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Could the cellular mechanisms that cause sunburns help creating more stable therapeutics? Studying the effect of ultraviolet light on strands of DNA put together in various structures, we have discovered that gentle irradiation could protect the DNA from being degraded. This overcomes a major hurdle for translation into clinics without requiring extensive modifications.

Here, we present a new approach based on manifold learning for knowledge discovery and inverse design with minimal complexity in photonic nanostructures. Our approach builds on studying sub-manifolds of responses of a class of nanostructures with different design complexities in the latent space to obtain valuable insight about the physics of device operation to guide a more intelligent design. In contrast to the current methods for inverse design of photonic nanostructures, which are limited to pre-selected and usually over-complex structures, we show that our method allows evolution from an initial design towards the simplest structure while solving the inverse problem., Comment: 10 pages, 6 figures, 2 tables

PURPOSE: To determine the interreader agreement for incomplete retinal pigment epithelium (RPE) and outer retinal atrophy (iRORA) and complete RPE and outer retinal atrophy (cRORA) and their related features in age-related macular degeneration (AMD). DESIGN: Interreader agreement study. PARTICIPANTS: Twelve readers from 6 reading centers. METHODS: After formal training, readers qualitatively assessed 60 OCT B-scans from 60 eyes with AMD for 9 individual features associated with early atrophy and performed 7 different annotations to quantify the spatial extent of OCT features within regions of interest. The qualitative and quantitative features were used to derive the presence of iRORA and cRORA and also in an exploratory analysis to examine if agreement could be improved using different combinations of features to define OCT atrophy. MAIN OUTCOME MEASURES: Interreader agreement based on Gwet's first-order agreement coefficient (AC1) for qualitatively graded OCT features and classification of iRORA and cRORA, and smallest real difference (SRD) for quantitatively graded OCT features. RESULTS: Substantial or better interreader agreement was observed for all qualitatively graded OCT features associated with atrophy (AC1 = 0.63-0.87), except for RPE attenuation (AC1 = 0.46) and disruption (AC1 = 0.26). The lowest SRD for the quantitatively graded horizontal features was observed for the zone of choroidal hypertransmission (± 190.8 μm). Moderate agreement was found for a 3-category classification of no atrophy, iRORA, and cRORA (AC1 = 0.53). Exploratory analyses suggested a significantly higher level of agreement for a 3-category classification using (1) no atrophy; (2) presence of inner nuclear layer and outer plexiform layer subsidence, or a hyporeflective wedge-shaped band, as a less severe atrophic grade; and (3) the latter plus an additional requirement of choroidal hypertransmission of 250 μm or more for a more severe atrophic grade (AC1 = 0.68; P = 0.013). CONCLUSIONS: Assessment of iRORA and cRORA, and most of their associated features, can be performed relatively consistently and robustly. A refined combination of features to define early atrophy could further improve interreader agreement.

This article describes how community need was addressed through a traffic calming pop-up event in rural Arkansas. The event was conducted on routes connecting a neighborhood, two schools, and a municipal park. A brief survey assessed safety concerns of parents and/or guardians related to children walking or biking to school. Prior to the event, parents/guardians reported it was not safe for their children to walk or bike to school; however, the majority agreed the event made the area safer. Small-scale traffic calming events can provide evidence to stakeholders that built environment changes are an important childhood obesity prevention strategy in rural Extension work.

Histone arginine methylation is a prevalent posttranslational modification (PTM) in eukaryotic cells and contributes to the histone codes for epigenetic regulation of gene transcription. In this study, we determined how local changes on adjacent residues in the histone H4 substrate regulate arginine asymmetric dimethylation and symmetric dimethylation catalysed by the major protein arginine methyltransferase (PRMT) enzymes PRMT1 and PRMT5, respectively. We found that phosphorylation at histone H4 Ser-1 site (H4S1) was inhibitory to activities of PRMT1 and PRMT5 in both monomethylating and dimethylating H4R3. Also, a positively charged H4K5 was important for PRMT1 catalysis because acetylation of H4K5 or the loss of the H4K5 ��-amine had a similar effect in reducing the catalytic efficiency of asymmetric dimethylation of H4R3. An opposite effect was observed in that acetylation of H4K5 or the loss of the H4K5 ��-amine enhanced PRMT5-mediated symmetric dimethylation of H4R3. Furthermore, we observed that N-terminal acetylation of H4 modestly decreased asymmetric dimethylation of H4R3 by PRMT1 and symmetric dimethylation of H4R3 by PRMT5. This work highlights the significance of local chemical changes in the substrate to regulating PRMT activity and unravels the pattern complexities and subtleties of histone codes.

