Background and purpose: Angelicae Sinensis Raidx (Chinese Angelica, Dang Gui, DG), the dry root of Angelica sinensis (Oliv.) Diels, is one of the most popular herbs used around the world. It has been named as the “female ginseng and served as an indispensable herb to treat many obstetrical and gynecological diseases. Traditionally, DG was recommended to pregnant women to ease delivery and to eliminate complications. It is believed that the body of DG (Dang Gui Shen, DGS) is superior in nourishing blood, while the tail of DG (Dang Gui Wei, DGW) is commonly used to remove blood stagnation. Clinically, DG is commonly combined with Paeoniae Radix Alba (White Peony Root, Bai Shao, BS) and Rehmanniae Radix (Unprocessed Rehmannia Root, Sheng Di Huang, SDH) to treat disorders during pregnancy as it may not only the strengthen therapeutic effects but also eliminate adverse effects caused by each single herb. However, it is contradictory that DG may increase the risk of miscarriages reported by previous studies: the use of DGS among pregnant women, while avoiding using DGW has always been recommended since ancient times to avoid miscarriage. To date, there is no clear evidence to identify the safety of DG in pregnant women and to support the theory that different pharmaceutical effects are attributed to chemical difference between DGS and DGW. Furthermore, little is known regarding the specific effects of DG on fetal bone while limited research has been done to explore herb-herb interactions between DG and other herbs. The aims of this project are (1) to identify the safety of DG in maternal and fetal health; (2) to compare the chemical composition of DGS and DGW and their cytotoxicity; (3) to analyze the integrated role of herb-pair (DG plus BS or SDH); (4) to investigate the mechanism of specific impact of herb-herb interaction emphasis on embryonic development. Based on the theory of traditional Chinese medicine, our project is believed to provide experimental evidence to rationalize clinical use of DG in pregnant women. Method: (1) For the herbal quality control, aqueous extracts of DG, DGS, DGW, BS and SDH were prepared respectively, and their reference marker compounds were quantitatively authenticated by HPLC. In addition, pesticide residues and heavy metals in DG extract were examined by GC-MS and ICP-MS. Moreover, comparison of composition of DGS and DGW extract in terms of main constituents was performed by GC-MS and LC-MS analysis. (2) In-vivo mouse study (Segment II study), pregnant mice were randomly assigned into different dosage groups: oral administration of either distilled water as negative control, or DG extract of 2, 8, 16, 32 g/kg/day, or BS extract of 2, 16, 32 g/kg/day, or SDH extract of 2, 16, 32 g/kg/day, or DG (32 g/kg/day) plus BS (32 g/kg/day), or DG (32 g/kg/day) plus SDH (32 g/kg/day), respectively from the gestation day (GD) 6 to 15; another group mice were treated with vitamin A (200,000 IU) on the GD7, 9 and 11 as positive control. The mice were sacrificed for assessing parameters on GD18. (3) In-vitro assay using embryonic stem cell (ESC) and fibroblast 3T3 cell was conducted to investigate the cytotoxicity of DG, Z-LIG, FA, DGS, DGW, BS and SDH by MTT test, according to European Centre for the Validation of Alternative Methods. (4) For mechanistic study of DG impacts and herb-herb interactions, the expression of a characteristic set of bone formation/resorption markers, and some site-specific bone regulatory factors in fetal tissues and amniotic fluids on the GD15 were measured by ELISA. Result: (1) In the study to evaluate the safety of DG extract, maternal body weight (BW), gravid uterine weight, corrected BW change, live fetus/litter, mean fetal body weight in the group of DG (32 g/kg/day) were significantly lower than those of the negative control (p < 0.05); while resorption site/litter, post-implantation loss (PIL)/litter, percentage of abnormal skeleton were significantly higher than those of the negative control (p < 0.05). Although there was no statistical difference between IC50 values of ESCs (IC50 ESC) and 3T3 cells (IC50 3T3) after treatment with DG, Z-LIG and FA samples respectively, the IC50 Z-LIG was significantly less than IC50 FA in both ESCs and 3T3 cells (p < 0.05). It was indicated that DG extract (32 g/kg/day) might result in adverse impacts to maternal function and fetal development in mice. Z-LIG in DG extracts might be less safe compared