Treating Glaucoma with Porous Contact Lens

Glaucoma is a family of diseases that afflicts 65 million people worldwide. Primary open angle glaucoma is the most common type of glaucoma. This is characterized by increased intraocular pressure (IOP) within the eye that results in vision loss. Current therapeutic drugs include Timolol and Brimonidine which studies have shown to yield a greater decrease in IOP through combined drug therapy than monotherapy. In 2007 Combigan, an eye drop that combines the therapeutic effects of Timolol and Brimonidine, was approved for use by the FDA. This project proposes a method for treating glaucoma through delivery of Combigan via a contact lens through which the drugs will diffuse into the eye over a period of time. We modeled the diffusion of two drugs, Timolol and Brimonidine, through four layers of the human eye. The drug was delivered via a contact lens, so that the concentration of drug in the aqueous humor would remain above the minimum effective dosage for longer than if it were delivered via eye drops. We calculated the concentration of each drug in all layers of the eye for 12 hours. Our model was verified by experimental data in the published literature. Our model failed to deliver solely Timolol or Brimonidine for 12 hours, which was our goal, but still was significantly more effective than eye drops. However, throughout the twelve hours there was at least one drug in the aqueous humor and since both drugs lower IOP through different mechanisms our model did deliver treat the glaucoma for the whole twelve hours. If it were possible to lower the diffusivity of Timolol through the stroma, this would allow for Timolol to remain longer in the aqueous humor thus making the contacts better at treating glaucoma. A sensitivity analysis demonstrated that our model was robust in the tear film and relatively robust in the contact lens. However, the model was particularly sensitive to diffusivity in the stroma layer, as the stroma acts as the final barrier to aqueous humoral penetration and is quite thick. Brimonidine was delivered at a more constant rate, but at a lower concentration than Timolol. It also took six times longer than Timolol to reach its maximum concentration in the aqueous humor. Drug delivery via contact lenses is a feasible technology as more effective than eye drops, but can be improved by designing a time-release drug that diffuses more slowly. Further research needs to be conducted in order to investigate the practicality of this method

The effect of development on spatial pattern separation in the hippocampus as quantified by the Homer1a immediate-early gene

ix, 51 leaves : ill. ; 29 cmThis study sought to determine whether the DG, CA3, and CA1 regions contain uniformly excitable populations and test the hypothesis that rapid addition of new, more excitable, granule cells in prepubescence results in a low activation probability (P1) in the DG. The immediate-early gene Homer1a was used as a neural activity marker to quantify activation in juvenile (P28) and adult (~5 mo) rats during track running. The main finding was that P1 in juveniles was substantially lower not only the DG, but also CA3 and CA1. The P1 for a DG granule cell was close to 0 in juveniles, versus 0.58 in adults. The low P1 in juveniles indicates that sparse, but non-overlapping, subpopulations participate in encoding events. Since sparse, orthogonal coding enhances a network’s ability to decorrelate input patterns (Marr, 1971; McNaughton & Morris, 1987), the findings suggest that juveniles likely possess greatly enhanced pattern separation ability

Involvement of fast-spiking cells in ictal sequences during spontaneous seizures in rats with chronic temporal lobe epilepsy

Epileptic seizures represent altered neuronal network dynamics, but the temporal evolution and cellular substrates of the neuronal activity patterns associated with spontaneous seizures are not fully understood. We used simultaneous recordings from multiple neurons in the hippocampus and neocortex of rats with chronic temporal lobe epilepsy to demonstrate that subsets of cells discharge in a highly stereotypical sequential pattern during ictal events, and that these stereotypical patterns were reproducible across consecutive seizures. In contrast to the canonical view that principal cell discharges dominate ictal events, the ictal sequences were predominantly composed of fast-spiking, putative inhibitory neurons, which displayed unusually strong coupling to local field potential even before seizures. The temporal evolution of activity was characterized by unique dynamics where the most correlated neuronal pairs before seizure onset displayed the largest increases in correlation strength during the seizures. These results demonstrate the selective involvement of fast spiking interneurons in structured temporal sequences during spontaneous ictal events in hippocampal and neocortical circuits in experimental models of chronic temporal lobe epilepsy