Computability theory is used to evaluate the complexity of classifying various kinds of Lebesgue spaces and associated isometric isomorphism problems.

Mean sensitivity (MS) derived from a standard test grid using microperimetry is a sensitive outcome measure in clinical trials investigating new treatments for degenerative retinal diseases. This study hypothesizes that the functional decline is faster at the edge of the dense scotoma (eMS) than by using the overall MS.Multicenter, international, prospective cohort study: ProgStar Study.Stargardt disease type 1 patients (carrying at least 1 mutation in the ABCA4 gene) were followed over 12 months using microperimetry with a Humphrey 10-2 test grid. Customized software was developed to automatically define and selectively follow the test points directly adjacent to the dense scotoma points and to calculate their mean sensitivity (eMS).Among 361 eyes (185 patients), the mean age was 32.9 ± 15.1 years old. At baseline, MS was 10.4 ± 5.2 dB (n = 361), and the eMS was 9.3 ± 3.3 dB (n = 335). The yearly progression rate of MS (1.5 ± 2.1 dB/year) was significantly lower (β = -1.33; P.001) than that for eMS (2.9 ± 2.9 dB/year). There were no differences between progression rates using automated grading and those using manual grading (β = .09; P = .461).In Stargardt disease type 1, macular sensitivity declines significantly faster at the edge of the dense scotoma than in the overall test grid. An automated, time-efficient approach for extracting and grading eMS is possible and appears valid. Thus, eMS offers a valuable tool and sensitive outcome parameter with which to follow Stargardt patients in clinical trials, allowing clinical trial designs with shorter duration and/or smaller cohorts.

Suppose $$p \ge 1$$ is a computable real. We extend previous work of Clanin, Stull, and McNicholl by determining the degrees of categoricity of the separable $$L^p$$ spaces whose underlying measure spaces are atomic but not purely atomic. In addition, we ascertain the complexity of associated projection maps.

Background Although adolescents and young adults may be particularly prone to mental health symptoms after heart transplant, screening practices are variable. Objective To assess the feasibility of using patient-reported outcome (PRO) measures to assess mental health, functional status, and resiliency in posttransplant adolescents and young adult patients. Methods Patients transplanted between ages 15 and 25 years at 3 centers completed 6 PRO instruments via web-based platforms: PROMIS instruments for anxiety, depression, satisfaction with social roles, and physical functioning; the Posttraumatic Stress Diagnostic Scale for Diagnostic and Statistical Manual of Mental Disorders, version 5; and the Connor-Davidson Resilience Scale-10. Feasibility (completion, time to completion, and measure missingness) and PRO results were described and compared between patients with congenital heart disease and cardiomyopathy. Results Nineteen patients (median age at transplant 17.7 y [interquartile range 16.3, 19.2 y], 84% male) were enrolled at an average of 3 ± 1.8 years after transplant. Enrollment was 90% among eligible patients. Measure missingness was zero. The average completion time was 12 ± 15 minutes for all instruments. Timely PRO completion was facilitated by in-clinic application. The PRO results indicated that 9 patients (47%) had at least mild posttraumatic stress disorder symptoms (≥11 points on Posttraumatic Stress Diagnostic Scale for Diagnostic and Statistical Manual of Mental Disorders, version 5). Among them, 4 patients had scores >28 suggestive of probable posttraumatic stress disorder. Two (11%) and 6 (32%) patients had anxious and depressive symptoms, respectively. The cardiomyopathy cohort had a higher median Posttraumatic Stress Diagnostic Scale for Diagnostic and Statistical Manual of Mental Disorders, version 5 score than that of the congenital heart disease subgroup (11.0 vs 6.0; P = 0.015). Twelve (63%) had resiliency scores that were lower than the population average. No significant differences were found in PRO results between patients with cardiomyopathy and congenital heart disease apart from the posttraumatic stress disorder assessment. Conclusions This novel PRO-based approach to psychiatric screening of adolescents and young adult patients after transplant appears feasible for assessing mental health, functional status, and resiliency, with excellent enrollment and completion rates. These instruments characterized the burden of mental health symptoms within this adolescents and young adult heart transplant cohort, with a high prevalence of posttraumatic stress disorder symptoms. Resiliency scores were lower than in a comparison population. Electronically-administered PRO administration could facilitate more consistent mental health screening in this at-risk group.