to FA in in-vitro cultured cells and its potential impacts should be further examined its potential impacts in in-vivo studies. (2) In the study to compare the composition of main constituents from DGS and DGW water extract, HPLC quantitative analysis indicated that the ratio of FA and Z-LIG between extract from DGS and DGW is 1:1.83 and 1:1.35, respectively. Sathulenol (1), 3-butylphthalide (2), Z-butylidenephthalide (3), benzeneacetic acid (4), Z-LIG (5) and E-LIG (6) were identified by GC-MS analysis. The peak area of compound 5 in DGW extract was close to 5 times of that in DGS extract. The amounts of compound 2 and 3 in DGW extract were respectively over 20 times and 2 times higher than that in DGS extract, respectively. Except for compound 3, 5, 6, additional three compounds: coniferyl ferulate (7), FA (8), senkyunolide A (9) were identified by LC-MS analysis. The amount of compound 3, 5, 6, 7, 8, and 9 in DGW extract was higher than that in DGS extract. The peak area of compound 3 and 5 in DGW extract was over 2 times of that in the DGS extract. In MTT assay, the effect of DGS and DGW water extract on inhibition of cell viability of cultured ESCs and 3T3 cells was in a dose-dependent manner, respectively. The difference between IC50 ESC and IC50 3T3 after DGS extract treatment was statistically significance (p < 0.05), however no statistical significance was identified in DGW (p > 0.05). Both IC50 ESC and IC50 3T3 values of DGW were much lower than those of DGS (p < 0.05). (3) In the study to evaluate the role of DG plus BS or SDH, expectedly DG extract (32 g/kg/day) resulted in significant abnormalities in maternal and fetal parameters when compared with the negative control. Whereas BS or SDH extracts at a dosage of 2, 16, or 32 g/kg/day did not result in any adverse effect for both maternal health and embryonic development. There was no statistically significant difference between the IC50 ESC and IC50 3T3 value in the cytotoxicity assays of BS or SDH extracts (p > 0.05). It was indicated that the use of BS or SDH extract should be safer than DG extract in pregnant mice. More importantly, the treatment with DG plus BS or DG plus SDH extract could significantly correct abnormalities caused by DG extract alone as seen in the corrected BW change, mean fetal body weight, live fetus/litter (%), resorption site/litter (%), PIL/litter (%), skeletal variation (%), etc. (p < 0.05) in pregnant mice. (4) In the study to analyze the mechanism of herb-herb interactions, the mean values of PICP, ALP-Bone, osteocalcin, BMPs and GDF-5 in fetal tissues were significantly lower in mice treated with DG extract (32g/kg/day) alone when compared with the negative control (p < 0.05); while there was no significant difference among the mice treated respectively with BS, SDH, DG plus BS and DG plus SDH extracts with the same dosage. The outcome was similar to those of the negative control (p > 0.05). In addition, there were no significant differences in the mean value of ICTP in both fetal tissues and amniotic fluids among all mice groups (p > 0.05). Conclusion: (1) High dosage and long-term use of DG water extract may result in adverse effects on embryonic development including fetal bone malformations, hence its use is considered as not safe in pregnant women. As DG extract in this study was not contaminated by pesticide residues and heavy metals, the embryonic toxicity of DG extract can be considered as due to the intrinsic constituents of the herb. (2) As seen in cytotoxicity assay, that water extract of DGW had the lower IC50 value, hence it is believed that the higher phthalides level (3-butylphthalide, Z-butylidenephthalide, senkyunolide A Z-LIG and E-LIG) contributes to a more toxicity on both ESC and 3T3 cells. (3) Herb-pair extract of DG plus BS or SDH could significantly correct abnormalities caused by DG extract alone in pregnant mice. Therefore, herb BS or SDH not only has beneficial effects when used for treating pregnant disorders safety, but also has attenuated effects for DG when used together as herb-pair extract. (4) At the molecular biomarker level, DG extract might significantly affect bone formation rather than bone resorption. However, it could be ameliorated when applied combination with either BS or SDH. These results should be valuable for further analysis on the integrated effects of herb-herb interactions and complex mechanism of formula therapies in Chinese herbal medicine.

