Spatiotemporal responses to emotional conflict and its psychiatric correlates in adolescents with epilepsy using magnetoencephalography.

People with epilepsy often suffer from comorbid psychiatric disorders, which negatively affects their quality of life. Emotion regulation is an important cognitive process that is impaired in individuals with psychiatric disorders, such as depression. Adults with epilepsy also show difficulties in emotion regulation, particularly during later-stage, higher-order cognitive processing. Yet, the spatiotemporal and frequency correlates of these functional brain deficits in epilepsy remain unknown, as do the nature of these deficits in adolescent epilepsy. Here, we aim to elucidate the spatiotemporal profile of emotional conflict processing in adolescents with epilepsy, relative to controls, using magnetoencephalography (MEG) and relate these findings to anxiety and depression symptom severity assessed with self-report scales. We hypothesized to see blunted brain activity during emotional conflict in adolescents with epilepsy, relative to controls, in the posterior parietal, prefrontal and cingulate cortices due to their role in explicit and implicit regulation around participant response (500-1000 ms). We analyzed MEG recordings from 53 adolescents (28 epilepsy [14focal,14generalized], 25 controls) during an emotional conflict task. We showed that while controls exhibited behavioral interference to emotional conflict, adolescents with epilepsy failed to exhibit this normative response time pattern. Adolescents with epilepsy showed blunted brain responses to emotional conflict in brain regions related to error evaluation and learning around the average response time (500-700 ms), and in regions involved in decision making during post-response monitoring (800-1000 ms). Interestingly, behavioral patterns and psychiatric symptom severity varied between epilepsy subgroups, wherein those with focal epilepsy showed preserved response time interference. Thus, brain responses were regressed with depression and anxiety levels for each epilepsy subgroup separately. Analyses revealed that under activation in error evaluation regions (500-600 ms) predicted anxiety and depression in focal epilepsy, while regions related to learning (600-700 ms) predicted anxiety in generalized epilepsy, suggesting differential mechanisms of dysfunction in these subgroups. Despite similar rates of anxiety and depression across the groups, adolescents with epilepsy still exhibited deficits in emotional conflict processing in brain and behavioral responses. This suggests that these deficits may exist independently from psychopathology and may stem from underlying dysfunctions that predispose these individuals to develop both disorders. Findings such as these may provide potential targets for future research and therapies.

The potent and selective RIPK2 inhibitor BI 706039 improves intestinal inflammation in the TRUC mouse model of inflammatory bowel disease.

Mouse and human data implicate the NOD1 and NOD2 sensors of the intestinal microbiome and the associated signal transduction via the receptor interacting protein kinase 2 (RIPK2) as a potential key signaling node for the development of inflammatory bowel disease (IBD) and an attractive target for pharmacological intervention. The TRUC mouse model of IBD was strongly indicated for evaluating RIPK2 antagonism for its effect on intestinal inflammation based on previous knockout studies with NOD1, NOD2, and RIPK2. We identified and profiled the BI 706039 molecule as a potent and specific functional inhibitor of both human and mouse RIPK2 and with favorable pharmacokinetic properties. We dosed BI 706039 in the spontaneous TRUC mouse model from age 28 to 56 days. Oral, daily administration of BI 706039 caused dose-responsive and significant improvement in colonic histopathological inflammation, colon weight, and terminal levels of protein-normalized fecal lipocalin (all P values <0.001). These observations correlated with dose responsively increasing systemic levels of the BI 706039 compound, splenic molecular target engagement of RIPK2, and modulation of inflammatory genes in the colon. This demonstrates that a relatively low oral dose of a potent and selective RIPK2 inhibitor can modulate signaling in the intestinal immune system and significantly improve disease associated intestinal inflammation.NEW & NOTEWORTHY The RIPK2 kinase at the apex of microbiome immunosensing is an attractive target for pharmacological intervention. A low oral dose of a RIPK2 inhibitor leads to significantly improved intestinal inflammation in the murine TRUC model of colitis. A selective and potent inhibitor of the RIPK2 kinase may represent a new class of therapeutics that target microbiome-driven signaling for the treatment of IBD.

Cooperativity of membrane-protein and protein-protein interactions control membrane remodeling by epsin 1 and affects clathrin-mediated endocytosis.

