity of transcriptomic signatures. Our improved model in contrast to currently used SH-SY5Y models does capture early neurodevelopmental processes with high fidelity. We applied regression modelling, dynamic time warping analysis, parallel independent component analysis and weighted gene co-expression network analysis to identify activated gene sets and networks. Finally, we tested and compared these sets for enrichment of risk genes for neuropsychiatric disorders. We confirm a significant overlap of genes implicated in ASD with FXS, ID and SCZ. However, counterintuitive to this observation, we report that risk genes affect pathways specific for each disorder during early neurodevelopment. Genes implicated in ASD, ID, FXS and SCZ were enriched among the positive regulators, but only ID-implicated genes were also negative regulators of neuronal differentiation. ASD and ID genes were involved in dendritic branching modules, but only ASD risk genes were implicated in histone modification or axonal guidance. Only ID genes were over-represented among cell cycle modules. We conclude that the underlying signatures are disorder-specific and that the shared genetic architecture results in overlaps across disorders such as ID in ASD. Thus, adding developmental network context to genetic analyses will aid differentiating the pathophysiology of neuropsychiatric disorders

Genome engineering of isogenic human ES cells to model autism disorders.

Isogenic pluripotent stem cells are critical tools for studying human neurological diseases by allowing one to study the effects of a mutation in a fixed genetic background. Of particular interest are the spectrum of autism disorders, some of which are monogenic such as Timothy syndrome (TS); others are multigenic such as the microdeletion and microduplication syndromes of the 16p11.2 chromosomal locus. Here, we report engineered human embryonic stem cell (hESC) lines for modeling these two disorders using locus-specific endonucleases to increase the efficiency of homology-directed repair (HDR). We developed a system to: (1) computationally identify unique transcription activator-like effector nuclease (TALEN) binding sites in the genome using a new software program, TALENSeek, (2) assemble the TALEN genes by combining golden gate cloning with modified constructs from the FLASH protocol, and (3) test the TALEN pairs in an amplification-based HDR assay that is more sensitive than the typical non-homologous end joining assay. We applied these methods to identify, construct, and test TALENs that were used with HDR donors in hESCs to generate an isogenic TS cell line in a scarless manner and to model the 16p11.2 copy number disorder without modifying genomic loci with high sequence similarity

Dementia assessment and management in primary care settings: a survey of current provider practices in the United States.

BACKGROUND:Primary care providers (PCPs) are typically the first to screen and evaluate patients for neurocognitive disorders (NCDs), including mild cognitive impairment and dementia. However, data on PCP attitudes and evaluation and management practices are sparse. Our objective was to quantify perspectives and behaviors of PCPs and neurologists with respect to NCD evaluation and management. METHODS:A cross-sectional survey with 150 PCPs and 50 neurologists in the United States who evaluated more than 10 patients over age 55 per month. The 51-item survey assessed clinical practice characteristics, and confidence, perceived barriers, and typical practices when diagnosing and managing patients with NCDs. RESULTS:PCPs and neurologists reported similar confidence and approaches to general medical care and laboratory testing. Though over half of PCPs performed cognitive screening or referred patients for cognitive testing in over 50% of their patients, only 20% reported high confidence in interpreting results of cognitive tests. PCPs were more likely to order CT scans than MRIs, and only 14% of PCPs reported high confidence interpreting brain imaging findings, compared to 70% of specialists. Only 21% of PCPs were highly confident that they correctly recognized when a patient had an NCD, and only 13% were highly confident in making a specific NCD diagnosis (compared to 72 and 44% for neurologists, both p < 0.001). A quarter of all providers identified lack of familiarity with diagnostic criteria for NCD syndromes as a barrier to clinical practice. CONCLUSIONS:This study demonstrates how PCPs approach diagnosis and management of patients with NCDs, and identified areas for improvement in regards to cognitive testing and neuroimaging. This study also identified all providers' lack of familiarity with published diagnostic criteria for NCD syndromes. These findings may inform the development of new policies and interventions to help providers improve the efficacy of their decision processes and deliver better quality care to patients with NCDs

Spatiotemporal dynamics of the postnatal developing primate brain transcriptome.

Developmental changes in the temporal and spatial regulation of gene expression drive the emergence of normal mature brain function, while disruptions in these processes underlie many neurodevelopmental abnormalities. To solidify our foundational knowledge of such changes in a primate brain with an extended period of postnatal maturation like in human, we investigated the whole-genome transcriptional profiles of rhesus monkey brains from birth to adulthood. We found that gene expression dynamics are largest from birth through infancy, after which gene expression profiles transition to a relatively stable state by young adulthood. Biological pathway enrichment analysis revealed that genes more highly expressed at birth are associated with cell adhesion and neuron differentiation, while genes more highly expressed in juveniles and adults are associated with cell death. Neocortex showed significantly greater differential expression over time than subcortical structures, and this trend likely reflects the protracted postnatal development of the cortex. Using network analysis, we identified 27 co-expression modules containing genes with highly correlated expression patterns that are associated with specific brain regions, ages or both. In particular, one module with high expression in neonatal cortex and striatum that decreases during infancy and juvenile development was significantly enriched for autism spectrum disorder (ASD)-related genes. This network was enriched for genes associated with axon guidance and interneuron differentiation, consistent with a disruption in the formation of functional cortical circuitry in ASD

Nonresectable Hepatocellular Carcinoma: Long-term Toxicity in Patients Treated with Transarterial Chemoembolization - Single-Center Experience

Purpose: To determine the toxicity profile of transarterial chemoembolization (TACE) at 6 months and 1 year after treatment in patients with hepatocellular carcinoma (HCC) in a standardized oncology protocol so that TACE could be compared with systemic chemotherapeutic regimens for liver cancer. Materials and Methods: The study was authorized by the institutional review board. Between January 2002 and January 2007, 190 patients (155 men, 35 women; median age, 65 years; age range, 18 – 84 years) with HCC who underwent TACE treatment were identified from a prospectively collected database. Clinical records of complete blood cell counts and chemical profiles at baseline and at 6 and 12 months after treatment were studied retrospectively. Toxicity was graded according to the common terminology criteria for adverse events (CTCAE). A transition (survival) analysis perspective was used to estimate the distribution of toxicity grades. Patient survival from the first TACE session was calculated with Kaplan-Meier analysis. Results: Grade 3 or 4 toxicity 6 and 12 months, respectively, after treatment included leukocytopenia (7% and 19%); anemia (9% and 19%); thromobocytopenia (13% and 23%); prolonged activated partial thromboplastin time (8% and 18%); elevated aspartate aminotransferase (15% and 18%), alanine aminotransferase (10% and 18%), and alkaline phosphatase (8% and 18%) levels; hypoalbuminemia (10% and 19%); hyperbilirubinemia (10% and 22%); and alopecia (18%). The cumulative survival rate was 58% at 1 year, 39% at 2 years, and 29% at 3 years. These toxicity rates were considerably lower than those reported after treatment with currently used systemic chemotherapeutic agents. Conclusion: Study results show that TACE has a favorable long-term toxicity profile in patients with HCC. Data clearly support the role of TACE in the treatment of patients with nonresectable HHC