No description available.

The National Health Service (NHS) focuses on quality of care as a priority. With the NHS planning to go paperless by 2018, more hospitals in England are making the transition from paper to electronic prescribing (ePrescribing) systems. The aim of this programme of work was to understand and explore the influence different in-patient prescribing systems can have on key NHS healthcare professionals (doctors, nurses and pharmacists) working practices in England and quality healthcare. The programme of work, a three phase sequential design, used both qualitative and quantitative approaches. The first phase involved structured telephone interviews with chief pharmacists. Chief pharmacist interviews (n=65) focused upon the type of in-patient prescribing systems in use within each Trust and gained a management perspective of the different prescribing systems. Phases two and three were carried out at three acute NHS hospitals in England, at various stages of developing and implementing their prescribing systems. Phase two data were collected through multidisciplinary team (MDT) focus group discussions. The MDT discussions explored a number of areas associated with the prescribing systems in use: these included clinical workflow, communication, collaboration, patient safety and the use of a clinical indication on the prescription chart. Phase three data were collected using documentation analysis of the prescribing system and medical records, taken from patients cared for by the MDTs involved in phase two. Information extracted included any documentation made of a newly initiated medication, as well as the design of the prescribing system. The clarity and accuracy of documentation in the prescribing system and medical notes were compared to the GMC standards Good Practice in Prescribing Guidelines. Triangulation of data indicated how a change in prescribing system can impact upon individuals working practices by changing the design and clarity of the prescription chart, enforcing of regulations, accessibility and reliability, communication between key HCPs and the patient. These influences can be considered latent conditions in the systems that need addressing to prevent quality of patient care being compromised. The use of Socio-technical systems (STS) theory considered the interaction between humans and technology when using the prescribing systems. Understanding the issues where social and technical aspects interact in the prescribing system, emphasised where healthcare quality is impacted and therefore facilitated recommendations to improve working practices. The findings will help healthcare organisations to consider the impact a change in prescribing system can have on working practices and the latent failures that need consideration within the prescribing systems. The Electronic Prescribing and Medicines Administration (EPMA) system design must take into account the visual and physical needs of the user and consider how they can be improved to facilitate clinical workflow.

S. pneumoniae is one of the most significant human pathogens, causing high morbidity and mortality rates globally. Although there are vaccine available such as PPV 23, PCV7, PCV10, and PCV13, they are ineffective in some situations due to the differing epidemiology of various serotypes depending on the site of infection and the geographical location. Furthermore, they are expensive to produce and distribute. Universal research is presently concentrated on establishing other pneumococcalvaccine approaches such as using pneumococcal surface protein A (PspA) which relate to pathogenesis and are common to all serotypes. In this study polymeric nanoparticles (NPs) encapsulating PspA4Pro were incorporated into microcarriers using L-leucine and spray dried to produce nanocomposite micro#particles (NCMPs) dry powder for inhalation. Parameters for the preparation of protein-loaded polyester poly (Glycerol Adipate-co-ω-Pentadecalactone), (PGA-co-PDL) NCMPs were optimised using Taguchi design and BSA as a model protein, by the double emulsion solvent evaporation method followed by spray drying. Particle size was mainly affected by the polymer mass and small particle size ≤ 500nm was achieved. The most important factor for obtaining a high BSA loading was BSA concentration. The spray drying process was optimised to produce NCMPs with a porous corrugated surface, 50% yield, MMAD of 1.71±0.10 μm and FPF% of 78.57±0.1%. Adsorption of chitosan hydrochloride (CHL) onto PGA-co-PDL NPs can be used assuccessful strategies to produce cationic NPs. Cationic NPs were prepared with similarparticle size to anionic NPs ≤ 500nm. The In vitro aerosolisation performance ofcationic NPs/NCMPs showed FPF% of 46.79±11.21% and MMAD of 1.49±0.29 μm. Further cell viability studies on A549 cell line showed a good profile with a cell viability of 79±4.7% for anionic NPs/NCMPs and 78.85±9.96% for cationic xviii NPs/NCMPs at 2.5 mg/ml concentration after 24 h exposure. The previous results introduced a successful method for preparing anionic and cationic NPs/NCMPs for delivering PspA4Pro as dry powder via inhalation. The particle size of PspAPro4 loaded anionic NPs and cationic NPs were 310±25.3 nm and 409.7±49.5 nm, respectively, to be effectively taken up by dendritic cells (DCs). The PspA4Pro loading in anionic NPs was 65.73±5.6 μg/mg and in cationic NPs was 9.84±1.4 μg/mg. The PspA4Pro released from anionic and cationic NPs/NCMPs preserved its primary and secondary structure as evaluated by SDS-PAGE and circular dichroism. In vitro release studies showed that the anionic NPs/NCMPs formulations achieved a cumulative release of 21.01±1.5% while the cationic NPs/NCMPs formulation released 83.13 ±0.84% after 48 h. DCs uptake studies provide evidence of particles uptake by DCs upon incubation for 1 h as visualized by confocal microscopy. These results indicate the use of optimised methods for developing polymeric based NCMPs for vaccine delivery via inhalation against pneumococcal diseases.