Methyllysine reader proteins bind to methylated lysine residues and alter gene transcription by changing the compaction state of chromatin or by the recruitment of other multiprotein complexes. The polycomb paralog family of methyllysine readers bind to trimethylated lysine on the tail of histone 3 via a highly conserved aromatic cage located in their chromodomains. Each of the polycomb paralogs are implicated in several disease states. CBX6 and CBX8 are members of the polycomb paralog family with two structurally similar chromodomains. By exploring the structure-activity relationships of a previously reported CBX6 inhibitor we have discovered more potent and cell permeable analogs. Our current report includes potent, dual-selective inhibitors of CBX6 and CBX8. We have shown that the –2 position in our scaffold is an important residue for selectivity amongst the polycomb paralogs. Preliminary cell-based studies show that the new inhibitors impact cell proliferation in a rhabdoid tumor cell line. This report includes data on inhibitor design, inhibitor synthesis, compound characterization by LCMS, compound activity by fluorescence polarization, analysis of structure-activity relationships, rhabdoid tumor cell line activity.

A new artificial-intelligence (AI) approach based on dimensionality reduction techniques for the design and knowledge discovery in metamaterial structures will be presented. It is shown that reducing the dimensionality of the response and design spaces by using a pseudoencoder can reduce the computation time by 2–3 orders of magnitude. In addition, using pruning techniques can simplify the trained algorithm to further reduce the computation time while providing simpler paths for relating input-output relationships for understanding the role of design parameters (i.e., knowledge discovery). It is also shown that this approach can enable an evolutionary design method in which the initial design can be evolved intelligently into an alternative with favorable specifications. The application of these AI approaches for both optical and acoustic metamaterials will be presented.

Improving change of direction (COD) with the use of strength training has led to mixed results. To date, the modified single leg squat (MSLS) and the bilateral squat (BS) have been successfully used to improve COD, with equal improvement. COD is primarily performed at a 45-75° frontal plane angle; however, the MSLS and BS are performed at a 90° frontal plane angle. Based on the force vector theory, it is proposed that a more mechanically similar strength training exercise, the Laterally Resisted Split Squat (LRSS), be used. The purpose of this study is to compare COD with the LRSS, MSLS, and the BS via kinetic measurements. Ten healthy and recreationally active female individuals volunteered for this study. Participants were pre-screened using a COD test to verify proper mechanics. Participant's weight was measured and 1RM (using Bryzcki formula/technique) for the LRSS, MSLS, and BS calculated. Peak ground reaction force (GRF) of participant's dominant leg in the frontal plane for COD and the three exercises at 70% 1RM was collected and used to calculate peak magnitude and vector angle. Peak GRF magnitude was significantly larger in COD (2.13 ± 0.52 bodyweight: BW) than the LRSS (0.85 ± 0.07 BW; p < 0.001), MSLS (0.99 ± 0.10 BW; p = 0.001), and BS (0.52 ± 0.07 BW; p < 0.001). COD (66.70° ± 4.98°) vector angle was not significantly difference than the LRSS (74.94° ± 4.11°; p = 0.057) as compared to the MSLS (89.04° ± 0.48°; p < 0.001) and BS (82.69° ± 4.30°; p < 0.001). In an application of the force vector theory, the LRSS more closely matches COD than the MSLS or BS.

Nanoparticle‐based therapeutic formulations are being increasingly explored for the treatment of various ailments. Despite numerous advances, the success of nanoparticle‐based technologies in treating brain diseases has been limited. Translational hurdles of nanoparticle therapies are attributed primarily to their limited ability to cross the blood–brain barrier (BBB), which is one of the body's most exclusive barriers. Several efforts have been focused on developing affinity‐based agents and using them to increase nanoparticle accumulation at the brain endothelium. Very little is known about the role of fundamental physical parameters of nanoparticles such as size, shape, and flexibility in determining their interactions with and penetration across the BBB. Using a three‐dimensional human BBB microfluidic model (μHuB), we investigate the impact of these physical parameters on nanoparticle penetration across the BBB. To gain insights into the dependence of transport on nanoparticle properties, two separate parameters were measured: the number of nanoparticles that fully cross the BBB and the number that remain associated with the endothelium. Association of nanoparticles with the brain endothelium was substantially impacted by their physical characteristics. Hard particles associate more with the endothelium compared to soft particles, as do small particles compared to large particles, and spherical particles compared to rod‐shaped particles. Transport across the BBB also exhibited a dependence on nanoparticle properties. A nonmonotonic dependence on size was observed, where 200 nm particles exhibited higher BBB transport compared to 100 and 500 nm spheres. Rod‐shaped particles exhibited higher BBB transport when normalized by endothelial association and soft particles exhibited comparable transport to hard particles when normalized by endothelial association. Tuning nanoparticles' physical parameters could potentially enhance their ability to cross the BBB for therapeutic applications.

