Impulsive Partial Hyperbolic Functional Differential Equations of Fractional Order with State-Dependent Delay

MSC 2010: 26A33, 34A37, 34K37, 34K40, 35R11

Mixed Fractional Integration Operators in Mixed Weighted Hölder Spaces

MSC 2010: 26A33

Bochner-Hecke Theorems for the Weinstein Transform and Application

MSC 2010: 42B10, 44A15

Anti-Periodic Boundary Value Problem for Impulsive Fractional Integro Differential Equations

MSC 2010: 34A37, 34B15, 26A33, 34C25, 34K37

On Fractional Helmholtz Equations

MSC 2010: 26A33, 33E12, 33C60, 35R11

Fractional Calculus of P-transforms

MSC 2010: 44A20, 33C60, 44A10, 26A33, 33C20, 85A99

A Poster about the Recent History of Fractional Calculus

MSC 2010: 26A33, 05C72, 33E12, 34A08, 34K37, 35R11, 60G22

(Table 1) Helium and Thorium 230 excess concentrations in sediment cores B18 and B25

At four sites in the central equatorial Pacific Ocean the flux of extraterrestrial 3He, determined using the excess 230Th profiling method, is 8 * 10**-13 cm**3 STP/cm**2/ka. This supply rate is constant to within 30%. At these same sites, however, the burial rate of 3He, determined using chronostratigraphic accumulation rates, varies by more than a factor of 3. The lowest burial rates, which occur north of the equator at 1°N, 139°W are lower than the global average rate of supply of extraterrestrial 3He by 20% and indicate that sediment winnowing may have occurred. The highest burial rates, which are recorded at the equator and at 2°S, are higher than the rate of supply of extraterrestrial 3He by 100%, and these provide evidence for sediment focusing. By analyzing several proxies measured in core PC72 sediments spanning the past 450 kyr we demonstrate that periods of maximum burial rates of 230Th, 3He, 10Be, Ti, and barite, with a maximum peak-to-trough amplitude of a factor of 6, take place systematically during glacial time. However, the ratio of any one proxy to another is constant to within 30% over the entire length of the records. Given that each proxy represents a different source (234U decay in seawater, interplanetary dust, upper atmosphere, continental dust, or upper ocean), our preferred interpretation for the covariation is that the climate-related changes in burial rates are driven by changes in sediment focusing.

Pelo olhar de quem não sente a diferença : comparação dos Cores Sets da Classificação Internacional de Funcionalidade, Incapacidade e Saúde (CIF) para a Paralisia Cerebral com a perspetiva de crianças/ jovens e cuidadores, de Portugal

Introdução: A CIF foi considerada, por alguns clínicos, como não sendo totalmente viável para a aplicação na rotina clínica, já que este sistema de classificação contém mais de 1400 categorias. Posto isto, o processo de desenvolvimento de Core Sets da CIF tem sido priorizado pela OMS, tornando a CIF acessível para a avaliação das cs específicas. Estes pretendem orientar uma avaliação multidisciplinar abrangente, incluindo as categorias da CIF para descrever, de uma forma suficiente, a funcionalidade e incapacidade dos indivíduos. Contudo, podem existir divergências entre a perspetiva de crianças e jovens portugueses com PC e cuidadores sobre a sua cs e os core sets da CIF estabelecidos para a mesma. Objetivo: Identificar os problemas percecionados pelas crianças e jovens com paralisia cerebral e pelos cuidadores em Portugal e analisar em que medida estes aspetos são representados pela versão atual do Comprehensive Core Set da CIF para esta cs. Metodologia: Este estudo é qualitativo, tendo-se utilizado uma amostra conveniente de crianças/jovens com PC e cuidadores. Todos os dados foram recolhidos por meio de entrevistas e posteriormente analisados segundo o protocolo de Coenen. Foi efetuado o linking dos conceitos obtidos das entrevistas para as categorias da CIF, tendo sido comparadas com os Core Sets da CIF para esta condição. Resultados: Este estudo tem uma amostra de 48 indivíduos, sendo que 28 eram crianças e jovens com PC e os restantes 20 eram cuidadores. A média de idades das crianças/jovens incluídos foi 13,04 (±3,26), sendo que a idade mínima incluída foi 8 anos e a idade máxima, 18 anos. A média de idades dos cuidadores incluídos foi de 35,20 (±8,01) anos, sendo que a idade mínima incluída foi 22 anos e a idade máxima 55 anos. Das 256 categorias identificadas, 101 estão contempladas nas categorias dos Comprehensive Core Set da CIF. Estas encontram-se presentes em 58 categorias de 2º nível dos Comprehensive Core Set de um total de 135, correspondendo a 43% dos mesmos. Conclusões: Tendo em conta os resultados obtidos, podemos concluir que os Comprehensive Core Set da CIF para a PC contemplam a grande maioria dos problemas percecionados pela população-alvo, ainda que integre várias categorias que não foram relevantes para esta população em estudo.