A estabilidade de agregados é influenciada pelos sistemas de manejo do solo, com reflexo na estabilização da matéria orgânica e estoques de C e N no solo. O efeito de longo duração (30 anos) de dois sistemas de preparo [plantio direto (PD) e preparo convencional (PC)] e de três sistemas de culturas: [aveia/milho (A/M), ervilhaca/milho (V/M) e aveia+ ervilhaca/milho+ caupi (A+V/M+C)] sobre os índices de agregação, conteúdo e frações de C e N de um Argissolo Vermelho distrófico tipico, foram avaliados. Amostras de solo foram coletadas nas camadas de 0-5, 5-10 e 10-20 cm e separadas em seis classes de agregados (>4,76; 4,76-2,00; 2,00-0,50; 0,50-0,250, 0,250-0,053 e <0,053 mm) por via úmida e seca, e avaliadas em relação ao teor de C e N e submetidas ao fracionamento granulométrico da matéria orgânica do solo (MOS). As concentrações de C e N no solo foram maiores no solo em PD e na camada de 0-5 cm. Os estoques de C e N foram 23 e 32% maiores respectivamente no sistema de culturas (0-20 cm) com elevado aporte de resíduos (A+V/M+C), em relação ao sistema com gramíneas (A/M). O diâmetro médio ponderado (DMP) e o índice de estabilidade dos agregados do solo [ (DMPu/DMPs) x100], foram superiores no solo em PD em relação ao solo em PC, devido ao predomínio de macroagregados (≥ 4,76-2,00 mm). Nos estoques das frações da MOS, o carbono orgânico particulado (COP) e o nitrogênio particulado (NP) foram maiores nos sistemas de culturas com leguminosas no solo em PD, em relação ao PC, enquanto que o C e o N associado aos minerais foram influenciados somente pelos sistemas de culturas. As taxas anuais de acúmulo de C na camada de 0-20 cm nos sistemas de culturas variaram de 35,3 a 67,6 kg C ha-1 ano-1, o acúmulo de N variou de 4,7 a 16,7 kg N ha-1 ano-1 sendo maiores no sistema A+V/M+C. Os estoques de C e N no solo foram influenciados em maior grau pelo sistema de culturas do que pelo sistema de preparo de solo. Esses resultados demonstram que em sistemas conservacionistas o aumento nos estoques de C e N do solo e a estabilidade dos agregados estão associados tanto com a não mobilização do solo quanto com o aporte de resíduos vegetais pelos sistemas de culturas. / The aggregate stability is influenced by soil management systems, with reflex on soil organic matter stabilization and C and N stocks. We evaluated the long term (30-yr) effect of two tillage systems [no-tillage (NT) and conventional tillage (CT) ] and three cropping systems [oat/maize (O/M), vetch/maize (V/M), and oat + vetch/maize + cowpea (O+V/M+C)] on stability of soil aggregates, C and N content in total soil organic matter (OM) and particulate and mineral-associated fractions of a sandy clay loam Typic Paleudult. Soil samples were collected at 0-5, 5-10 and 10-20 cm. Disturbed soil samples were collected for C and N analysis and OM fractionation; undisturbed soil samples were collected for soil aggregates analysis. Aggregates were separated in six classes (> 4.76; 4.76-2.00; 2.00-0.50; 0.50-0.250, 0.250- 0.053 and <0.053 mm) by dry (d) and wet (w) methods, the mean weighted diameter (MWD) of aggregates and the stability index [(MWDw/MWDd)x100] were calculated. ). The concentrations of C and N in soil were higher in NT in 0-5 cm layer. The C and N stocks were 23 and 32% higher in cropping system (0-20 cm) with a high crop residue input (O+V/M+C) than of grasses only based cropping system (O/M). The average diameter and stability index of soil aggregates were higher in NT in relation to CT, mainly due to predominance of macroaggregates (≥ 4.76 to 2.00 mm). In SOM fractions, particulate organic carbon (POC) and particulate nitrogen (NP) were higher in legume-based cropping systems in NT, related to CT, while the C and N in mineral-associated soil organic matter was affected by only cropping systems. The annual rates of C accumulation at 0-20 cm in cropping systems ranged from 35.3 to 67.6 kg ha-1 yr-1, N accumulation ranged from 4.7 to 16.7 kg ha-1 yr-1 and it was higher in the system O+V/M+C. Soil C and N stocks were influenced mainly by cropping systems than the tillage systems. Our results highlight that increase of soil C and N stocks are related both by no soil disturbance plus higher C input under conservationist soil management systems.

Para investigar o efeito de diferentes sistemas de manejo do solo no estoque de carbono e na composição química da matéria orgânica ao longo do perfil do solo e sobre sua capacidade de retenção de carbono, foram desenvolvidos dois estudos em Latossolos subtropicais. No primeiro estudo, foi investigada a influência do sistema de plantio direto (PD) e do sistema de preparo convencional (PC) do solo sobre o estoque de carbono e qualidade da matéria no perfil do solo e nas frações leve livre (FLL), leve oclusa (FLO) e pesada (FP) até 20 cm de profundidade de um Latossolo Bruno (LB) e de um Latossolo Vermelho (LV). No segundo, foi estudado o efeito de sistema de manejo do solo (PD e PC) sobre a capacidade de retenção de carbono nas frações silte e argila dos mesmos Latossolos do estudo I. Para tais finalidades, foram coletadas amostras deformadas de solo nas camadas de 0-2,5; 2,5-5; 5-10; 10-20; 20-30; 30-40; 40-60; 60-80 e 80-100 cm e indeformadas nas profundidades 0-5; 5-10 e 10-20 cm. O teor de carbono do solo e das frações foi determinado por combustão seca e a composição química da matéria orgânica foi analisada por técnicas espectroscópicas. Sob PD, o estoque de C foi superior (9,7 e 12,2 Mg ha-1 nas camadas de 0-2,5 cm e de 2,5-5 cm respectivamente) ao observado sob PC até 5 cm de profundidade (6,4 e 8,5 Mg ha-1 nas camadas de 0-2,5 cm e de 2,5-5 respectivamente) no LB e até 2,5 cm no LV (5,6 Mg ha-1 sob PD e 4,7 Mg ha-1 sob PC). A subsuperfície do solo armazenou 69% (no LB) e 75% (no LV) do carbono aportado anualmente ao perfil do solo em virtude do manejo do solo sob PD. Tanto no solo inteiro quanto nas frações (FLL, FLO e FP), o PD favoreceu a preservação de estruturas orgânicas lábeis e tal efeito foi mais pronunciado no LB em comparação ao LV. O LB apresentou maior retenção de C nas frações silte (52 g kg-1 sob PD e 41 g kg-1 sob PC) e argila (61 g kg-1 sob PD e 54 