Histone methylation plays an important regulatory role in chromatin restructuring and RNA transcription. Arginine methylation that is enzymatically catalyzed by the family of protein arginine methyltransferases (PRMTs) can either activate or repress gene expression depending on cellular contexts. Given the strong correlation of PRMTs with pathophysiology, great interest is seen in understanding molecular mechanisms of PRMTs in diseases and in developing potent PRMT inhibitors. Herein, we reviewed key research advances in the study of biochemical mechanisms of PRMT catalysis and their relevance to cell biology. We highlighted how a random binary, ordered ternary kinetic model for PRMT1 catalysis reconciles the literature reports and endorses a distributive mechanism that the enzyme active site utilizes for multiple turnovers of arginine methylation. We discussed the impacts of histone arginine methylation and its biochemical interplays with other key epigenetic marks. Challenges in developing small-molecule PRMT inhibitors were also discussed.

Purpose To investigate the natural history of Stargardt disease (STGD1) using fixation location and fixation stability. Design Multicenter, international, prospective cohort study. Methods Fixation testing was performed using the Nidek MP-1 microperimeter as part of the prospective, multicenter, natural history study on the Prog ression of Star gardt disease (ProgStar). A total of 238 patients with ABCA4-related STGD1 were enrolled at baseline (bilateral enrollment in 86.6%) and underwent repeat testing at months 6 and 12. Results Outcome measures included the distance of the preferred retinal locus from the fovea (PRL) and the bivariate contour ellipse area (BCEA). After 12 months of follow-up, the change in the eccentricity of the PRL from the anatomic fovea was −0.0014 degrees (95% confidence interval [CI], −0.27 degrees, 0.27 degrees; P = .99). The deterioration in the stability of fixation as expressed by a larger BCEA encompassing 1 standard deviation of all fixation points was 1.21 degrees squared (deg2) (95% CI, −1.23 deg2, 3.65 deg2; P = .33). Eyes with increases and decreases in PRL eccentricity and/or BCEA values were observed. Conclusions Our observations point to the complexity of fixation parameters. The association of increasingly eccentric and unstable fixation with longer disease duration that is typically found in cross-sectional studies may be countered within individual patients by poorly understood processes like neuronal adaptation. Nevertheless, fixation parameters may serve as useful secondary outcome parameters in selected cases and for counseling patients to explain changes to their visual functionality.

The present study combines the theory and the experimental data to predict the changes on intestinal bacterial populations during ingestion of beneficial probiotic bacteria. Our proposed model is a modified version of the Lotka-Volterra model, which takes the probiotic administration into account. Using the linear stability analysis of the model, the conditions for coexistence of the probiotics with other bacteria are established. Using the model fitted to the data of C. coccoides species and Bifidobacterium species, the effects of oral probiotics on autochthonous bacterial cultures is investigated. The estimated parameter values suggest that C. coccoides and Bifidobacterium facilitate each other during the probiotics administration, whereas they compete in the absence of the probiotics administration. This may suggest the beneficial effect of probiotic administration as it promotes the growth of C. coccoides species. The results also confirm prior studies showing that once probiotic supplementation is discontinued, the probiotic population and the promoting effect within the digestive tract will diminish.

Epigenetic regulation of gene expression is in part controlled by post-translational modifications on histone proteins. Histone methylation is a key epigenetic mark that controls gene transcription and repression. There are five human polycomb paralog proteins (Cbx2/4/6/7/8) which use their chromodomains to recognize trimethylated lysine 27 on Histone 3 (H3K27me3). Recognition of the methyllysine side chain is achieved through multiple cation-pi interactions within an ‘aromatic cage’ motif. Despite high structural similarity within the chromodomains of this protein family, they each have unique functional roles and are linked to different cancers. Selective inhibition of different CBX proteins is highly desirable for both fundamental studies and potential therapeutic applications. We will report on a series of peptidic inhibitors that selectively target certain polycomb paralogs. We have identified peptidic scaffolds with sub-micromolar potency, and will report examples that are pan-specific and that are partially selective for individual members within the family. The data presented include extensive new synthesis with characterization by LC, Mass Spectrometry, and NMR. The binding interactions are measured by fluorescence polarization, molecular dynamics simulations, and protein microarray assays. These results highlight important structure-activity relationships that allow for selectivity to be achieved through interactions outside of the methyllysine binding aromatic cage motif.

