Synthesis, Characterization, and Evaluation of Novel BODIPY Dyes With Theranostic Applications

Boron dipyrromethene (BODIPY) dyes, have garnered much attention in recent decades due to their enticing photophysical properties and their bioimaging applicability. Despite the progression of this field, the development of BODIPY based anti-cancer agents and radioimaging dyes has seen little progress. The utilization of fluorescent BODIPYs as photosensitizers for photodynamic therapy, and as boron delivery agents for boron neutron capture therapy offers promise as theranostic agents. Additionally, BODIPY derivatives that absorb and emit in the near-IR regions of the electromagnetic spectrum and bear radioisotopes suitable for radioimaging techniques are of great interest. Chapter 1 is a concise overview of the fundamental concepts of the BODIPY fluorophores. The synthetic routes, post-synthetic modification strategies, and several biological applications of BODIPYs are introduced and will be elaborated upon in subsequent chapters. Chapter 2 describes the synthesis, characterization, computational modeling and in vitro biological investigations of a series of meso-aryl tetramethyl BODIPYs and their diiodo derivatives as photodynamic therapy photosensitizers. Variances in the meso-substituent of BODIPY were found to influence the phototoxicity of diiodo-BODIPYs, with some possessing phototoxicity while others were non-toxic. The photophysical properties of these compounds were also explored computationally in collaboration with Dr. Petia Bobadova-Parvanova of Rockhurst University. Chapter 3 reports on the synthesis of several near-IR styrylated diiodo-BODIPYs prepared via the Knoevenagel reaction strategy from one of the most phototoxic BODIPYs described in Chapter 2. The effects of the number and type of styryl substituents on their photophysical properties and in vitro photodynamic activities are discussed. Chapter 4 explores the synthesis, photophysical, and in vitro biological properties of near-IR styryl BODIPYs with applications in near-IR fluorescence, PET, and SPECT imaging. The exploration of radiolabelling highly functionalized long wavelength BODIPYs is detailed herein. Chapter 5 conveys an effective method towards the preparation of carborane-appended BODIPYs for boron neutron capture therapy. The use of highly efficient palladium-catalyzed Suzuki coupling yielded two carboranyl-BODIPYs of varying optical properties in good yield. The photophysical properties and blood brain permeability of these novel-carboranyl BODIPYs was reported

Long non-coding RNA FAM83H-AS1 is regulated by human papillomavirus 16 E6 independently of p53 in cervical cancer cells

High-risk human papillomavirus (HPV) infection is one of the first events in the process of carcinogenesis in cervical and head and neck cancers. The expression of the viral oncoproteins E6 and E7 are essential in this process by inactivating the tumor suppressor proteins p53 and Rb, respectively, in addition to their interactions with other host proteins. Non-coding RNAs, such as long non-coding RNAs (lncRNAs) have been found to be dysregulated in several cancers, suggesting an important role in tumorigenesis. In order to identify host lncRNAs affected by HPV infection, we expressed the high-risk HPV-16 E6 oncoprotein in primary human keratinocytes and measured the global lncRNA expression profile by high-throughput sequencing (RNA-seq). We found several host lncRNAs differentially expressed by E6 including GAS5, H19, and FAM83H-AS1. Interestingly, FAM83H-AS1 was found overexpressed in HPV-16 positive cervical cancer cell lines in an HPV-16 E6-dependent manner but independently of p53 regulation. Furthermore, FAM83H-AS1 was found to be regulated through the E6-p300 pathway. Knockdown of FAM83H-AS1 by siRNAs decreased cellular proliferation, migration and increased apoptosis. FAM83H-AS1 was also found to be altered in human cervical cancer tissues and high expression of this lncRNA was associated with worse overall survival, suggesting an important role in cervical carcinogenesis

