Somatic Mutational Landscape of Splicing Factor Genes and Their Functional Consequences across 33 Cancer Types

Hotspot mutations in splicing factor genes have been recently reported at high frequency in hematological malignancies, suggesting the importance of RNA splicing in cancer. We analyzed whole-exome sequencing data across 33 tumor types in The Cancer Genome Atlas (TCGA), and we identified 119 splicing factor genes with significant non-silent mutation patterns, including mutation over-representation, recurrent loss of function (tumor suppressor-like), or hotspot mutation profile (oncogene-like). Furthermore, RNA sequencing analysis revealed altered splicing events associated with selected splicing factor mutations. In addition, we were able to identify common gene pathway profiles associated with the presence of these mutations. Our analysis suggests that somatic alteration of genes involved in the RNA-splicing process is common in cancer and may represent an underappreciated hallmark of tumorigenesis

A method for measuring the Neel relaxation time in a frozen ferrofluid

We report a novel method of determining the average Neel relaxation time and its temperature dependence by calculating derivatives of the measured time dependence of temperature for a frozen ferrofluid exposed to an alternating magnetic field. The ferrofluid, composed of dextran-coated Fe3O4 nanoparticles (diameter 13.7 nm +/- 4.7 nm), was synthesized via wet chemical precipitation and characterized by x-ray diffraction and transmission electron microscopy. An alternating magnetic field of constant amplitude (H0 = 20 kA/m) driven at frequencies of 171 kHz, 232 kHz and 343 kHz was used to determine the temperature dependent magnetic energy absorption rate in the temperature range from 160 K to 210 K. We found that the specific absorption rate of the ferrofluid decreased monotonically with temperature over this range at the given frequencies. From these measured data, we determined the temperature dependence of the Neel relaxation time and estimate a room-temperature magnetocrystalline anisotropy constant of 40 kJ/m3, in agreement with previously published results

Electron spin relaxation in intrinsic bulk InP semiconductor

Electron spin dynamics in intrinsic bulk Indium Phosphide (InP) semiconductor is studied by time resolved pump probe reflectivity (TRPPR) technique using the co- and counter-circularly polarized femtosecond pulses at room temperature and 70 K. The reflectivity change from bleaching into absorption is observed with increasing pump photon energy, which can be explained in terms of the spin sensitive band filling and band gap renormalization effects. Density dependence of electron spin relaxation time shows similar tendency at room temperature and 70 K. With increasing carrier density, the electron spin relaxation time increases and then decreases after reaching a maximum value. Our experimental results agree well with the recent theoretical prediction [Jiang and Wu, Phys. Rev. B 79, 125206 (2009)] and D'yakonov-Perel' mechanism is considered as a dominating contribution to the electron spin relaxation in intrinsic bulk InP semiconductor.Comment: 23 pages, 4figures,40referenc

Access and Health System Impact of an Early Intervention Treatment Program for Emerging Adults with Mood and Anxiety Disorders

Objectives: Early intervention programs are effective for improving outcomes in first-episode psychosis; however, less is known about their effectiveness for mood and anxiety disorders. We sought to evaluate the impact of an early intervention program for emerging adults with mood and anxiety disorders in the larger health system context, relative to standard care. Methods: Using health administrative data, we constructed a retrospective cohort of cases of mood and anxiety disorders among emerging adults aged 16 to 25 years in the catchment of the First Episode Mood and Anxiety Program (FEMAP) in London, Ontario, between 2009 and 2014. This cohort was linked to primary data from FEMAP to identify service users. We used proportional hazards models to compare indicators of service use between FEMAP users and a propensity score–matched group of nonusers receiving care elsewhere in the health system. Results: FEMAP users (n = 490) had more rapid access to a psychiatrist relative to nonusers (hazard ratio [HR], 2.82; 95% confidence interval, 2.45 to 3.26; median time, 16 vs. 71 days). In the year following admission, FEMAP users also had lower rates of emergency department use for mental health reasons (HR, 0.73; 95% CI, 0.53 to 0.99). We did not observe differences in psychiatric hospitalization rates. Conclusions: An early intervention model of care for mood and anxiety disorders is associated with better access to psychiatric care and lower use of the emergency department. Our findings suggest that early intervention services for mood and anxiety disorders may be beneficial from a health systems perspective, and further research on the effectiveness of this model of care is warranted

