Controlled Drug Delivery from Biomaterials used for Cardiac Repair

The continued risk of death due to heart failure has spurred the advancement of biomaterials-based treatments for cardiac repair, two of which are the application of a cardiac patch or intramyocardial material injection. The inclusion of signaling molecules in these materials can improve the treatment results; however, appropriate molecule delivery is not trivial. This research presents the broad application of therapeutics from both a patch and injectable system to demonstrate how system properties influence drug delivery and how these systems may be engineered to provide added benefit in the desired application. We demonstrated the ability to release a gene-inducing molecule, Rheoswitch ligand 1 (RSL1), from a biodegradable elastomer that has been used as a cardiac patch. Not only was bioactive RSL1 released over an extended period, the ability to differentially load scaffolds with RSL1 allowed for spatial patterning of gene expression in cells cultured on the scaffold surface, which has implications for creating complex 3D tissues in vitro. This same elastomeric material was able to release bioactive insulin-like growth factor 1 (IGF1) and hepatocyte growth factor (HGF) in vitro. The complex release behavior of IGF1 into saline was replaced by a much simpler release profile during simulated in vivo degradation, demonstrating that the implant environment must be considered when studying drug delivery behavior. A strong, thermoresponsive and degradable hydrogel was developed for intramyocardial injection. We showed the release rates of a model protein from this gel, or from protein-loaded microparticles inside the gel, could be controlled by changing the material composition. The combination of hydrogel with microparticles delivered two proteins in a sequential manner. We further used this system to release bioactive basic fibroblast growth factor (bFGF) followed by IGF1 in vitro. Injection of the unloaded polymer into infarcted rat hearts was able to improve the remodeling process for at least 16 weeks. While increased tissue bFGF and IGF1 were demonstrated following injection of growth factor-loaded gels, there were no clear benefits seen from protein inclusion. This points to the primary ability of the hydrogel alone to benefit cardiac function and cellular environment and warrants further investigation

Decrypting the Link Between Elliptic Primes and Twin Primes

From Caesar’s cipher to Germany’s enigma machine to modern day cryptosytems, cryptography spans throughout history. Methods of encryption have evolved over hundreds of years and continue to evolve as computational efficiency increases. Over 2.5 quintillion bytes of data are generated per day through online networks such as banking, shopping, and social media. More than 90% of the total data in the world has been generated in the past two years, thereby requiring more sophisticated cybersecurity systems and an increasing demand for research in the field of cryptography. A curve of the form y2 = x3 + Ax + B, where A and B are constants, is what is known as an elliptic curve, which have become increasingly prevalent in modern cryptosystems. Our research focuses on the notion of elliptic primes, some of their properties, as well as some of their applications in cryptography. We also examine the primes that are both an elliptic prime and a twin prime

The Intermediate Higgs

Two paradigms for the origin of electroweak superconductivity are a weakly coupled scalar condensate, and a strongly coupled fermion condensate. The former suffers from a finetuning problem unless there are cancelations to radiative corrections, while the latter presents potential discrepancies with precision electroweak physics. Here we present a framework for electroweak symmetry breaking which interpolates between these two paradigms, and mitigates their faults. As in Little Higgs theories, the Higgs is a pseudo-Nambu Goldstone boson, potentially composite. The cutoff sensitivity of the one loop top quark contribution to the effective potential is canceled by contributions from additional vector-like quarks, and the cutoff can naturally be higher than in the minimal Standard Model. Unlike the Little Higgs models, the cutoff sensitivity from one loop gauge contributions is not canceled. However, such gauge contributions are naturally small as long as the cutoff is below 6 TeV. Precision electroweak corrections are suppressed relative to those of Technicolor or generic Little Higgs theories. In some versions of the intermediate scenario, the Higgs mass is computable in terms of the masses of these additional fermions and the Nambu-Goldstone Boson decay constant. In addition to the Higgs, new scalar and pseudoscalar particles are typically present at the weak scale

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Comparative and demographic analysis of orang-utan genomes

Orang-utan- is derived from a Malay term meaning man of the forest- and aptly describes the southeast Asian great apes native to Sumatra and Borneo. The orang-utan species, Pongo abelii (Sumatran) and Pongo pygmaeus (Bornean), are the most phylogenetically distant great apes from humans, thereby providing an informative perspective on hominid evolution. Here we present a Sumatran orang-utan draft genome assembly and short read sequence data from five Sumatran and five Bornean orang-utan genomes. Our analyses reveal that, compared to other primates, the orang-utan genome has many unique features. Structural evolution of the orang-utan genome has proceeded much more slowly than other great apes, evidenced by fewer rearrangements, less segmental duplication, a lower rate of gene family turnover and surprisingly quiescent Alu repeats, which have played a major role in restructuring other primate genomes. We also describe a primate polymorphic neocentromere, found in both Pongo species, emphasizing the gradual evolution of orang-utan genome structure. Orang-utans have extremely low energy usage for a eutherian mammal, far lower than their hominid relatives. Adding their genome to the repertoire of sequenced primates illuminates new signals of positive selection in several pathways including glycolipid metabolism. From the population perspective, both Pongo species are deeply diverse; however, Sumatran individuals possess greater diversity than their Bornean counterparts, and more species-specific variation. Our estimate of Bornean/Sumatran speciation time, 400,000years ago, is more recent than most previous studies and underscores the complexity of the orang-utan speciation process. Despite a smaller modern census population size, the Sumatran effective population size (N e) expanded exponentially relative to the ancestral N e after the split, while Bornean N e declined over the same period. Overall, the resources and analyses presented here offer new opportunities in evolutionary genomics, insights into hominid biology, and an extensive database of variation for conservation efforts. © 2011 Macmillan Publishers Limited. All rights reserved

Collaborative International Research in Clinical and Longitudinal Experience Study in NMOSD.

Objective: To develop a resource of systematically collected, longitudinal clinical data and biospecimens for assisting in the investigation into neuromyelitis optica spectrum disorder (NMOSD) epidemiology, pathogenesis, and treatment. Methods: To illustrate its research-enabling purpose, epidemiologic patterns and disease phenotypes were assessed among enrolled subjects, including age at disease onset, annualized relapse rate (ARR), and time between the first and second attacks. Results: As of December 2017, the Collaborative International Research in Clinical and Longitudinal Experience Study (CIRCLES) had enrolled more than 1,000 participants, of whom 77.5% of the NMOSD cases and 71.7% of the controls continue in active follow-up. Consanguineous relatives of patients with NMOSD represented 43.6% of the control cohort. Of the 599 active cases with complete data, 84% were female, and 76% were anti-AQP4 seropositive. The majority were white/Caucasian (52.6%), whereas blacks/African Americans accounted for 23.5%, Hispanics/Latinos 12.4%, and Asians accounted for 9.0%. The median age at disease onset was 38.4 years, with a median ARR of 0.5. Seropositive cases were older at disease onset, more likely to be black/African American or Hispanic/Latino, and more likely to be female. Conclusions: Collectively, the CIRCLES experience to date demonstrates this study to be a useful and readily accessible resource to facilitate accelerating solutions for patients with NMOSD

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Prolactinomas, Cushing's disease and acromegaly: debating the role of medical therapy for secretory pituitary adenomas

Pituitary adenomas are associated with a variety of clinical manifestations resulting from excessive hormone secretion and tumor mass effects, and require a multidisciplinary management approach. This article discusses the treatment modalities for the management of patients with a prolactinoma, Cushing's disease and acromegaly, and summarizes the options for medical therapy in these patients