g kg-1 sob PC) do que o LV (Csilte = 32 g kg-1 sob PD e 31 g kg-1 sob PC e Cargila = 25 g kg-1 sob PD e sob PC), independente do manejo de solo. No LB, o sistema PD promoveu maior retenção de C nas frações comparativamente ao PC, enquanto no LV, a capacidade de retenção de C das frações não diferiu em função do manejo. Em ambos os Latossolos, a retenção de C pode ser explicada por dois processos principais de sorção; interação organo-mineral e auto-associação da matéria orgânica em estruturas tipo micelares. No LV, este último processo parece ser predominante, ao passo que no LB, ambos os mecanismos contribuem igualmente para o sequestro de carbono. / Two studies were developed in Oxisols for investigating the effect of different management systems on soil C stocks and on chemical composition of organic matter along the profile, and on the carbon retention capacity. In the first study, we investigated the the effect of no-tillage (NT) and conventional tillage (PC) on C stocks and composition of organic matter of the soil profile and of the free light fraction (FLF), occluded light fraction (OLF) and heavy fraction (HF) to 20 cm depth of a Brown Oxisol (BO) and a Red Oxisol (RO). In the second study, we investigated the C retention capacity in the silt and clay fractions of the Oxisols used in the first study. For these purposes, soil samples were collected in soil layers of 0-2.5, 2.5 to 5, 5-10, 10-20, 20-30, 30-40, 40-60, 60-80 and 80 -100 cm and undisturbed soil samples in the depth of 0-5, 5-10, 10-20 cm. The C content in soil and fractions was determined by dry combustion and chemical composition of organic matter was analyzed by spectroscopic techniques. Under NT, C stock was greater (9.7 e 12.2 Mg ha-1 in surface layers 0-2.5 cm and 2.5-5 cm respectively) than that found under CT (6.4 e 8.5 Mg ha-1 in surface layers 0-2.5 cm and 2.5-5 cm respectively) in the BO and up to 2.5 cm in the RO (5.6 Mg ha-1 under NT and 4.7 Mg ha-1 under CT). The subsoil stored 69% (in BO) and 75% (in RO) of carbon added annually to the soil profile due to soil management under NT system. In bulk soil and in the fractions (FLF, OLF and HF) as well, the NT promoted the preservation of labile organic structures. Such effect was more pronounced in BO in comparison to RO. The BO showed a greater C retention in silt (52 g kg-1 under NT and 41 g kg-1 under CT) and clay fractions (61 g kg-1 under NT and 54 g kg-1 under CT) than RO (Csilt = 32 g kg-1 under NT and 31 g kg-1 under CT and Cclay = 25 g kg-1 under NT and CT), regardless the soil management. Furthermore, in BO, the NT system promoted a greater C retention in the two fractions compared to CT, while in RO, the C retention capacity of the silt and clay fraction was not affected by the management system. In both Oxisols, C sequestration can be explained by two main sorption processes: organo-mineral interaction and self-assemblage of organic matter in micelle-like structures. In the RO, the latter process seems to be predominant, whereas in BO both mechanisms contribute equally to the C sequestration.