Control of the innate immune response by the mevalonate pathway.

Deficiency in mevalonate kinase (MVK) causes systemic inflammation. However, the molecular mechanisms linking the mevalonate pathway to inflammation remain obscure. Geranylgeranyl pyrophosphate, a non-sterol intermediate of the mevalonate pathway, is the substrate for protein geranylgeranylation, a protein post-translational modification that is catalyzed by protein geranylgeranyl transferase I (GGTase I). Pyrin is an innate immune sensor that forms an active inflammasome in response to bacterial toxins. Mutations in MEFV (encoding human PYRIN) result in autoinflammatory familial Mediterranean fever syndrome. We found that protein geranylgeranylation enabled Toll-like receptor (TLR)-induced activation of phosphatidylinositol-3-OH kinase (PI(3)K) by promoting the interaction between the small GTPase Kras and the PI(3)K catalytic subunit p110δ. Macrophages that were deficient in GGTase I or p110δ exhibited constitutive release of interleukin 1β that was dependent on MEFV but independent of the NLRP3, AIM2 and NLRC4 inflammasomes. In the absence of protein geranylgeranylation, compromised PI(3)K activity allows an unchecked TLR-induced inflammatory responses and constitutive activation of the Pyrin inflammasome.

The Effects of Brominated Flame Retardants on Thyroid Hormone Homeostasis in Human Placenta Tissues and Cell Culture

Polybrominated diphenyl ethers (PBDEs) are a class of brominated flame retardants (BFRs) that have been heavily used in consumer products such as furniture foams, plastics, and textiles since the mid-1970’s. BFRs are added to products in order to meet state flammability standards intended to increase indoor safety in the event of a fire. The three commercial PBDE mixtures, Penta-, Octa-, and DecaBDE, have all been banned in the United States, however, limited use of DecaBDE is still permitted. PBDEs were phased out of production and added to the Stockholm Convention due to concerns over their environmental persistence and toxicity. Human exposure to PBDEs occurs primarily through the inadvertent ingestion of contaminated house dust, as well as though dietary sources. Despite the phase-out and discontinued use of PBDEs, human exposure to this class of chemicals is likely to continue for decades due to the continued use of treated products and existing environmental reservoirs of PBDEs. Extensive research over the years has shown that PBDEs disrupt thyroid hormone (TH) levels and neurodevelopmental endpoints in rodent and fish models. Additionally, there is growing epidemiological evidence linking PBDE exposure in humans to altered TH homeostasis and neurodevelopmental impairments in children. Due to the importance of THs throughout gestation, there is a great need to understand the effects of BFRs on the developing fetus. Specifically, the placenta plays a critical role in the transport, metabolism, and delivery of THs to the fetal compartment during pregnancy and is a likely target for BFR bioaccumulation and endocrine disruption. The central hypothesis of this dissertation research is that BFRs disrupt the activity of TH sulfotransferase (SULT) enzymes, thereby altering TH concentrations in the placenta.

In the first aim of this dissertation research, the concentrations of PBDEs and 2,4,6-TBP were measured in a cohort of 102 placenta tissue samples from an ongoing pregnancy cohort in Durham, NC. Methods were developed for the extraction and analysis of the BFR analytes. It was found that 2,4,6-TBP was significantly correlated with all PBDE analytes, indicating that 2,4,6-TBP may share common product applications with PBDEs or that 2,4,6-TBP is a metabolite of PBDE compounds. Additionally, this was the first study to measure 2,4,6-TBP in human placenta tissues.