Single infrastructure utility provision to households: Technological feasibility study

This paper contemplates the future of utility infrastructure, and considers whether an “All-in-One” approach could supply all necessary utility services to tomorrow's households. The intention is not to propose infrastructure solutions that are currently technically feasible or justifiable, however; the objective is to present visions of future infrastructure that would only be possible with new advances in science and technology, or significant improvements and adaptations of existing knowledge and techniques. The All-in-One vision is explored using several vignettes, each of which envisions a novel, multi-functional infrastructure for serving future communities. The vignettes were conceived using imaginative exercises and brain-storming activities; each was then rooted in technological and scientific feasibility, as informed by extensive literature searches and the input of domain leaders. The vignettes tell their own stories, and we identify the challenges that would need to be overcome to make these visions into reality. The main aim of this work is to encourage radical approaches to thinking about future infrastructure provision, with a focus on rationalisation, efficiency, sustainability and resilience in preparation for the challenging times ahead. The All-in-One concept introduces the possibility of a unified and singular system for infrastructure service provision; this work seeks to explore the possibility space opened thereby

Somatic ‘Soluble’ Adenylyl Cyclase Isoforms Are Unaffected in Sacytm1Lex/Sacytm1Lex ‘Knockout’ Mice

BACKGROUND: Mammalian Soluble adenylyl cyclase (sAC, Adcy10, or Sacy) represents a source of the second messenger cAMP distinct from the widely studied, G protein-regulated transmembrane adenylyl cyclases. Genetic deletion of the second through fourth coding exons in Sacy(tm1Lex)/Sacy(tm1Lex) knockout mice results in a male sterile phenotype. The absence of any major somatic phenotype is inconsistent with the variety of somatic functions identified for sAC using pharmacological inhibitors and RNA interference. PRINCIPAL FINDINGS: We now use immunological and molecular biological methods to demonstrate that somatic tissues express a previously unknown isoform of sAC, which utilizes a unique start site, and which 'escapes' the design of the Sacy(tm1Lex) knockout allele. CONCLUSIONS/SIGNIFICANCE: These studies reveal increased complexity at the sAC locus, and they suggest that the known isoforms of sAC play a unique function in male germ cells

North American Climate in CMIP5 Experiments: Part III: Assessment of Twenty-First-Century Projections

In part III of a three-part study on North American climate in phase 5 of the Coupled Model Intercomparison Project (CMIP5) models, the authors examine projections of twenty-first-century climate in the representative concentration pathway 8.5 (RCP8.5) emission experiments. This paper summarizes and synthesizes results from several coordinated studies by the authors. Aspects of North American climate change that are examined include changes in continental-scale temperature and the hydrologic cycle, extremes events, and storm tracks, as well as regional manifestations of these climate variables. The authors also examine changes in the eastern North Pacific and North Atlantic tropical cyclone activity and North American intraseasonal to decadal variability, including changes in teleconnections to other regions of the globe. Projected changes are generally consistent with those previously published for CMIP3, although CMIP5 model projections differ importantly from those of CMIP3 in some aspects, including CMIP5 model agreement on increased central California precipitation. The paper also highlights uncertainties and limitations based on current results as priorities for further research. Although many projected changes in North American climate are consistent across CMIP5 models, substantial intermodel disagreement exists in other aspects. Areas of disagreement include projections of changes in snow water equivalent on a regional basis, summer Arctic sea ice extent, the magnitude and sign of regional precipitation changes, extreme heat events across the northern United States, and Atlantic and east Pacific tropical cyclone activity

Inhibition of Hedgehog Signaling Antagonizes Serous Ovarian Cancer Growth in a Primary Xenograft Model