Endothelial cells represent the first biological barrier for compounds, including nanoparticles, administered via the intravascular route. In the case of ischemic stroke and other vascular diseases, the endothelium overexpresses specific markers, which can be used as molecular targets to facilitate drug delivery and imaging. However, targeting these markers can be quite challenging due to the presence of blood flow and the associated hydrodynamic forces, reducing the likelihood of adhesion to the vessel wall. To overcome these challenges, various parameters including size, shape, charge or ligand coating have been explored to increase the targeting efficiency. Geometric shape can modulate nanoparticle binding to the cell, especially by counteracting part of the hydrodynamic forces of the bloodstream encountered by the classical spherical shape. In this study, the binding affinity of polystyrene nanoparticles with two different shapes, spherical and rod-shaped, were compared. First, vascular adhesion molecule-1 (VCAM-1) was evaluated as a vascular target of inflammation, induced by lipopolysaccharide (LPS) stimulation. To evaluate the effect of nanoparticle shape on particle adhesion, nanoparticles were coated with anti-VCAM-1 and tested under static conditions in cell culture dishes coated with cerebral microvasculature cells (bEnd.3) and under dynamic flow conditions in microfluidic channels lined with hCMEC/D3 cells. Effect of particle shape on accumulation was also assessed in two in vivo models including systemic inflammation and local brain inflammation. The elongated rod-shaped particles demonstrated greater binding ability in vitro, reaching a 2.5-fold increase in the accumulation for static cultures and 1.5-fold for flow conditions. Anti-VCAM-1 coated rods exhibited a 3.5-fold increase in the brain accumulation compared to control rods. These results suggest shape offers a useful parameter in future design of drug delivery nanosystems or contrast agents for neurovascular pathologies. This study has been partially supported by grants from Instituto de Salud Carlos III (PI13/00292 and PI17/0054), Spanish ResearchNetwork on Cerebrovascular Diseases RETICS-INVICTUS (RD12/0014),Fundación Mutua Madrileña. The Ministry of Economy and Competitiveness of Spain (SAF2017-84267-R). The European Union program FEDER and the European Regional Development Fund–ERDF, MADIA project No. 732678 to FC. Furthermore, F. Campos (CP14/00154) recipients a research contract from Miguel Servet Program of Instituto de Salud Carlos III. National Science Foundation Graduate Research Fellowship under Grant DGE-1745303 SI

Regarding classification of materials as ionic liquids (ILs) and deep eutectic solvents (DESs), Rogers and coworkers elegantly stated in their previous article (1) that the current definitions are based on extreme behaviors and the reality is somewhere in the middle. By definition, the behavior of ILs is dominated by ionic interactions, whereas DESs exhibit a strong contribution from hydrogen bonding. Our choline and geranate (CAGE) compound fits the definition of an IL since it comprises largely ionic species, cholinium and geranate, and has a melting point below 100 °C. At the same time, CAGE is not a classical IL since it also contains neutral geranic acid. … [↵][1]1To whom correspondence should be addressed. Email: mitragotri{at}seas.harvard.edu. [1]: #xref-corresp-1-1

The inclusion of plant meals in diets of farmed Atlantic salmon can elicit inflammatory responses in the distal intestine (DI). For the present work, fish were fed a standard fish meal (FM) diet or a diet with partial replacement of FM with solvent-extracted camelina meal (CM) (8, 16, or 24 % CM inclusion) during a 16-week feeding trial. A significant decrease in growth performance was seen in fish fed all CM inclusion diets (Hixson et al. in Aquacult Nutr 22:615–630, 2016). A 4x44K oligonucleotide microarray experiment was carried out and significance analysis of microarrays (SAM) and rank products (RP) methods were used to identify differentially expressed genes between the DIs of fish fed the 24 % CM diet and those fed the FM diet. Twelve features representing six known transcripts and two unknowns were identified as CM responsive by both SAM and RP. The six known transcripts (including thioredoxin and ependymin), in addition to tgfb, mmp13, and GILT, were studied using qPCR with RNA templates from all four experimental diet groups. All six microarray-identified genes were confirmed to be CM responsive, as was tgfb and mmp13. Histopathological analyses identified signs of inflammation in the DI of salmon fed CM-containing diets, including lamina propria and sub-epithelial mucosa thickening, infiltration of eosinophilic granule cells, increased goblet cells and decreased enterocyte vacuolization. All of these were significantly altered in 24 % CM compared to all other diets, with the latter two also altered in 16 % CM compared with 8 % CM and control diet groups. Significant correlation was seen between histological parameters as well as between five of the qPCR analyzed genes and histological parameters. These molecular biomarkers of inflammation arising from long-term dietary CM exposure will be useful in the development of CM-containing diets that do not have deleterious effects on salmon growth or physiology. Electronic supplementary material The online version of this article (doi:10.1007/s10126-016-9704-x) contains supplementary material, which is available to authorized users.