Managing Local Order in Conjugated Polymer Blends via Polarity Contrast

The optoelectronic landscape of conjugated polymers is intimately related to their molecular arrangement and packing, with minute changes in local order, such as chain conformation and torsional backbone order/disorder, frequently having a substantial effect on macroscopic properties. While many of these local features can be manipulated via chemical design, the synthesis of a series of compounds is often required to elucidate correlations between chemical structure and macromolecular ordering. Here, we show that blending semiconducting polymers with insulating commodity plastics enables controlled manipulation of the semiconductor backbone planarity. The key is to create a polarity difference between the semiconductor backbone and its side chains, while matching the polarity of the side chains and the additive. We demonstrate the applicability of this approach through judicious comparison of regioregular poly(3-hexylthiophene) (P3HT) with two of its more polar derivatives, namely the diblock copolymer poly(3-hexylthiophene)-block-poly(ethylene oxide) (P3HT-b-PEO) and the graft polymer poly[3-but(ethylene oxide)thiophene] (P3BEOT), as well as their blends with poly(ethylene oxide) (PEO). Proximity between polar side chains and a similarly polar additive reduces steric hindrance between individual chain segments by essentially "expelling" the side chains away from the semiconducting backbones. This process, shown to be facilitated via exposure to polar environments such as humid air/water vapor, facilitates backbone realignment toward specific chain arrangements and, in particular, planar backbone configurations

Developmental Origin of PreBotzinger Complex Respiratory Neurons

A subset of preBötzinger Complex (preBötC) neurokinin 1 receptor (NK1R) and somatostatin peptide (SST)-expressing neurons are necessary for breathing in adult rats, in vivo. Their developmental origins and relationship to other preBötC glutamatergic neurons are unknown. Here we show, in mice, that the “core” of preBötC SST+/NK1R+/SST 2a receptor+ (SST2aR) neurons, are derived from Dbx1-expressing progenitors. We also show that Dbx1-derived neurons heterogeneously coexpress NK1R and SST2aR within and beyond the borders of preBötC. More striking, we find that nearly all non-catecholaminergic glutamatergic neurons of the ventrolateral medulla (VLM) are also Dbx1 derived. PreBötC SST+ neurons are born between E9.5 and E11.5 in the same proportion as non-SST-expressing neurons. Additionally, preBötC Dbx1 neurons are respiratory modulated and show an early inspiratory phase of firing in rhythmically active slice preparations. Loss of Dbx1 eliminates all glutamatergic neurons from the respiratory VLM including preBötC NK1R+/SST+ neurons. Dbx1 mutant mice do not express any spontaneous respiratory behaviors in vivo. Moreover, they do not generate rhythmic inspiratory activity in isolated en bloc preparations even after acidic or serotonergic stimulation. These data indicate that preBötC core neurons represent a subset of a larger, more heterogeneous population of VLM Dbx1-derived neurons. These data indicate that Dbx1-derived neurons are essential for the expression and, we hypothesize, are responsible for the generation of respiratory behavior both in vitro and in vivo

Texas Lifestyle Limits Transmission of Dengue Virus

Urban dengue is common in most countries of the Americas, but has been rare in the United States for more than half a century. In 1999 we investigated an outbreak of the disease that affected Nuevo Laredo, Tamaulipas, Mexico, and Laredo, Texas, United States, contiguous cities that straddle the international border. The incidence of recent cases, indicated by immunoglobulin M antibody serosurvey, was higher in Nuevo Laredo, although the vector, Aedes aegypti, was more abundant in Laredo. Environmental factors that affect contact with mosquitoes, such as air-conditioning and human behavior, appear to account for this paradox. We conclude that the low prevalence of dengue in the United States is primarily due to economic, rather than climatic, factors

Modelling the fraction of Lyman Break Galaxies with strong Lyman alpha emission at 5 < z < 7

We present theoretical results for the expected fraction of Lyman Break Galaxies (LBGs) to be detected as strong Lyman alpha emitters (LAEs) in the redshift range 5 < z < 7. We base our analysis on the 2-billion particle SPH simulation MareNostrum High-z Universe. We approximate galaxies as static dusty slabs with an additional clumpy dust distribution affecting stellar populations younger than 25 Myr. The model for the Lyman alpha escape fraction is based on the results of our Monte-Carlo radiative transfer code (CLARA) for a slab configuration. We also fix the transmission of Lyman alpha photons through the intergalactic medium to a constant value of 50% at all redshifts. From the results of this model we calculate xLya, the fraction of Lyman Break Galaxies with Lyman alpha equivalent width (EW) larger than 50 Angstrom. We find a remarkable agreement with observational data at 4.5 < z < 6. For bright (-22 < MUV < -20.5) and faint (-20.5 < MUV < -18.5) galaxies our model predicts xLya = 0.02 \pm 0.01 and xLya = 0.47 \pm 0.01 while observers report xLya = 0.08 \pm 0.02 and xLya = 0.47 \pm 0.16, respectively. Additional evolution of the extinction model at redshift z \sim 7, that decreases the intensity of transmitted Lyman alpha radiation by a factor of f_T = 0.4 as to match the LAE luminosity function at z \sim 6.5, naturally provides a good match for the recently reported xLya fractions at z > 6.3. Exploring different toy models for the Lyman alpha escape fraction, we show that a decreasing Lyman alpha escape fraction with increasing UV galaxy luminosity is a key element in our model to explain the of larger xLya fractions for fainter LBGs.Comment: 7 pages, 3 figures. Accepted for publication in MNRA