Recent evidence links aberrant activation of Hedgehog (Hh) signaling with the pathogenesis of several cancers including medulloblastoma, basal cell, small cell lung, pancreatic, prostate and ovarian. This investigation was designed to determine if inhibition of this pathway could inhibit serous ovarian cancer growth.We utilized an in vivo pre-clinical model of serous ovarian cancer to characterize the anti-tumor activity of Hh pathway inhibitors cyclopamine and a clinically applicable derivative, IPI-926. Primary human serous ovarian tumor tissue was used to generate tumor xenografts in mice that were subsequently treated with cyclopamine or IPI-926.Both compounds demonstrated significant anti-tumor activity as single agents. When IPI-926 was used in combination with paclitaxel and carboplatinum (T/C), no synergistic effect was observed, though sustained treatment with IPI-926 after cessation of T/C continued to suppress tumor growth. Hh pathway activity was analyzed by RT-PCR to assess changes in Gli1 transcript levels. A single dose of IPI-926 inhibited mouse stromal Gli1 transcript levels at 24 hours with unchanged human intra-tumor Gli1 levels. Chronic IPI-926 therapy for 21 days, however, inhibited Hh signaling in both mouse stromal and human tumor cells. Expression data from the micro-dissected stroma in human serous ovarian tumors confirmed the presence of Gli1 transcript and a significant association between elevated Gli1 transcript levels and worsened survival.IPI-926 treatment inhibits serous tumor growth suggesting the Hh signaling pathway contributes to the pathogenesis of ovarian cancer and may hold promise as a novel therapeutic target, especially in the maintenance setting

Connecting Network Properties of Rapidly Disseminating Epizoonotics

To effectively control the geographical dissemination of infectious diseases, their properties need to be determined. To test that rapid microbial dispersal requires not only susceptible hosts but also a pre-existing, connecting network, we explored constructs meant to reveal the network properties associated with disease spread, which included the road structure.Using geo-temporal data collected from epizoonotics in which all hosts were susceptible (mammals infected by Foot-and-mouth disease virus, Uruguay, 2001; birds infected by Avian Influenza virus H5N1, Nigeria, 2006), two models were compared: 1) 'connectivity', a model that integrated bio-physical concepts (the agent's transmission cycle, road topology) into indicators designed to measure networks ('nodes' or infected sites with short- and long-range links), and 2) 'contacts', which focused on infected individuals but did not assess connectivity.THE CONNECTIVITY MODEL SHOWED FIVE NETWORK PROPERTIES: 1) spatial aggregation of cases (disease clusters), 2) links among similar 'nodes' (assortativity), 3) simultaneous activation of similar nodes (synchronicity), 4) disease flows moving from highly to poorly connected nodes (directionality), and 5) a few nodes accounting for most cases (a "20:80" pattern). In both epizoonotics, 1) not all primary cases were connected but at least one primary case was connected, 2) highly connected, small areas (nodes) accounted for most cases, 3) several classes of nodes were distinguished, and 4) the contact model, which assumed all primary cases were identical, captured half the number of cases identified by the connectivity model. When assessed together, the synchronicity and directionality properties explained when and where an infectious disease spreads.Geo-temporal constructs of Network Theory's nodes and links were retrospectively validated in rapidly disseminating infectious diseases. They distinguished classes of cases, nodes, and networks, generating information usable to revise theory and optimize control measures. Prospective studies that consider pre-outbreak predictors, such as connecting networks, are recommended

The Metagenomics and Metadesign of the Subways and Urban Biomes (MetaSUB) International Consortium inaugural meeting report

The Metagenomics and Metadesign of the Subways and Urban Biomes (MetaSUB) International Consortium is a novel, interdisciplinary initiative comprised of experts across many fields, including genomics, data analysis, engineering, public health, and architecture. The ultimate goal of the MetaSUB Consortium is to improve city utilization and planning through the detection, measurement, and design of metagenomics within urban environments. Although continual measures occur for temperature, air pressure, weather, and human activity, including longitudinal, cross-kingdom ecosystem dynamics can alter and improve the design of cities. The MetaSUB Consortium is aiding these efforts by developing and testing metagenomic methods and standards, including optimized methods for sample collection, DNA/RNA isolation, taxa characterization, and data visualization. The data produced by the consortium can aid city planners, public health officials, and architectural designers. In addition, the study will continue to lead to the discovery of new species, global maps of antimicrobial resistance (AMR) markers, and novel biosynthetic gene clusters (BGCs). Finally, we note that engineered metagenomic ecosystems can help enable more responsive, safer, and quantified cities