The large-scale deployment of geologic carbon storage will require minimizing the risk of CO2 leakage. Here we report on a novel strategy to seal leakage pathways by injecting functionalized reactive calcium silicate (CaSiO3) particles. The particles consist of a mineral silicate core within a temperature-sensitive Poly(N,N-dimethylaminoethyl methacrylate) coating that limits contact between the core and the surrounding CO2(aq) above a switching temperature making them relatively unreactive deep in the subsurface. If the CO2 leaks to shallower depths and cooler temperatures, the coatings would extend and enable the silicate core to react with CO2(aq) to form solid carbonate precipitates that reduce the permeability of the fracture or flow path. A combined laboratory- and simulation-based investigation was conducted to explore key early-stage research questions related to the feasibility of this leakage management strategy. Sand columns were injected with either coated or uncoated CaSiO3 particles and the permeability was measured before and after exposure to CO2. Experiments were conducted at 35 °C and 70 °C, a range that spans the switching temperature for the coatings. Results show that at the cooler temperature the coating effectively enabled reaction and permeability reduction. At higher temperatures, the coated particles limited mineral carbonation and the permeability decrease was minimal compared to columns with uncoated particles. The morphology and location of the precipitates provides insight about permeability evolution. Model simulations of 2D radial particle transport from an injection point provided insight into the effects of particle size, coating properties, and concentrations of particles in several representative rock formations.

Digoxin use has been associated with lower interstage mortality in infants with HLHS and variants. The NEONATE score was developed to risk stratify patients for interstage mortality or transplantation; risk factors included type of stage 1 palliation (S1P)—Norwood with BT or Sano shunt vs. Hybrid

Developing selective enzyme inhibitors allows for the expansion of molecular toolboxes to investigate functions and activities of target enzymes. The histone acetyltransferase 1 (HAT1) is among the first histone acetyltransferase (HAT) enzymes that were discovered in the mid-1990s; however, it remains one of the poorly studied enzymes in comparison to the other HATs. Although HAT1 has been linked to various disease states, no inhibitors have been reported to target HAT1. Here we designed a set of peptide-CoA conjugates as bisubstrate inhibitors of HAT1 with submicromolar potency. In particular, the bisubstrate inhibitor H4K12CoA exhibited a low K(i) value of 1.1 nM for HAT1. In addition, H4K12CoA was shown to be a competitive inhibitor with respect to both AcCoA and H4 peptide, suggesting a unique kinetic mechanism of HAT1 catalysis. Creating these submicromolar inhibitors offers a mechanistic tools to better understand how HAT1 recognizes substrates and cofactors, as well as provides chemical leads to further develop therapeutic agents to target this important enzyme for disease therapy.

With the rise in diabetes mellitus cases worldwide and lack of patient adherence to glycemia management using injectable insulin, there is an urgent need for the development of efficient oral insulin formulations. However, the gastrointestinal tract presents a formidable barrier to oral delivery of biologics. Here we report the development of a highly effective oral insulin formulation using choline and geranate (CAGE) ionic liquid. CAGE significantly enhanced paracellular transport of insulin, while protecting it from enzymatic degradation and by interacting with the mucus layer resulting in its thinning. In vivo, insulin-CAGE demonstrated exceptional pharmacokinetic and pharmacodynamic outcome after jejunal administration in rats. Low insulin doses (3–10 U/kg) brought about a significant decrease in blood glucose levels, which were sustained for longer periods (up to 12 hours), unlike s.c. injected insulin. When 10 U/kg insulin-CAGE was orally delivered in enterically coated capsules using an oral gavage, a sustained decrease in blood glucose of up to 45% was observed. The formulation exhibited high biocompatibility and was stable for 2 months at room temperature and for at least 4 months under refrigeration. Taken together, the results indicate that CAGE is a promising oral delivery vehicle and should be further explored for oral delivery of insulin and other biologics that are currently marketed as injectables.