Membrane remodeling is a critical process for many membrane trafficking events, including clathrin-mediated endocytosis. Several molecular mechanisms for protein-induced membrane curvature have been described in some detail. Contrary, the effect that the physico-chemical properties of the membrane have on these processes is far less well understood. Here, we show that the membrane binding and curvature-inducing ENTH domain of epsin1 is regulated by phosphatidylserine (PS). ENTH binds to membranes in a PI(4,5)P2-dependent manner but only induces curvature in the presence of PS. On PS-containing membranes, the ENTH domain forms rigid homo-oligomers and assembles into clusters. Membrane binding and membrane remodeling can be separated by structure-to-function mutants. Such oligomerization mutants bind to membranes but do not show membrane remodeling activity. In vivo, they are not able to rescue defects in epidermal growth factor receptor (EGFR) endocytosis in epsin knock-down cells. Together, these data show that the membrane lipid composition is important for the regulation of protein-dependent membrane deformation during clathrin-mediated endocytosis.

Left turn crash risk analysis: Development of a microsimulation modeling approach.

The use of traffic simulation to analyze complex transportation issues has become common practice in transportation engineering. The further application of microsimulation to the analysis of traffic safety in a systematic, rigorous, and controlled fashion is becoming increasingly viable as simulation models improve and tools for quantifying surrogate safety measures become readily accessible. Using a calibrated traffic microsimulation model and surrogate safety assessment model analysis, this paper examined how the risk for left-turn crashes varied as traffic conditions changed at a signalized intersection. Safety impacts for 750 unique combinations of intersection geometry, traffic, and signal timing parameters were simulated and the number of left-turn conflicts per hour noted. Results of the simulation analyses were used to develop statistical models that expressed the risk of occurrence of a left-turn crash during a given hour as a function of the left-turn phasing mode and prevailing conditions during that hour. The study was motivated by the recent widespread application of the flashing yellow arrow (FYA) which provides the opportunity to vary left-turn phasing mode by time of day-potentially leading to more efficient traffic operations at signalized intersections. In this regard, the study addresses a basic need for tools that predict how the risk for left-turn crashes might vary at a more disaggregated level than that provided by existing crash prediction models, which typically predict yearly totals of left-turn crashes, often based on annual average daily traffic volumes. Potential application of the model to the implementation of a time-variable safety-based left-turn phasing selection scheme using FYA was successfully demonstrated.

TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7-9.

Toll-like receptors (TLRs) have a crucial role in the recognition of pathogens and initiation of immune responses1-3. Here we show that a previously uncharacterized protein encoded by CXorf21-a gene that is associated with systemic lupus erythematosus4,5-interacts with the endolysosomal transporter SLC15A4, an essential but poorly understood component of the endolysosomal TLR machinery also linked to autoimmune disease4,6-9. Loss of this type-I-interferon-inducible protein, which we refer to as 'TLR adaptor interacting with SLC15A4 on the lysosome' (TASL), abrogated responses to endolysosomal TLR agonists in both primary and transformed human immune cells. Deletion of SLC15A4 or TASL specifically impaired the activation of the IRF pathway without affecting NF-κB and MAPK signalling, which indicates that ligand recognition and TLR engagement in the endolysosome occurred normally. Extensive mutagenesis of TASL demonstrated that its localization and function relies on the interaction with SLC15A4. TASL contains a conserved pLxIS motif (in which p denotes a hydrophilic residue and x denotes any residue) that mediates the recruitment and activation of IRF5. This finding shows that TASL is an innate immune adaptor for TLR7, TLR8 and TLR9 signalling, revealing a clear mechanistic analogy with the IRF3 adaptors STING, MAVS and TRIF10,11. The identification of TASL as the component that links endolysosomal TLRs to the IRF5 transcription factor via SLC15A4 provides a mechanistic explanation for the involvement of these proteins in systemic lupus erythematosus12-14.

Heart Failure and Frailty in the Community-Living Elderly Population: What the UFO Study Will Tell Us.