Fully Automatic Facial Deformation Transfer

Facial Animation is a serious and ongoing challenge for the Computer Graphic industry. Because diverse and complex emotions need to be expressed by different facial deformation and animation, copying facial deformations from existing character to another is widely needed in both industry and academia, to reduce time-consuming and repetitive manual work of modeling to create the 3D shape sequences for every new character. But transfer of realistic facial animations between two 3D models is limited and inconvenient for general use. Modern deformation transfer methods require correspondences mapping, in most cases, which are tedious to get. In this paper, we present a fast and automatic approach to transfer the deformations of the facial mesh models by obtaining the 3D point-wise correspondences in the automatic manner. The key idea is that we could estimate the correspondences with different facial meshes using the robust facial landmark detection method by projecting the 3D model to the 2D image. Experiments show that without any manual labelling efforts, our method detects reliable correspondences faster and simpler compared with the state-of-the-art automatic deformation transfer method on the facial models

Electrochemical Investigation of Calcium Substituted Monoclinic Li3_3 V2_2(PO4_4)3_3 Negative Electrode Materials for Sodium‐ and Potassium‐Ion Batteries

Herein, the electrochemical properties and reaction mechanism of Li$_{3‒2x}$Ca$_x$V$_2$(PO$_4$)$_3$/C (x = 0, 0.5, 1, and 1.5) as negative electrode materials for sodium-ion/potassium-ion batteries (SIBs/PIBs) are investigated. All samples undergo a mixed contribution of diffusion-controlled and pseudocapacitive-type processes in SIBs and PIBs via Trasatti Differentiation Method, while the latter increases with Ca content increase. Among them, Li$_3$V$_2$(PO$_4$)$_3$/C exhibits the highest reversible capacity in SIBs and PIBs, while Ca$_{1.5}$V$_2$(PO$_4$)$_3$/C shows the best rate performance with a capacity retention of 46% at 20 C in SIBs and 47% at 10 C in PIBs. This study demonstrates that the specific capacity of this type of material in SIBs and PIBs does not increase with the Ca-content as previously observed in lithium-ion system, but the stability and performance at a high C-rate can be improved by replacing Li$^+$ with Ca$^{2+}$. This indicates that the insertion of different monovalent cations (Na$^+$/K$^+$) can strongly influence the redox reaction and structure evolution of the host materials, due to the larger ion size of Na$^+$ and K$^+$ and their different kinetic properties with respect to Li$^+$. Furthermore, the working mechanism of both LVP/C and Ca$_{1.5}$V$_2$(PO$_4$)$_3$/C in SIBs are elucidated via in operando synchrotron diffraction and in operando X-ray absorption spectroscopy

Evolving prion-like tau conformers differentially alter postsynaptic proteins in neurons inoculated with distinct isolates of Alzheimer’s disease tau

OBJECTIVES: Although accumulation of misfolded tau species has been shown to predict cognitive decline in patients with Alzheimer’s disease (AD) and other tauopathies but with the remarkable diversity of clinical manifestations, neuropathology profiles, and time courses of disease progression remaining unexplained by current genetic data. We considered the diversity of misfolded tau conformers present in individual AD cases as an underlying driver of the phenotypic variations of AD and progressive loss of synapses. METHODS: To model the mechanism of tau propagation and synaptic toxicity of distinct tau conformers, we inoculated wild-type primary mouse neurons with structurally characterized Sarkosyl-insoluble tau isolates from the frontal cortex of six AD cases and monitored the impact for fourteen days. We analyzed the accumulation rate, tau isoform ratio, and conformational characteristics of de novo-induced tau aggregates with conformationally sensitive immunoassays, and the dynamics of synapse formation, maintenance, and their loss using a panel of pre-and post-synaptic markers. RESULTS: At the same concentrations of tau, the different AD tau isolates induced accumulation of misfolded predominantly 4-repeat tau aggregates at different rates in mature neurons, and demonstrated distinct conformational characteristics corresponding to the original AD brain tau. The time-course of the formation of misfolded tau aggregates and colocalization correlated with significant loss of synapses in tau-inoculated cell cultures and the reduction of synaptic connections implicated the disruption of postsynaptic compartment as an early event. CONCLUSIONS: The data obtained with mature neurons expressing physiological levels and adult isoforms of tau protein demonstrate markedly different time courses of endogenous tau misfolding and differential patterns of post-synaptic alterations. These and previous biophysical data argue for an ensemble of various misfolded tau aggregates in individual AD brains and template propagation of their homologous conformations in neurons with different rates and primarily postsynaptic interactors. Modeling tau aggregation in mature differentiated neurons provides a platform for investigating divergent molecular mechanisms of tau strain propagation and for identifying common structural features of misfolded tau and critical interactors for new therapeutic targets and approaches in AD