Background Patients presenting with mild stroke symptoms are excluded inconsistently from intravenous (IV) thrombolysis. We aimed to compare acute magnetic resonance imaging findings in patients with mild symptoms to those with more severe deficits to identify clinically mild patients who might benefit from IV thrombolysis. Methods We retrospectively studied consecutive stroke patients presenting with perfusion deficit who underwent time-of-flight magnetic resonance angiography within 24 hours of time last seen normal. Two raters measured the lesion volumes on diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) with mismatch (MM) calculated as PWI minus DWI. Occlusion site was categorized as "proximal," "distal," or "magnetic resonance angiography-negative" by consensus review. Stroke with mild symptoms was defined as admit National Institutes of Health Stroke Scale score of 4 or less. Values were reported as n (%). Results Ninety-one patients were included; 56 (61.5%) with nonmild and 35 (38.5%) with mild symptoms. After stratifying for occlusion site, there were no differences in PWI and MM lesion volumes for the nonmild versus mild patients ( P = .34-.98 and P = .54-1, respectively). Furthermore, there was a trend for thrombolyzed mild stroke patients (88%, n = 7 of 8) to more likely have a favorable clinical outcome (discharge modified Rankin score ≤ 2) versus untreated patients (70%, n = 16 of 23). Conclusions When present, conspicuous vessel occlusions in clinically mild stroke patients are concomitant with similar perfusion deficit and MM volumes in more clinically severe stroke patients. Coupled with a trend toward better outcomes in mild stroke patients who were treated with IV tissue plasminogen activator (t-PA), this could indicate that advanced imaging may be used in standardizing the way these patients are selected for IV t-PA therapy.

Severe (massive and sub-massive) pulmonary embolism (PE) is associated with significant rates of morbidity and mortality. We sought to assess severe PE before and after the inception of a multidisciplinary PE Response Team (PERT). Acute PE patients in the pre-PERT and early-PERT years (2013-2016)

Recent work exploring the use of high-molecular weight alcohols to treat essential tremor (ET) has identified octanoic acid as a potential novel tremor-suppressing agent. We used an established harmaline-based mouse model of ET to compare tremor suppression by 1-octanol and octanoic acid. The dose-related effect on digitized motion power within the tremor bandwidth as a fraction of overall motion power was analyzed. Both 1-octanol and octanoic acid provided significant reductions in harmaline tremor. An 8-carbon alkyl alcohol and carboxylic acid each suppress tremor in a pre-clinical mouse model of ET. Further studies are warranted to determine the safety and efficacy of such agents in humans with ET.

Naturally occurring antimicrobial peptides (AMPs) display the ability to eliminate a wide variety of bacteria, without toxicity to the host eukaryotic cells. Synthetic polymers containing moieties mimicking lysine and arginine components found in AMPs have been reported to show effectiveness against specific bacteria, with the mechanism of activity purported to depend on the nature of the amino acid mimic. In an attempt to incorporate the antimicrobial activity of both amino acids into a single water-soluble copolymer, a series of copolymers containing lysine mimicking aminopropyl methacrylamide (APMA) and arginine mimicking guanadinopropyl methacrylamide (GPMA) were prepared via aqueous RAFT polymerization. Copolymers were prepared with varying ratios of the comonomers, with degree of polymerization of 35-40 and narrow molecular weight distribution to simulate naturally occurring AMPs. Antimicrobial activity was determined against Gram-negative and Gram-positive bacteria under conditions with varying salt concentration. Toxicity to mammalian cells was assessed by hemolysis of red blood cells and MTT assays of MCF-7 cells. Antimicrobial activity was observed for APMA homopolymer and copolymers with low concentrations of GPMA against all bacteria tested, with low toxicity toward mammalian cells.

This paper analyzes the performance of a system consisting of a central base transmitter transmitting to a group of mobiles with on-off orthogonal modulation over a fast fading channel. Because the channel is changing across the symbol interval, inter-code interference appears at the output of each user's matched filter. The cumulative distribution function at one user's matched filter output is derived. From this distribution, a metric is introduced to evaluate which pairs of codes lead to the most severe inter-code interference for a particular fading spectrum.

Background and Purpose: We implemented new temporal correlation perfusion (TCP) analyses that were rapid, model-free and automated. We assessed the reliability and robustness of TCP mapping compared to the standard method of time-to-peak (TTP) mapping used in the identification of perfusion deficit in acute ischemic stroke. Methods: A model-free and automated method of detecting aberrant perfusion was developed to create TCP maps based on the maximum temporal correlations of the signal time-intensity waveforms following contrast injection. For validation purposes, the TCP and TTP maps from IV tPA treated ischemic stroke (n=20) and untreated imaging negative TIA (n=20) patients were visually read for presence of perfusion deficit by two expert readers blinded to the clinical diagnosis. Next, the perfusion lesion volumes on the TCP and TTP maps were segmented by two other experts and were compared for inter-rater reliability, volumetric and spatial concordance, and contrast to noise ratio. Pearson’s r correlation and t-test for TCP and TTP maps were used with degrees of freedom indicated by parentheses. Additionally, inter-rater reliability and contrast to noise ratios were compared. Results: Both readers identified all of the subjects (40/40) correctly as either having perfusion deficits or not based on the TCP maps alone. Improved rater inter-reliability in lesion volume segmentation was found in TCP compared to TTP maps, with high correlation in lesion volume (r (18) = 0.85) and spatial overlap (91.1+/-9.5%) between TCP and TTP maps. Better contrast to noise ratio in lesions segmented with TCP compared to TTP maps (t (19) = 14.9, p Conclusions: We conclude that temporal correlation mapping holds promise as a reliable and more robust method for perfusion deficit identification as demonstrated by correct identification and improved lesion segmentation compared to current standard methods.