In the second aim of this dissertation research, the placenta tissue concentrations of THs, as well as the endogenous activity of deiodinase (DI) and TH SULT enzymes were quantified using the same cohort of 102 placenta tissue samples. Enzyme activity was detected in all samples and this was the first study to measure TH DI and SULT activity in human placenta tissues. Enzyme activities and TH concentrations were compared with BFR concentrations measured in Aim 1. There were few statistically significant associations observed for the combined data, however, upon stratifying the data set based on infant sex, additional significant associations were observed. For example, among males, those with the highest concentrations of BDE-99 in placenta had T3 levels 0.80 times those with the lowest concentration of BDE-99 (95% confidence interval (CI): 0.59, 1.07). Whereas females with the highest concentrations of BDE-99 in placenta had T3 levels 1.50 times those with the lowest concentration of BDE-99 (95% CI: 1.10, 2.04). Additionally, all BFR analyte concentrations were higher in the placenta of males versus females and they were significantly higher for 2,4,6-TBP and BDE-209. 3,3’-T2 SULT activity was significantly higher in female placenta tissues, while type 3 DI activity was significantly higher in male placenta tissues. This research is the first to show sex-specific differences in the bioaccumulation of BFRs in human placenta tissue, as well as differences in TH concentrations and endogenous DI and SULT activity. The underlying mechanisms of these observed sex differences warrant further investigation.

In the third aim of this dissertation research, the effects of BFRs were examined in a human choriocarcinoma placenta cell line, BeWo. Michaelis-Menten parameters and inhibition curves were calculated for 2,4,6-TBP, 3-OH BDE-47, and 6-OH BDE-47. 2,4,6-TBP was shown to be the most potent inhibitor of 3,3’-T2 SULT activity with a calculated IC50 value of 11.6 nM. It was also shown that 2,4,6-TBP and 3-OH BDE-47 exhibit mixed inhibition of 3,3’-T2 sulfation in BeWo cell homogenates. Next, a series of cell culture exposure experiments were performed using 1, 6, 12, and 24 hour exposure durations. Once again, 2,4,6-TBP was shown to be the most potent inhibitor of basal 3,3’-T2 SULT activity by significantly decreasing activity at the high and medium dose (1 M and 0.5 M, respectively) at all measured time points. Interestingly, BDE-99 was also shown to inhibit basal 3,3’-T2 SULT activity in BeWo cells following the 24 hour exposure, despite exhibiting no inhibitory effects in the BeWo cell homogenate experiments. This indicates that BDE-99 must act through a pathway other than direct enzyme inhibition. Following exposures, the TH concentrations in the cell culture growth media and mRNA expression of TH-related genes were also examined. There was no observed effect of BFR treatment on these endpoints. Future work should focus on determining the downstream biological effects of TH SULT disruption in placental cells, as well as the underlying mechanisms of action responsible for reductions in basal TH SULT activity following BFR exposure.

This was one of the first studies to measure BFRs in a cohort of placenta tissue samples from the United States and the first study to measure THs, DI activity, and SULT activity in human placenta tissues. This research provides a novel contribution to our growing understanding of the effects of BFRs on TH homeostasis within the human placenta, and provides further evidence for sex-specific differences within this important organ. Future research should continue to investigate the effects of environmental contaminants on TH homeostasis within the placenta, as this represents the most critical and vulnerable stage of human development.

Seasonal variations in surface metabolite composition of Fucus vesiculosus and Fucus serratus sampled at outer Kiel Fjord (August 2012 - July 2013)