The Fourteenth Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the extended Baryon Oscillation Spectroscopic Survey and from the second phase of the Apache Point Observatory Galactic Evolution Experiment

The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in operation since July 2014. This paper describes the second data release from this phase, and the fourteenth from SDSS overall (making this, Data Release Fourteen or DR14). This release makes public data taken by SDSS-IV in its first two years of operation (July 2014-2016). Like all previous SDSS releases, DR14 is cumulative, including the most recent reductions and calibrations of all data taken by SDSS since the first phase began operations in 2000. New in DR14 is the first public release of data from the extended Baryon Oscillation Spectroscopic Survey (eBOSS); the first data from the second phase of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2), including stellar parameter estimates from an innovative data driven machine learning algorithm known as "The Cannon"; and almost twice as many data cubes from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous release (N = 2812 in total). This paper describes the location and format of the publicly available data from SDSS-IV surveys. We provide references to the important technical papers describing how these data have been taken (both targeting and observation details) and processed for scientific use. The SDSS website (www.sdss.org) has been updated for this release, and provides links to data downloads, as well as tutorials and examples of data use. SDSS-IV is planning to continue to collect astronomical data until 2020, and will be followed by SDSS-V.Comment: SDSS-IV collaboration alphabetical author data release paper. DR14 happened on 31st July 2017. 19 pages, 5 figures. Accepted by ApJS on 28th Nov 2017 (this is the "post-print" and "post-proofs" version; minor corrections only from v1, and most of errors found in proofs corrected

CLARA's view on the escape fraction of Lyman-Alpha photons in high redshift galaxies

Using CLARA (Code for Lyman Alpha Radiation Analysis) we constrain the escape fraction of Lyman-Alpha radiation in galaxies in the redshift range 5<z<7, based on the MareNostrum High-z Universe, a SPH cosmological simulation with more than 2 billion particles. We approximate Lyman-Alpha Emitters (LAEs) as dusty gaseous slabs with Lyman-Alpha radiation sources homogeneously mixed in the gas. Escape fractions for such a configuration and for different gas and dust contents are calculated using our newly developed radiative transfer code CLARA. The results are applied to the MareNostrum High-z Universe numerical galaxies. The model shows a weak redshift evolution and good agreement with estimations of the escape fraction as a function of reddening from observations at z \sim 2.2 and z \sim 3. We extend the slab model by including additional dust in a clumpy component in order to reproduce the UV con- tinuum luminosity function and UV colours at redshifts z>~5. The LAE Luminosity Function (LF) based on the extended clumpy model reproduces broadly the bright end of the LF derived from observations at z \sim 5 and z \sim 6. At z \sim 7 our model over-predicts the LF by roughly a factor of four, presumably because the effects of the neutral intergalactic medium are not taken into account. The remaining tension between the observed and simulated faint end of the LF, both in the UV-continuum and Lyman-Alpha at redshifts z \sim 5 and z \sim 6 points towards an overabundance of simulated LAEs hosted in haloes of masses 1.0x10^10h-1Msol < Mh < 4.0x10^10h-1Msol. Given the difficulties in explaining the observed overabundance by dust absorption, a probable origin of the mismatch are the high star formation rates in the simulated haloes around the quoted mass range. A more efficient supernova feedback should be able to regulate the star formation process in the shallow potential wells of these haloes.Comment: 17 pages, 9 figures. Accepted for publication in MNRA

Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128·9 million children, adolescents, and adults