An algorithm for the estimation of the frequency of a complex sinusoid in noise is proposed. The estimator consists of multiple applications of lowpass filtering and decimation, frequency estimation by linear prediction, and digital heterodyning. The estimator has a significantly reduced threshold relative to existing phase-based algorithms and performance close to that of maximum likelihood estimation. In addition, the mean-squared error performance is within 0.7 dB of the Cramer-Rao bound (CRB) at signal-to-noise ratios (SNRs) above threshold. Unlike many autocorrelation and phase-based methods, the proposed algorithm's performance is uniform across a frequency range of -/spl pi/ to /spl pi/. The computational complexity of the algorithm is shown to be favorable compared with maximum likelihood estimation via the fast Fourier transform (FFT) algorithm when significant zero-padding is required.

The channel code bit log likelihood ratio (LLR) for soft decision decoding is derived for quadrature amplitude modulated signals (QAM). The effect of imperfect channel knowledge on soft decision decoding performance is studied. Our results indicate this effect increases with channel estimation error and/or QAM modulation level. A metric based on generalized log likelihood ratio (GLLR) is derived for soft decision channel decoding with imperfect channel knowledge. Numerical results show that the GLLR-based metric outperforms the conventional minimum distance decoding metric that does not take into account channel estimation error.

The power controlled IS-95 reverse-link is studied. It is observed that received signals from multiple links under soft handoff and power control are not independent but anticorrelated. The cause of the anticorrelation is investigated through analysis and simulation. It is shown that due to this anticorrelation, the required signal-to-interference ratio (SIR) to achieve a given frame error rate can be /spl sim/0.7 dB less than previously estimated based on the independence assumption. Such an observation also leads to a more accurate reverse-link capacity estimate. Finally, it is pointed out that by using a postselection power control configuration an additional capacity increase of up to 11% is obtained.

A spatial light modulator design consisting of cascaded or sandwiched layers of ferroelectric liquid crystals (FLC's) is investigated. The interrelation between the FLC material, the polarization of the incident illumination, and the achievable modulation states is characterized. Magnitude modulation is accomplished by standard methods by addressing the FLC layer with linearly polarized light and following it with a properly oriented analyzer. When the FLC is addressed with circularly polarized light, lossless phase modulation results with the phase states separated by twice the angle of rotation of the optical axes. A continuum of elliptical polarization states ties together the lossless phase states achievable by using circular polarization with the more well-known 0 degrees -180 degrees phase states obtainable with linearly polarized light. Layers of various bistable FLC materials can be cascaded, possibly with polarization control layers between some of the layers, to yield a spatial light modulator that produces multip e quantized bits of complex-valued modulation and with independent control of magnitude and phase states. Four-state phase modulation, ternary amplitude-phase modulation, and four-state magnitude modulation are demonstrated experimentally by using two layers of FLC.

Traditional teaching-and-learning environments often do not address the learning needs of today's “millennial” generation of students who prefer team work, experiential activities, structure and the use of technology. In fact, millennial students view technology as a necessity, both in life and in learning and highly regard “doing rather than knowing”, making interactive, experiential learning, a necessity for their educational success. Recently, there has been a push on the development of interactive simulations for educational and training purposes and such simulations are being incorporated into a large number of curriculums. To develop effective simulations that meet the needs of both millennial students, and educators, end users’ views and perceptions of simulation use in the classroom must be assessed and accounted for. We must develop an understanding of the sentiments and demand for simulations in teaching and learning. Such information provides valuable input into the development of simulations and ensures their use and integration within the classroom. In order to assess this, a single institution, survey study consisting of a two part survey (one geared towards students and the other to faculty) was developed and conducted at the University of Ontario Institute of Technology (UOIT), a laptop-based university, that prides itself on the use of technology in the classroom, to gauge users perceptions of virtual simulations. Results indicate that students and faculty alike do appreciate the use of virtual simulations but care should be taken to ensure that the simulations are relevant to the course material and that educators are familiar with the use of the simulations to assist students should any problems arise.