CoordenaÃÃo de AperfeiÃoamento de NÃvel Superior / O objetivo principal dessa dissertaÃÃo à pesquisar, atravÃs de alguns modelos de Teoria de Campos, a influÃncia de trabalharmos com uma simetria de gauge nÃo-abeliana sobre as soluÃÃes das equaÃÃes de movimento. Faremos isso tomando Teoria de Campos especificamente em trÃs dimensÃes. Veremos que os sistemas planares nos trarÃo uma quantidade de informaÃÃes suficientes para descrever a teoria em questÃo. Faremos um estudo sobre defeitos topolÃgicos com enfoque especial para os vÃrtices, que sÃo o nosso principal objeto de estudo. Inicialmente faremos uma revisÃo sobre simetrias em fÃsica afim de chegar à simetria nÃo-abeliana. ApÃs termos descrito sob um ponto vista particular a teoria de Yang-Mills revisaremos os principais modelos que exibem soluÃÃes do tipo vÃrtices, como o modelo Maxwell-Higgs abeliano e o modelo Chern-Simons-Higgs. Posteriormente faremos a inclusÃo do momento de dipolo magnÃtico anÃmalo atravÃs do chamado acoplamento nÃo-mÃnimo. Estudaremos entÃo, detalhadamente, como poderemos incluir este tipo de acoplamento numa teoria de Yang-Mills. Apresentamos no fim desta dissertaÃÃo como tÃpico novo, a adiÃÃo de um background gravitacional a alguns modelos descritos anteriormente. Faremos isso ainda com o acoplamento nÃo mÃnimo e simetria nÃo-abeliana. / The main purpose of this thesis is to investigate how the non-Abelian gauge symmetry affects the solutions of the equations of motion in some field theory models. We concern ourselves specifically with three dimensional field theories. We will note here that planar systems give us the needed informations about the theories approached here. Topological defects were studied with special attention to the vortex solutions. We will do a general survey on physical symmetries, concerning mainly with the non-abelian symmetry. After describing in a particular view the Yang-Mills theory we will review mainly the models in which vortex solutions appear. For example the abelian Maxwell- Higgs model and the Chern-Simons-Higgs model. The next step is to include the Anomalous Magnetic Dipole Moment(AMDM) with the so called non-minimal coupling. A deeper study envisaging how to implement the non-minimal coupling in a Yang-Mills theory is made. New results were found about the addition of a gravitational background in some of the models cited above. We will also study non minimal coupling and non-abelian symmetry in this gravitational background.

Nasopharyngeal cancer lies in the upper part of throat behind the nose and near the base of the skull called the nasopharynx. It is more commonly diagnosed in parts of Asia, particularly in the southern China. Five local edible plants from different families; namely curry leaf (Murraya koenigii), temu kunci (Boesenbergia rotunda), spring onion leaf (Allium cepa), mushroom bean (Phaseolus vulgaris) and bunga kantan (Phaeomeria imperialis) were macerated to obtain methanol, ethyl acetate and hexane crude extracts. Each crude extract was tested against nasopharyngeal carcinoma (HK-1) and normal nasopharyngeal epithelial (NP-69) cell lines. All crude extracts from temu kunci (Boesenbergia rotunda) were found to contain flavonoids, alkaloids and polyphenols. Both methanolic and hexane crude extracts were found to exhibit cytotoxic effects against HK-1 cells but non-toxic against NP-69 cell line. Of all the bioactive compounds previously extracted from B. Rotunda, we have selected four commercially available flavonoids and polyphenols to narrow down our search to one potential anticancer agent. These compounds were tested against HK-1 and NP-69 cell lines for cytotoxicity and it was found that cardamonin exhibits highest cytotoxic effect against HK-1 cells with IC50 of 22 μg/mL. Cardamonin, a naturally occurring chalcone from the rhizome of Boesenbergia rotunda (locally known as temu kunci) was found to induce apoptosis in human nasopharyngeal carcinoma (HK-1) cell line in vitro. It exhibits a significant cytotoxic effect against human nasopharyngeal carcinoma cell line without affecting normal immortalized nasopharyngeal epithelial cell line (NP-69) in MTT assay. Based on these results, HK-1 cell line was treated with IC50 22 μg/mL in time-dependent manner 24, 48 and 72 hrs to further investigate the mechanisms of apoptosis. Apoptotic cells induced by cardamonin were illustrated by change in cellular morphology, increase in G2/M phase population and DNA fragmentation. Furthermore, up-regulation of caspase-3 and caspase-8 activities substantiated the induction of apoptosis through caspase-dependent pathway. Cardamonin leads to a decrease in overproduction of reactive oxygen species (ROS), disruption in mitochondrial membrane potential and drop in intracellular ATP level in HK-1 cells. Present study also revealed up-regulation of pro-apoptotic protein, Bax and apoptotic signalling factor, cytochrome c resulting in down-regulation of anti-apoptotic protein, Bcl-2. There was no fold change in caspase-9 gene expression level suggesting that HK-1 cellular apoptosis occurred independent of caspase-9. Activation of caspase-3 was directly regulated by caspase-8 and does not require caspase-9. Current findings on the mode of actions of cardamonin suggested its potential application as an anticancer agent against nasopharyngeal carcinoma.