Exploring the DNA-recognition potential of homeodomains

The recognition potential of most families of DNA-binding domains (DBDs) remains relatively unexplored. Homeodomains (HDs), like many other families of DBDs, display limited diversity in their preferred recognition sequences. To explore the recognition potential of HDs, we utilized a bacterial selection system to isolate HD variants, from a randomized library, that are compatible with each of the 64 possible 3′ triplet sites (i.e., TAANNN). The majority of these selections yielded sets of HDs with overrepresented residues at specific recognition positions, implying the selection of specific binders. The DNA-binding specificity of 151 representative HD variants was subsequently characterized, identifying HDs that preferentially recognize 44 of these target sites. Many of these variants contain novel combinations of specificity determinants that are uncommon or absent in extant HDs. These novel determinants, when grafted into different HD backbones, produce a corresponding alteration in specificity. This information was used to create more explicit HD recognition models, which can inform the prediction of transcriptional regulatory networks for extant HDs or the engineering of HDs with novel DNA-recognition potential. The diversity of recovered HD recognition sequences raises important questions about the fitness barrier that restricts the evolution of alternate recognition modalities in natural systems

Risk of involuntary admission among first-generation ethnic minority groups with early psychosis: A retrospective cohort study using health administrative data

AimsEthnic minority groups often have more complex and aversive pathways to mental health care. However, large population-based studies are lacking, particularly regarding involuntary hospitalisation. We sought to examine the risk of involuntary admission among first-generation ethnic minority groups with early psychosis in Ontario, Canada.MethodsUsing health administrative data, we constructed a retrospective cohort (2009-2013) of people with first-onset non-affective psychotic disorder aged 16-35 years. This cohort was linked to immigration data to ascertain migrant status and country of birth. We identified the first involuntary admission within 2 years and compared the risk of involuntary admission for first-generation migrant groups to the general population. To control for the role of migrant status, we restricted the sample to first-generation migrants and examined differences by country of birth, comparing risk of involuntary admission among ethnic minority groups to a European reference. We further explored the role of migrant class by adjusting for immigrant vs refugee status within the migrant cohort. We also explored effect modification of migrant class by ethnic minority group.ResultsWe identified 15 844 incident cases of psychotic disorder, of whom 19% (n = 3049) were first-generation migrants. Risk of involuntary admission was higher than the general population in five of seven ethnic minority groups. African and Caribbean migrants had the highest risk of involuntary admission (African: risk ratio (RR) = 1.52, 95% CI = 1.34-1.73; Caribbean: RR = 1.58, 95% CI = 1.37-1.82), and were the only groups where the elevated risk persisted when compared to the European reference group within the migrant cohort (African: RR = 1.24, 95% CI = 1.04-1.48; Caribbean: RR = 1.29, 95% CI = 1.07-1.56). Refugee status was independently associated with involuntary admission (RR = 1.16, 95% CI = 1.02-1.32); however, this risk varied by ethnic minority group, with Caribbean refugees having an elevated risk of involuntary admission compared with Caribbean immigrants (RR = 1.72, 95% CI = 1.15-2.58).ConclusionsOur findings are consistent with the international literature showing increased rates of involuntary admission among some ethnic minority groups with early psychosis. Interventions aimed at improving pathways to care could be targeted at these groups to reduce disparities

Involuntary hospitalization among young people with early psychosis: A population-based study using health administrative data.

OBJECTIVE: Early psychosis is an important window for establishing long-term trajectories. Involuntary hospitalization during this period may impact subsequent service engagement in people with newly diagnosed psychotic disorder. However, population-based studies of involuntary hospitalization in early psychosis are lacking. We sought to estimate the proportion of people aged 16 to 35 years with early psychosis in Ontario who are hospitalized involuntarily at first admission, and to identify the associated risk factors and outcomes. METHODS: Using linked population-based health administrative data, we identified incident cases of non-affective psychosis over a five-year period (2009-2013) and followed cases for two years to ascertain the first psychiatric hospitalization. We used modified Poisson regression to model sociodemographic, clinical, and service-related risk factors, and compared service-related outcomes for cases admitted on an involuntary versus voluntary basis. RESULTS: Among 17,725 incident cases of non-affective psychosis, 38% were hospitalized within two years, and 81% of these admissions occurred on an involuntary basis (26% of cohort). Sociodemographic factors associated with an increased risk of involuntary admission included younger age (16-20), and first-generation migrant status. The strongest risk factors were poor illness insight, recent police involvement, and admission to a general (versus psychiatric) hospital. Outcomes associated with involuntary admission included increased likelihood of control intervention use and a shorter length of stay. CONCLUSIONS: One in four young people with first-episode psychosis will have an involuntary admission early in the course of their illness. Our findings highlight areas for intervention to improve pathways to care for people with psychotic disorder