Heart failure and frailty are clinical syndromes that present with overlapping phenotypic characteristics. Importantly, their co-presence is associated with increased mortality and morbidity. While mechanical and electrical device therapies for heart failure are vital for select patients with advanced stage disease, the majority of patients and especially those with undiagnosed heart failure would benefit from early disease detection and prompt initiation of guideline-directed medical therapies. In this article, we review the problematic interactions between heart failure and frailty, introduce a focused cardiac screening program for community-living elderly initiated by a mobile communication device app leading to the Undiagnosed heart Failure in frail Older individuals (UFO) study, and discuss how the knowledge of pre-frailty and frailty status could be exploited for the detection of previously undiagnosed heart failure or advanced cardiac disease. The widespread use of mobile devices coupled with increasing availability of novel, effective medical and minimally invasive therapies have incentivized new approaches to heart failure case finding and disease management.

Nonlinear Metasurface for Simultaneous Control of Spin and Orbital Angular Momentum in Second Harmonic Generation.

The spin and orbital angular momentum (SAM and OAM) of light is providing a new gateway toward high capacity and robust optical communications. While the generation of light with angular momentum is well studied in linear optics, its further integration into nonlinear optical devices will open new avenues for increasing the capacity of optical communications through additional information channels at new frequencies. However, it has been challenging to manipulate the both SAM and OAM of nonlinear signals in harmonic generation processes with conventional nonlinear materials. Here, we report the generation of spin-controlled OAM of light in harmonic generations by using ultrathin photonic metasurfaces. The spin manipulation of OAM mode of harmonic waves is experimentally verified by using second harmonic generation (SHG) from gold meta-atom with 3-fold rotational symmetry. By introducing nonlinear phase singularity into the metasurface devices, we successfully generate and measure the topological charges of spin-controlled OAM mode of SHG through an on-chip metasurface interferometer. The nonlinear photonic metasurface proposed in this work not only opens new avenues for manipulating the OAM of nonlinear optical signals but also benefits the understanding of the nonlinear spin-orbit interaction of light in nanoscale devices.

A GPBAR1 (TGR5) small molecule agonist shows specific inhibitory effects on myeloid cell activation in vitro and reduces experimental autoimmune encephalitis (EAE) in vivo.

GPBAR1 is a G protein-coupled receptor that is activated by certain bile acids and plays an important role in the regulation of bile acid synthesis, lipid metabolism, and energy homeostasis. Recent evidence suggests that GPBAR1 may also have important effects in reducing the inflammatory response through its expression on monocytes and macrophages. To further understand the role of GPBAR1 in inflammation, we generated a novel, selective, proprietary GPBAR1 agonist and tested its effectiveness at reducing monocyte and macrophage activation in vitro and in vivo. We have used this agonist, together with previously described agonists to study agonism of GPBAR1, and shown that they can all induce cAMP and reduce TLR activation-induced cytokine production in human monocytes and monocyte-derived macrophages in vitro. Additionally, through the usage of RNA sequencing (RNA-Seq), we identified a select set of genes that are regulated by GPBAR1 agonism during LPS activation. To further define the in vivo role of GPBAR1 in inflammation, we assessed GPBAR1 expression and found high levels on circulating mouse monocytes. Agonism of GPBAR1 reduced LPS-induced cytokine production in mouse monocytes ex vivo and serum cytokine levels in vivo. Agonism of GPBAR1 also had profound effects in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis, where monocytes play an important role. Mice treated with the GPBAR1 agonist exhibited a significant reduction in the EAE clinical score which correlated with reduced monocyte and microglial activation and reduced trafficking of monocytes and T cells into the CNS. These data confirm the importance of GPBAR1 in controlling monocyte and macrophage activation in vivo and support the rationale for selective agonists of GPBAR1 in the treatment of inflammatory diseases.

Design and development of a mobile image overlay system for needle interventions.

Previously, a static and adjustable image overlay systems were proposed for aiding needle interventions. The system was either fixed to a scanner or mounted over a large articulated counterbalanced arm. Certain drawbacks associated with these systems limited the clinical translation. In order to minimize these limitations, we present the mobile image overlay system with the objective of reduced system weight, smaller dimension, and increased tracking accuracy. The design study includes optimal workspace definition, selection of display device, mirror, and laser source. The laser plane alignment, phantom design, image overlay plane calibration, and system accuracy validation methods are discussed. The virtual image is generated by a tablet device and projected into the patient by using a beamsplitter mirror. The viewbox weight (1.0 kg) was reduced by 8.2 times and image overlay plane tracking precision (0.21 mm, STD = 0.05) was improved by 5 times compared to previous system. The automatic self-calibration of the image overlay plane was achieved in two simple steps and can be done away from patient table. The fiducial registration error of the physical phantom to scanned image volume registration was 1.35 mm (STD = 0.11). The reduced system weight and increased accuracy of optical tracking should enable the system to be hand held by the physician and explore the image volume over the patient for needle interventions.