The discovery of antibiotics has played a significant role in raising public health standards and improving the outcomes for patients with bacterial infections. Unfortunately, drug discovery efforts have not kept pace with emergence and spread of antibiotic resistance. This project is part of a discovery programme designed to assess the metabolic potential of Actinoallomurus, a recently described genus within the Actinobacteria. The schedule of work included small-scale fermentations (from 200 strains) followed by bioactivity testing. The most promising positive samples were then subjected to a combination of bioassays with chemical analyses to determine the chemical identity of the active compounds, with the objective of finding novel antibiotics. The Results section is organized in four different but closely related chapters. These present Actinoallomurus as a potential new source for active metabolites. Firstly, by showing, in a sample of around 200 strains, over 40% inhibited antimicrobial growth in the conditions tested but also by adding to the elevated quantity of positive hits a high degree of diversity, with the major biosynthetic pathways being identified whether in the molecules screened or also in the genomes analysed. To illustrate not only the type of metabolites produced by Actinoallomurus, but also the multidisciplinary of Drug Discovery expeditions three chapters characterizing new compounds are presented followed by a genomic characterization of four Actinoallomurus Strains. These three chapters show how the delivery of new potential drug candidates demands an always broader set of diverse tools to be applied. While the three new molecules support not only the ability of Actinoallomurus to produce interesting active metabolites, but also the importance that a proper strain library plays in drug discovery, the genomic analyses predict, as for many other actinomycetes, an even brighter future, since the genetic potential for producing bioactive molecules surpasses the compounds that can be detected under routine cultivation conditions.

There is an acute clinical need for small-calibre (<6 mm) vascular grafts for surgery, but unlike their large counterparts they still fail in long-term clinical application. The failures of small diameter grafts are primarily due to the early formation of thrombosis and intimal hyperplasia. Dynamics of blood flow leading to wall shear rate and blood flow pattern and their effect on the endothelial cell proliferation along with other anomalies, have been identified as one of the major deciding factors for the efficiency of grafts. Research has showed that intimal hyperplasia and associated complications which leads to the failure of graft develop preferentially in regions where there is disturbed blood flow haemodynamics which leads to uneven shear stress and turbulence in the flow, followed by flow stagnancy in the periphery of the graft. On the basis of these findings and the established advantages of swirling physiological blood flow, a new graft design having a swirling flow inducer on the inner surface of the graft throughout the axis has been proposed. Initially, different swirling profiles have been analysed using final elemental analysis and compared with conventional or plain grafts. The numerical analysis has revealed that the proposed design could indeed produce the swirling blood flow with much better haemodynamics. These analyses have shown that compared to plain graft, in swirling graft, blood flow velocity near the vessel walls significantly enhanced with uniform distribution of shear stress and thus could theoretically enhance performance of the grafts by providing a "wash away" effect and prevent the plaque formation. Electrospinning has been used to fabricate the proposed design and prototype samples have been produced using polyvinyl alcohol (PVA) and gelatine. After cross linking, prototype grafts have been tested as per standard protocols and various tests such as; uniaxial tensile tests, bursting strength tests and suture retention test were carried out and results were evaluated and compared with the conventional grafts. Human coronary artery, endothelial cells (HCAEC) and human cardiac myocytes (HCM) were seeded on the helical and plain grafts using surface seeding technique. At various time intervals cell proliferation, viability and morphology were observed in the presence of static and circulating media and results were compared with their conventional counterpart kept under the same conditions. Results obtained showed considerable amount of difference in cell spreading and cell viability in the helical graft as compared to the conventional graft which provided the advantage edge. Also, in the case of helical graft more uniformly in arranged HCAEC were observed with elongated morphology. Pressure myography studies were performed on both grafts and after endothelization, the helical graft proved to be more reliable and capable of withstanding the pressure as compared to conventional counterparts. It is therefore suggested, that the electrospun helical graft designed and fabricated in this work may be an attractive candidate for use as a potential small diameter vascular graft for implantation. This is based on its ability to better regulate haemodynamics of blood flow and support endothelization, albeit in vivo studies are required to fully substantiate the in vitro results.