Background Underweight, overweight, and obesity in childhood and adolescence are associated with adverse health consequences throughout the life-course. Our aim was to estimate worldwide trends in mean body-mass index (BMI) and a comprehensive set of BMI categories that cover underweight to obesity in children and adolescents, and to compare trends with those of adults. Methods We pooled 2416 population-based studies with measurements of height and weight on 128·9 million participants aged 5 years and older, including 31·5 million aged 5–19 years. We used a Bayesian hierarchical model to estimate trends from 1975 to 2016 in 200 countries for mean BMI and for prevalence of BMI in the following categories for children and adolescents aged 5–19 years: more than 2 SD below the median of the WHO growth reference for children and adolescents (referred to as moderate and severe underweight hereafter), 2 SD to more than 1 SD below the median (mild underweight), 1 SD below the median to 1 SD above the median (healthy weight), more than 1 SD to 2 SD above the median (overweight but not obese), and more than 2 SD above the median (obesity). Findings Regional change in age-standardised mean BMI in girls from 1975 to 2016 ranged from virtually no change (−0·01 kg/m2 per decade; 95% credible interval −0·42 to 0·39, posterior probability [PP] of the observed decrease being a true decrease=0·5098) in eastern Europe to an increase of 1·00 kg/m2 per decade (0·69–1·35, PP\u3e0·9999) in central Latin America and an increase of 0·95 kg/m2 per decade (0·64–1·25, PP\u3e0·9999) in Polynesia and Micronesia. The range for boys was from a non-significant increase of 0·09 kg/m2 per decade (−0·33 to 0·49, PP=0·6926) in eastern Europe to an increase of 0·77 kg/m2 per decade (0·50–1·06, PP\u3e0·9999) in Polynesia and Micronesia. Trends in mean BMI have recently flattened in northwestern Europe and the high-income English-speaking and Asia-Pacific regions for both sexes, southwestern Europe for boys, and central and Andean Latin America for girls. By contrast, the rise in BMI has accelerated in east and south Asia for both sexes, and southeast Asia for boys. Global age-standardised prevalence of obesity increased from 0·7% (0·4–1·2) in 1975 to 5·6% (4·8–6·5) in 2016 in girls, and from 0·9% (0·5–1·3) in 1975 to 7·8% (6·7–9·1) in 2016 in boys; the prevalence of moderate and severe underweight decreased from 9·2% (6·0–12·9) in 1975 to 8·4% (6·8–10·1) in 2016 in girls and from 14·8% (10·4–19·5) in 1975 to 12·4% (10·3–14·5) in 2016 in boys. Prevalence of moderate and severe underweight was highest in India, at 22·7% (16·7–29·6) among girls and 30·7% (23·5–38·0) among boys. Prevalence of obesity was more than 30% in girls in Nauru, the Cook Islands, and Palau; and boys in the Cook Islands, Nauru, Palau, Niue, and American Samoa in 2016. Prevalence of obesity was about 20% or more in several countries in Polynesia and Micronesia, the Middle East and north Africa, the Caribbean, and the USA. In 2016, 75 (44–117) million girls and 117 (70–178) million boys worldwide were moderately or severely underweight. In the same year, 50 (24–89) million girls and 74 (39–125) million boys worldwide were obese. Interpretation The rising trends in children\u27s and adolescents\u27 BMI have plateaued in many high-income countries, albeit at high levels, but have accelerated in parts of Asia, with trends no longer correlated with those of adults. Funding Wellcome Trust, AstraZeneca Young Health Programme

Global estimates of mortality associated with long-term exposure to outdoor fine particulate matter.

Exposure to ambient fine particulate matter (PM2.5) is a major global health concern. Quantitative estimates of attributable mortality are based on disease-specific hazard ratio models that incorporate risk information from multiple PM2.5 sources (outdoor and indoor air pollution from use of solid fuels and secondhand and active smoking), requiring assumptions about equivalent exposure and toxicity. We relax these contentious assumptions by constructing a PM2.5-mortality hazard ratio function based only on cohort studies of outdoor air pollution that covers the global exposure range. We modeled the shape of the association between PM2.5 and nonaccidental mortality using data from 41 cohorts from 16 countries-the Global Exposure Mortality Model (GEMM). We then constructed GEMMs for five specific causes of death examined by the global burden of disease (GBD). The GEMM predicts 8.9 million [95% confidence interval (CI): 7.5-10.3] deaths in 2015, a figure 30% larger than that predicted by the sum of deaths among the five specific causes (6.9; 95% CI: 4.9-8.5) and 120% larger than the risk function used in the GBD (4.0; 95% CI: 3.3-4.8). Differences between the GEMM and GBD risk functions are larger for a 20% reduction in concentrations, with the GEMM predicting 220% higher excess deaths. These results suggest that PM2.5 exposure may be related to additional causes of death than the five considered by the GBD and that incorporation of risk information from other, nonoutdoor, particle sources leads to underestimation of disease burden, especially at higher concentrations