Lung parenchyma surgery in autosomal dominant hyper-IgE syndrome.

PURPOSE: Autosomal dominant hyper-IgE syndrome (AD-HIES) due to heterozygous STAT3 mutation is a primary immunodeficiency characterized by eczema, elevated serum IgE, recurrent infections, and connective tissue and skeletal findings. Healing of pneumonias is often abnormal with formation of pneumatoceles and bronchiectasis. We aimed to explore whether healing after lung surgery is also aberrant. METHODS: We retrospectively analyzed the medical records of 32 patients with AD-HIES who received lung surgery for the management of pulmonary infections from 1960 to 2011. We collected information including patient demographics, STAT3 mutation status, clinical history, surgical and medical procedures performed, complications, related medical treatments, and outcomes. RESULTS: More than 50% of lung surgeries had associated complications, with the majority being prolonged bronchopleural fistulae. These fistulae often led to empyemas that necessitated additional interventions including prolonged antibiotics, prolonged thoracostomy tube drainage and re-operations. CONCLUSION: Lung surgery in AD-HIES patients is associated with high complication rates. STAT3 mutations likely lead to abnormalities in tissue remodelling that are further exacerbated by infection.

Pegylated siRNA-loaded calcium phosphate nanoparticle-driven amplification of cancer cell internalization in vivo.

The cell membrane is a critical barrier to effective delivery for many therapeutics, including those which are nanoparticle-based. Improving nanoparticle transport across the cell membrane remains a fundamental challenge. Cancer cells preferentially internalized pegylated calcium phosphate nanoparticles over normal epithelial cells. Furthermore, non-cytotoxic levels of doxorubicin markedly amplified this difference by increasing free unbound caveolin-1 and resulted in enhanced caveolin-mediated nanoparticle endocytosis in cancer cells. Engineered pegylated siRNA-loaded triple-shell calcium phosphate nanoconstructs incorporating ultra-low levels of doxorubicin recapitulated these effects and delivered increased numbers of siRNA into cancer cells with target-specific results. Systemic administration of nanoparticles in vivo demonstrated highly preferential entry into tumors, little bystander organ biodistribution, and significant tumor growth arrest. In conclusion, siRNA-loaded calcium phosphate nanoparticles incorporating non-cytotoxic amounts of doxorubicin markedly enhances nanoparticle internalization and results in increased payload delivery with concomitant on-target effects.

Characterization and management of cardiac involvement of thymic epithelial tumors.

INTRODUCTION: Although thymic epithelial tumors (TETs) commonly infiltrate mediastinal structures, cardiac involvement is uncommon and has not been systematically studied. The purpose of this study was to describe our single-institution experience of the clinical presentation, treatment, and follow-up of cardiac involvement in patients with TETs. METHODS: A single-institution retrospective review of cardiac involvement among patients with TETs from 2008 to 2012. RESULTS: The frequency of cardiac involvement was 4%. All five patients with confirmed cardiac disease had left heart involvement. Only one patient was symptomatic. Myocardial invasion was the most common mode of involvement followed by transvenous spread. Surgical resection of the involved area was attempted in three patients: in one, surgery was aborted because of extensive myocardial involvement; in the other two patients, resection was incomplete. Surgery averted a potentially catastrophic hemodynamic complication in one patient. However, cardiac tumor recurred in both patients who underwent incomplete resection. One patient underwent radiation therapy resulting in complete regression of an aortic root mass. CONCLUSIONS: This study represents the most comprehensive review of cardiac involvement in patients with TETs. In contrast to previous single-case reports, we found a preponderance of asymptomatic presentation, left heart involvement, and myocardial invasion. Dynamic cardiovascular magnetic resonance imaging should be considered in cases when cardiac involvement is suspected. Although immediate surgical resection is indicated for impending hemodynamic compromise, long-term palliation with surgery for myocardial involvement seems poor, especially when complete resection cannot be performed. Radiation therapy should be considered in selected patients.