The chemical composition of surface associated metabolites of two Fucus species (Fucus vesiculosus and Fucus serratus) was analysed by means of gas chromatography-mass spectrometry (GC-MS) to describe temporal patterns in chemical surface composition. Method: The two perennial brown macroalgae F. vesiculosus and F. serratus were sampled monthly at Bülk, outer Kiel Fjord, Germany (54°27'21 N / 10°11'57 E) over an entire year (August 2012 - July 2013). Per month and species six non-fertile Fucus individuals were collected from mixed stands at a depth of 0.5 m under mid water level. For surface extraction approx. 50 g of the upper 5-10 cm apical thalli tips were cut off per species. The surface extraction of Fucus was performed according to the protocol of de Nys and co-workers (1998) with minor modifications (see Rickert et al. 2015). GC/EI-MS measurements were performed with a Waters GCT premier (Waters, Manchester, UK) coupled to an Agilent 6890N GC equipped with a DB-5 ms 30 m column (0.25 mm internal diameter, 0.25 mM film thickness, Agilent, USA). The inlet temperature was maintained at 250°C and samples were injected in split 10 mode. He carrier gas flow was adjusted to 1 ml min-1. Alkanes were used for referencing of retention times. For further details (GC-MS sample preparation and analysis) see the related publication (Rickert et al. submitted to PLOS ONE).

(Table 1) Concentrations of polybrominated diphenyl ethers in liver and plasma samples of ringed seals (Phoca hispida)

The present study investigated the concentrations and patterns of PBDEs and hydroxylated (OH) PBDE analogues in two ringed seal populations: less contaminated Svalbard and more contaminated Baltic Sea. Mean concentration of hepatic sum-PBDE, which was dominated by BDE47, was six times higher in the ringed seals from the Baltic Sea compared to the seals from Svalbard. BDE47/sum-PBDE was higher in the seals from Svalbard compared to that for Baltic seals, while the trend was opposite for BDE153 and 154. The geographical difference in contaminant pattern of PBDEs in ringed seals could be explained by biotransformation via oxidative metabolism and/or by dietary differences. OH-PBDEs were detectable in the majority of plasma samples from both locations, and dominated by bioaccumulation of naturally occurring congeners. Low levels of 3-OH-BDE47 and 4'-OH-BDE49 in the Baltic ringed seals suggested minor oxidative biotransformation of BDE47. In the Baltic seals, BDE153/sum-PBDEs and BDE154/sum-PBDEs increased and BDE28/sum-PBDE decreased with increasing sum-POP concentration, which suggests BDE153 and 154 are more persistent than BDE28. Contrasting diets of the ringed seals in these two locations may influence the PBDE congener pattern due to selective long-range transport and direct effluent emissions to Svalbard and the Baltic, respectively.

A Mineralogical Study of a Dravitic Tourmaline from the Grenville Province

Tourmaline from a gem-quality deposit in the Grenville province has been studied with X-ray diffraction, visible-near infrared spectroscopy, Fourier transform infrared spectroscopy, scanning electron microscopy, electron microprobe and optical measurements. The tourmaline is found within tremolite-rich calc-silicate pods hosted in marble of the Central Metasedimentary Belt. The crystals are greenish-greyish-brown and have yielded facetable material up to 2.09 carats in size. Using the classification of Henry et al. 2011 the tourmaline is classified as a dravite, with a representative formula shown to be (Na0.73Ca0.2380.032)(Mg2+2.913Fe2+0.057Ti4+0.030) (Al3+5.787Fe3+0.017Mg2+0.14)(Si6.013O18)(BO3)3(OH)3((OH,O)0.907F0.093). Rietveld analysis of powder diffraction data gives a = 15.9436(8) Å, c = 7.2126(7) Å and a unit cell volume of 1587.8 Å3. A polished thin section was cut perpendicular to the c-axis of one tourmaline crystal, which showed zoning from a dark brown core into a lighter rim into a thin darker rim and back into lighter zonation. Through the geochemical data, three key stages of crystal growth can be seen within this thin section. The first is the core stage which occurs from the dark core to the first colourless zone; the second is from this colourless zone increasing in brown colour to the outer limit before a sudden absence of colour is noted; the third is a sharp change from the end of the second and is entirely colourless. These events are the result of metamorphism and hydrothermal fluids resulting from nearby felsic intrusive plutons. Scanning electron microscope, and electron microprobe traverses across this cross-section revealed that the green colour is the result of iron present throughout the system while the brown colour is correlated with titanium content. Crystal inclusions in the tourmaline of chlorapatite, and zircon were identified by petrographic analysis and confirmed using scanning electron microscope data and occur within the third stage of formation.